C H A P T E R

4
Functional Anatomy and Physiology
Robin Crisler1, Nancy A. Johnston2, Christine Sivula3, Carl L. Budelsky4
1
Veterinary Services, Laboratory Animal Resource Center, Indiana University School of Medicine, Indianapolis, IN,
United States; 2Laboratory Animal Resource Center, Indiana University School of Medicine, Indianapolis, IN, United
States; 3Research Animal Resources, University of Minnesota, Minneapolis, MN, United States; 4VCA Advanced
Veterinary Care Center, Fishers, IN, United States

I. INTRODUCTION (Sundberg et al., 2018); in the young rat, the resting

This chapter describes and illustrates the most impor-
tant anatomical features of the laboratory rat (Norway
rat; Rattus norvegicus). It also gives a brief summary of
those features that are unique to the rat. An additional
goal is to highlight the anatomical and physiologic
features that make the rat important as an animal model
in research. This chapter is intended to describe the
general anatomy and basic physiology of the laboratory
rat. Significant variation exists between strains and
stocks in behavior, physiology, response to drugs, and
any other number of factors crucial to experimental
use (Festing and Lutz, 2011).
II. GENERAL APPEARANCE
A. Head and Body
The body of a normal, healthy Norway rat is long and
slender. The tail is hairless and may be as long as 85% of
the total body length. The tail is proportionately longer
in females than in males (Hughes and Tanner, 1970a).
Growth rates and maturation times for rats vary by stock
or strain (Hughes and Tanner, 1970b). Body weight
varies greatly, with large differences with age, between
sexes, stock or strain, and source (Otto et al., 2015).
Typical adult male rats weigh about 400e500 g as
compared to females, which are usually between 200
and 300 g. Growth may be permanently altered by
various conditions, including exposure to cold (Lee
et al., 1969) and sleep deprivation (Everson et al., 2012).
The hair coat covers the body surface except for the
nose, lips, palmar and plantar surface of the feet, and
of course the tail. Hair growth is cyclic in a wave pattern
period and growing period each are 17 days long (Otto
et al., 2015). Hair typically emerges in newborns
4 days postpartum (Sundberg et al., 2018). Rodents
have a variety of hair types. Different types of hair serve
different purposes: long guard hairs act as somatosen-
sory organs; auchene and awl hairs are medium length
and shape; and thin, short, zigzag hairs provide insula-
tion (Driskell et al., 2009). There are specialized hairs on
the inside and outside of the ears, in the perianal area,
and also serving as eyelashes and vibrissae (whiskersd
to be discussed later in this chapter) (Sundberg et al.,
2018). The skin of the rat serves a major role in several
systems: the immune system, the nervous system, and
the endocrine system (Sundberg et al., 2018). The skin
is loose over the body due to the structure of the dermis.
Female animals usually have 12 bilaterally symmetrical
teats (six pairs) positioned along the ventral milk line,
with three pairs in the pectoral and three in the abdom-
inal region. Male rats lack nipples but do have
mammary glandular tissue. Male rat mammary tissue
is histologically morphologically different from and
less branched than female rat tissue structures
(Martorell, 2017; Cardiff et al., 2018).
The ocular globe of the rat normally protrudes from
the orbit slightly, the appearance of which is enhanced
by a greatly reduced nictitating membrane called the
plica semilunaris. The eyelids are well developed and
have very fine, short eyelashes. Located within the eye-
lids are the large tarsal or meibomian glands. Hydration
of the corneal surface is maintained by secretions from
the laterally placed Harderian glands and lacrimal
glands.
The external nares are open on the lateral aspect of the
nose. The upper lip is cleft in the center by a vertical

The Laboratory Rat, Third Edition

https://doi.org/10.1016/B978-0-12-814338-4.00004-0 91 Copyright © 2020 Elsevier Inc. All rights reserved.
92 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY

groove called the philtrum, like many other animals,
which ends just below the nares.
Both fore- and hind limbs have five digits. The first
digit, analogous to the thumb or pollex, is smaller in
the forelimb than the hind limb and has a more flattened
nail compared to the rounded nails on the other digits.
The footpads (tori) are present on the ventral surface
and provide a cushion against forces placed in the feet
during walking and resting. The forelimb has five apical
pads at the ends of the digits, three interdigital pads, and
two basal pads. The hind limb is similar to the forelimb,
with the exception of having four interdigital pads
(Greene, 1935).
B. External Reproductive Genitalia
The sex of an animal can be determined based on
external genitalia by day 17 of gestation (Inomata
et al., 1985). In the adult female animal, the vaginal
opening is about 7 mm ventral to the anus. The clitoris
is located on the ventral aspect of the vaginal opening
in a small prepuce. At the tip of the clitoris is a shallow
depression called the clitoral fossa; the urethra opens
into this fossa (Boyd et al., 2018).
In the adult male rat, the scrotum is positioned caudo-
ventrally and may extend slightly beyond the abdomen,
depending on the position of the rat. The size of the
scrotum increases once the testes descend. The inguinal
canal in rats remains open throughout life, so the
scrotum may change in gross appearance depending
on the position of the testes. The anus may be obscured
by the scrotum in large, mature animals. The penis lies
within the prepuce on the ventral midline cranial to
the scrotum. The urethral orifice opens at the end of
the penis. Male rats have an os penis made of bone.
The os penis lies on the ventral wall of the penis and
ends distally in the tip of the glans as the male urogenital
mating protuberance (Knoblaugh et al., 2018).
C. Skeletal Structure
The skeleton of the rat is typical for quadruped
mammals. The bones of the skeleton are classified as
the axial skeleton and the appendicular skeleton. The
bones in the axial skeleton are the skull, spine, and
ribs. The bones of the limbs and their attachments are
part of the axial skeleton. The skeleton is shown in
Fig. 4.1. The vertebral formula is C7 T13 L6 S4
Cy27e30. The development of the skeleton in the rat
is in phase with overall body growth, with a peak
growth rate at about 7 weeks old (Puche et al., 1988;
O’Flaherty, 1991). Remnants of the growth plate in ro-
dents may be present throughout life, but active longi-
tudinal growth stops in rats after about 6 months of age
(Jerome et al., 2018). The dorsal segments of the ribs are
usually calcified, so the rat lacks true costal cartilages
(Greene, 1935). The clavicle connects the scapula to
the cranial end of the sternum (Farris and Griffith,
1949). The general orientation of the cervical vertebral
column when the rat is at rest is vertical and not

SCAPULAR CARTILAGE
EXTERNA ACOUSTIC MEATUSL PARIETAL BONE
THORACIC VERTEBRAE LUMBAR VERTEBRAE
ZYGOMATIC ARCH OCCIPITAL BONE
ORBIT FRONTAL BONE CERVICAL
SCAPULA COXAL BONE
MOLARS 1. ILIUM
VERTEBRAE 2. PUBIS
3. ISCHIUM
SACRUM
INCISIVE
BONE
ATLAS 1
AXIS
INCISORS FEMUR
MAXILLA MANDIBLE CAUDAL
RIB CARTILAGE VERTEBRAE
TEMPORAL BONE
STERNUM
PATELLA 3
CLAVICLE RIBS 2
OLECRANON PATELLAR LIGAMENT
HUMERUS
RADIUS TIBIA
FIBULA
ULNA
CARPAL BONES METATARSAL BONES
METACARPAL BONES
PHALANGES

PHALANGES
TARSAL BONES
Skeleton
Lateral View

FIGURE 4.1 Rat skeleton (left lateral aspect). From Constantinescu, G.M., 2011. Comparative Anatomy of the Mouse and the Rat: A Color Atlas and
Text. American Association for Laboratory Animal Science, Memphis, TN, courtesy of the American Association for Laboratory Animal Science.

BIOLOGY AND CARE

 II. GENERAL APPEARANCE
horizontal (Vidal et al., 1986), as might be thought
based on visual observation.
The scapula is positioned mostly horizontally. The
acromion and coracoid processes are larger and form a
deep socket for the head of the humerus. A larger del-
toid tuberosity is easily identified on the humerus. The
greater, lesser, and third trochanters of the femur are
larger compared to other mammals and have a relatively
smaller head and neck. The tibia and fibula are fused in
their distal quarter. For more detail about the skeleton of
the rat, the reader is referred to Greene (1935), Chiasson
(1958), and Hebel and Stromberg (1976).
Bone structure, biomechanical properties, and bone
mineral density vary greatly among different strains of
rats (Turner et al., 2001; Alam et al., 2006). Quantitative
trait loci analysis has identified several candidate genes
influencing bone traits in inbred rat strains, including a
locus on chromosome 4 linked to femoral neck structure
(Alam et al., 2006, 2010). The genetic regulation of bone
strength in the rat and other animal models has been the
focus of other work in an attempt to develop genetic
testing strategies in the human population for osteopo-
rosis and bone strength (Adams and Ackert-Bicknell,
2015). Although the thymus gland is believed to play a
role in the regulation of bone metabolism, athymic rats
are not significantly different from immunocompetent
rats in terms of bone structure, function, or regenerative
properties (Kirkeby, 1991).
Bone physiology is influenced by both estrogens and
androgens. Skeletal growth and maintenance, including
sex differences in size and bone structure, are also a
result of hormone levels (Vanderschueren, 1996; Vander-
schueren et al., 1996; Almeida et al., 2017). Androgens
help maintain skeletal integrity. In aged, nongrowing
male rats, androgen deficiency results in acceleration
of bone turnover and bone loss. Estrogen deficiency con-
tributes to osteoporosis and accelerated bone loss
(Ebeling, 2010). Changes in physiology associated with
pregnancy, lactation, and weaning have significant ef-
fects on the properties of bone in the maternal skeleton,
both short term and long lasting (de Bakker et al., 2017a).
The maternal skeleton responds to increased calcium
demand in pregnancy and lactation resulting in a revers-
ible deterioration of the trabecular thickness. Long-term
changes in the microstructure of the trabeculae are noted
in female rats after pregnancy and lactation (de Bakker
et al., 2017b).
The rat has been used as a model of bone physiology
in a variety of fields (Allen et al., 2014). Rat models are
useful to basic science research studying the skeleton
because of similarities to humans (Bagi et al., 2011).
However, some significant differences are present be-
tween rats and humans, including the difference be-
tween quadruped locomotion compared to biped, and
greatly reduced Haversian systems (Hillier and Bell,
BIOLOGY AND CARE
93
2007; Bagi et al., 2011). Some important fields of skeletal
and bone biology research using rat models include
space flight and microgravity (Chowdhury et al., 2013;
Keune et al., 2016), chronic kidney disease (Moe et al.,
2014), diabetes (Ortinau et al., 2017), and menopause
(Xu et al., 2016).
D. Musculature
The musculature of the rat is typical of mammals. A
comprehensive anatomical description of the muscles
has been published (Greene, 1935, 1949; Hebel and
Stromberg, 1976; Walker and Homberger, 1997). Termi-
nology for anatomic structures may be outdated in older
references and should be clarified with Nomina Anatom-
ica for the most current terms (World Association of
Veterinary Anatomists, 2017).
The basic organization of the rat muscle consists of a
perimysium composed of bundles of collagen fibers that
connect the epimysium to the endomysium. The endo-
mysium has at least four components: a dense woven
network that surrounds the myocytes; myocytee
myocyte collagen struts that connect adjacent myocytes;
myocyteecapillary struts that connect myocytes and
capillaries; and a complex of single collagen fibers, gly-
coproteins, and glycosaminoglycans. The amount of
collagen in each component varies with the function of
the muscle. An individual skeletal muscle is made up
of many muscle fibers, and the muscle fibers are made
up of numerous myofibrils. The myofibrils contain the
contractile elements of muscles. Near the attachment
of a muscle to a bone, each muscle fiber attaches to
collagen fibers through a myotendinous junction. A
tendon is formed from the collagen fibers that are held
together by connective tissue. A cord-like tendon is pre-
sent for a spindle-shaped muscle, and a sheet-like
aponeurosis is formed for a broad muscle (Walker and
Homberger, 1997). The tendon fibers and the surround-
ing connective tissue attach to the bone by interweaving
with the connective tissue of the periosteum. Collagen fi-
bers extend into the bone substance to anchor the tendon
and muscle to the bone.
The prime source of muscle fiber nuclei during pre-
and postnatal development are somite-derived skeletal
myoblasts, although other cell types may contribute. Pri-
mary fibroblasts undergo myogenic conversion when
cocultured with myoblasts, demonstrating the capacity
of mesodermal cells to undergo differentiation to myo-
cytes (Salvatori et al., 1995).
As is true with many other species, skeletal muscle
function declines with age in rats (Yorke et al., 2017;
Alev et al., 2018). The isometric twitch duration is pro-
longed with aging in both fast- and slow-twitch muscles,
though the degree of fatigue with contractile activity is
94 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
not affected by aging (Fitts et al., 1984). Decline in skel-
etal muscle function is also associated with other disease
conditions in which the rat is a model, such as chronic
kidney disease (Rao et al., 2017), diabetes (Reddy et al.,
2018), and cancer (Esau et al., 2017).
Rats are widely used as models for skeletal muscle
function and exercise physiology. The use of rats sur-
passes the use of all other rodents in this area of research
(Goutianos et al., 2015). The use of treadmills, voluntary
exercise wheels, and swimming set-ups for various rat
models has been widely used for decades (Kregel,
2006). A recent side-by-side comparison demonstrated
that rats adequately mimic human responses to exercise
(Goutianos et al., 2015).
E. Superficial Glands of the Head and Neck
The glands in this group lie superficially within the
neck and head and can be identified by their location
and appearance. They include the orbital glands, lateral
nasal glands, salivary and lymphatic glands (lymph
nodes) of the neck, and the brown (multilocular) adipose
tissue. Figs. 4.2 and 4.3 show the locations and relative
sizes of these glands. Two main glands produce secre-
tions to lubricate and moisten the cornea and eye: the
lacrimal glands and the Harderian gland. These glands
are also discussed later in this chapter in the description
of the eye. The extraorbital lacrimal gland lies just
ventral and rostral to the ear. Its duct joins with that of
the intraorbital lacrimal gland to open onto the conjunc-
tiva in the dorsolateral region of the eye. The intraorbital
gland occupies the caudal angle of the orbit and is
covered by a connective tissue sheath. The lacrimal
duct epithelium is thought to transport sodium, potas-
sium, and chloride ions. The presence of nerve terminals
FIGURE 4.2 Superficial glands of the head and neck (lateral aspect). Redrawn from Greene, E.C., 1935. Anatomy of the Rat, vol. 27. American
Philosophical Society, Philadelphia, PA.
BIOLOGY AND CARE
within these ducts suggests that the duct system of the
extraorbital gland is active in the production of lacrimal
fluid. The tear film is composed of three primary compo-
nents (and the producing gland): lipid (meibomian
glands), aqueous (lacrimal glands), and mucin (goblet
cells) (Zeiss et al., 2018).
The Harderian gland is a horseshoe-shaped structure
that occupies a large portion of the orbit as it extends
medially and caudally to encircle the optic nerve. It is
thought that this gland is present in most mammals,
except Chiroptera and Simidae. The gland was origi-
nally called Harder’s lacrimal gland and was first
described by Harder in 1694 in the anatomical descrip-
tion of the red deer (Norris and Carr, 2013). The gland
secretions contain porphyrins and will fluoresce (Otto
et al., 2015). The Harderian gland will overexpress secre-
tions when a rat experiences stress, no matter the source
(e.g., disease, surgery, dehydration, recent transport).
The red porphyrin is visible around the eyes and nose;
this condition is known as chromodacryorrhea.
The bilateral lateral nasal gland (LNG) also known as
glandula nasalis lateralis, or Steno’s gland, is the largest of
several well-developed rostral nasal glands (Harkema
et al., 2018). This gland is in the wall of the rostral
portion of the maxillary sinus and has an excretory
duct that courses to the vestibule along the root of the
nasoturbinates. The LNG is characterized by cytologic
features similar to those described for the major serous
salivary glands and is homologous with the salt gland
found in marine birds. It produces a watery, nonviscous
secretion that is discharged at the nasal airway entrance.
The secretions of the LGN have several functions. It
helps humidify the inspired air and may contribute to
the maintenance of the proper viscosity of the mucous
blanket covering the ciliated surfaces deeper within
the respiratory tract. The LGN is a major site for the
 II. GENERAL APPEARANCE
FIGURE 4.3 Superficial lymph nodes and glands of the neck (ventral aspect). Redrawn from Greene, E.C., 1935. Anatomy of the Rat, vol. 27.
American Philosophical Society, Philadelphia, PA.
synthesis and secretion of odorant-binding proteins that
serve as odorant carriers in nasal mucus (Pevsner et al.,
1988; Harkema et al., 2018). In addition, it synthesizes
immunoglobulin A, important for immune defense of
the upper respiratory tract, and testosterone and sali-
vary androgen-binding proteins, which are important
in both olfaction and reproductive behavior. The LGN
may be damaged from exposure to inhaled or ingested
toxic chemicals because of the high metabolic activity
(Harkema et al., 2018). Because of the large number of
autonomic nerves that are found in close contact with
the acinar cells, it is believed that the LGN is regulated
by the nervous system in such a way that rapid adjust-
ment of the secretory activity to changes in the humidity
of the inspired air or to airborne irritants is possible
(Moe and Bojsen-Moller, 1971).
There are three pairs of major salivary glands in the
rat: the parotid gland; the submandibular (also known
as the submaxillary) salivary glands; and the sublingual
glands. A full description of the glands, location, histol-
ogy, and innervation can be found in Amano et al. (2012)
and Hukkanen et al. (2018). Salivary glands and their
ducts secrete digestive enzymes as well as various cell
growth factors, including epidermal growth factor,
nerve growth factor, transforming growth factor-beta,
and basic fibroblast growth factor (Amano and Iseki,
2001). Myoepithelial contractions serve to accelerate
the salivary flow and to support the secreting acinar cells
and prevent backflow of fluid from the duct system into
the glandular tissue. These contractions occur through a
BIOLOGY AND CARE
95
cooperation of sympathetic and parasympathetic inner-
vation (Emmelin, 1981; Amano et al., 2012). The mois-
ture content of the diet determines the secreted
volume and flow rate of saliva. Dry diets stimulate a
high secreted volume (Ito et al., 2001; Matsuo et al.,
2015). Submandibular saliva secretion dominates during
grooming (Yanase et al., 1991).
The parotid gland is a diffuse structure extending
ventrorostrally beginning behind the ear, coursing along
the caudal facial vein, and terminating on the ventrolat-
eral surface of the neck. The gland is organized into mul-
tiple (three to four) lobes, producing serous secretions
(Hukkanen et al., 2018). The caudal border of the gland
sometimes extends to the shoulder and the clavicle. The
parotid duct is formed by the union of three main
branches and crosses the lateral surface of the masseter
muscle, in close association with the buccal and mandib-
ular branches of the facial nerve, to open into the vesti-
bule just opposite the molar teeth. The rat parotid
produces saliva with a protein concentration of about
2% (Hall and Schneyer, 1964). In the rat, the parotid
and submandibular salivary glands are of approxi-
mately equal size. The submandibular salivary glands
are large, elongated structures that lie just caudal to
the angle of the mandible and extend caudally to the cra-
nial aspect of the manubrium. Secretory granules found
in the acinar cells of the gland are mucinous, and gran-
ules found in the secretory ducts are serous. Sexual
dimorphism has been described with respect to the pres-
ence of mucous cells in this gland, with such cells
96 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
occurring in the glands of 100% of males but only 28.5%
of sexually mature females (Hatakeyama et al., 1987).
The epithelial cells of the ducts are testosterone sensitive
(Hukkanen et al., 2018). With age in both sexes, there is a
relative increase in duct volume and a decrease in the
number of acini (Hukkanen et al., 2018). The distal end
of the main excretory duct of the submandibular gland
has a salivary bladder, a dilation of the distal end of
the main excretory duct, which is lined by pseudostrati-
fied epithelium (Mercurio and Mitchell, 1987; Sato and
Miyoshi, 1998). The duct of the submandibular gland
opens into the oral cavity near the incisions at the sublin-
gual caruncle (Hukkanen et al., 2018). The primary fluid
of the gland is modified in the bladder by transepithelial
fluid and ion transport. The composition of the secre-
tions can be altered in response to a variety of factors,
including diabetes (Fukuoka et al., 2017; Nogueira and
Carvalho, 2017) and exercise (Kurimoto et al., 2016).
The sublingual glands are small, rounded structures
located at the rostral edge of the submandibular glands
and are sometimes partially embedded in them. The
ducts of the sublingual glands run parallel with those
of the submandibular glands to open in the oral cavity
at the sublingual caruncle (Hukkanen et al., 2018). The
production of sublingual glands is primarily mucinous
(Hukkanen et al., 2018). With age, the proportion of
the gland occupied by ducts increases in Fischer 344
male rats, and there is an increase in the squamous meta-
plasia of duct epithelium and periductal lymphocytic
foci (Mintz and Mooradian, 1987). Additional minor
salivary glands are present in most parts of the mouth,
and their secretions directly bathe the tissues (Hand
et al., 1999). Rats have minor salivary glands in the
lingual, buccal, and palatine regions of the mouth (Huk-
kanen et al., 2018). Individual glands are usually in the
submucosa or between muscle fibers, and consist of
groups of secretory end pieces made up of mucous, se-
rous, or seromucous cells. The minor salivary glands
contribute approximately 14% of protein and 1% of
amylase in whole saliva. They also secrete antimicrobial
proteins, and the lingual serous glands (also known as
von Ebner’s glands) secrete proteins with possible taste
perception functions (Blazsek and Varga, 1999). A
similar function has been postulated for minor sublin-
gual glands (also known as Weber’s glands), which lie
posteriorly in the root of the tongue (Nagato et al.,
1997). Lymph nodes lying superficially in the head and
neck are sometimes mistaken for salivary glands. The
lymph nodes are irregularly shaped and compact struc-
tures that lie in close association with the salivary
glands. One lymph node is typically found partially
embedded in the parotid salivary gland. Other lymph
nodes usually are found rostral to the submaxillary sali-
vary gland. Lymphoepithelium and nasal-associated
lymphoid tissue are present in the rat nasal passageway.
BIOLOGY AND CARE
Although the function is not completely understood,
these mucosal lymphoid tissues may have an important
function in regional immune defense of the upper air-
ways (Harkema et al., 2018). The thymus gland is
located along the ventral aspect of the trachea, dorsal
to the sternum at the thoracic inlet. It is composed of
two distinct encapsulated lobes, typically unequal in
size, and extends from the larynx to the heart. The
thymus may be the largest in size by 3e6 weeks of
age, and then begins to atrophy, also known as thymic
involution (Ward et al., 2018). This process is believed
to be under the control of beta-adrenoceptor receptors,
including those specific to glucocorticoids (Pazirandeh
et al., 2004; Plecas-Solarovic et al., 2004). The histology
of the thymus consists of a cortex and medulla. The cor-
tex is made up of lymphocytes (known as thymocytes)
and fewer epithelial cells. The medulla contains a major-
ity of epithelial cells, with fewer dendritic cells and lym-
phocytes (Ward et al., 2018). Ectopic cervical thymus
tissue can be found in rats on occasion in various cervi-
cal locations, including the thyroid and salivary glands.
F. Brown (Multilocular) Adipose Tissue
Also known as “brown fat” or the “hibernating
gland,” multilocular adipose tissue is distributed
diffusely throughout the ventral, lateral, and dorsal as-
pects of the superficial tissues of the neck and intrascap-
ular region. Because rats do not hibernate, the term
“hibernating gland” is misleading and other terms are
now used. Rats have both white adipose tissue used
for energy storage, and brown adipose tissue (BAT)
used for heat production (Jerome et al., 2018). BAT is
named for the brownish color on gross examination,
due to the abundant mitochondria present in this tissue
and high vascularization (Saely et al., 2012; Nam and
Cooper, 2015). Histological appearance of this tissue is
multilocular and glandular due to fat cells filled with
small lipid droplets. BAT is able to uncouple oxidative
phosphorylation to produce heat (Jerome et al., 2018).
BAT plays a critical role in nonshivering thermogenesis
during cold exposure (Slavin and Bernick, 1974). The
BAT is activated by the sympathetic nerves in this tissue.
In addition, BAT plays a major role in energy balance,
obesity, and whole-body energetics (Trayhurn, 2017).
G. Tissues and Organs Associated With Special
Senses
1. Sight and the Eye
The rat eye is like other mammalian eyes. It is
comprised of the eyelids, conjunctiva, cornea, iris, crys-
talline lens, vitreous, retina, optic nerve, and extraocular
muscles (Fig. 4.4). The eye develops from three different
 II. GENERAL APPEARANCE
FIGURE 4.4 Section of the eye, displaying internal structures.
embryonic layers. Surface ectoderm forms the lens,
corneal epithelium, and the eyelids. Mesoderm forms
the sclera, corneal stroma, blood vessels, muscles, and
the vitreous. The neuroectoderm forms the retina, ciliary
body, iris, and optic nerve (Walling and Marit, 2016).
The eyelids are important structures not only in the
protection of the eye but also in embryonic develop-
ment. Fusion of the eyelid structures is essential for
development of the extraocular structures in the rat
(Addison and How, 1921; Meng et al., 2014). The eyelids
open between days 12 and 14 after birth. This is impor-
tant for the further development of the cornea as well as
necessary for the maturation of the retina (Addison and
How, 1921; Walling and Marit, 2016; Van Crutchen et al.,
2017).
The eye has two lacrimal glands (intraorbital and
extraorbital) and a Harderian gland. The Harderian
gland is located medially within the orbit and with the
lacrimal glands, serves to lubricate the eye. The rat nor-
mally produces porphyrin-pigmented and lipid-laden
tears predominantly from the Harderian gland (Wil-
liams, 2012; Van Crutchen et al., 2017). There is little to
no aqueous component to the tear film (Chen et al.,
1997). The ocular surface is covered by a glycocalyx,
which allows the eye to resist desiccation. This film con-
tains a glycoprotein that appears on the ocular surface
after eyelid opening and is believed to facilitate mucin
spread across the ocular surface (Gipson et al., 1992;
Watanabe et al., 1993).
The cornea is a clear convex window that consists of
five layers. There is an outer nonkeratinized squamous
epithelium, basement membrane, stroma, Descemet’s
membrane, and endothelium (Dunn et al., 2018). The
cornea itself is about 0.25 mm in thickness (Massof and
Chang, 1972) and is approximately 5.64 mm in diameter,
as measured across the base (Hughes, 1979). The refrac-
tive power of the cornea is almost twice as great as that
of the lens (Heywood, 1973).
The anterior chamber of the eye is bordered exter-
nally by the cornea and internally by the iris and pupil
(Fig. 4.5). The posterior chamber of the eye is bordered
BIOLOGY AND CARE
97
FIGURE 4.5 Histologic cross-section of rat eye using H&E stain.
Courtesy of Leandro Teixeira DVM, MSc. DACVP, Comparative Ocular
Pathology of Wisconsin.
rostrally by the iris and caudally by the lens. Both the
anterior and posterior chambers are filled with aqueous
humor. The depth of the anterior chamber is
0.87e1.03 mm and has a volume of 13.6 mL (Hughes,
1979; Lozano and Twa, 2013). Normal intraocular pres-
sure in the adult rat has been shown to be
10e16.5 mmHg (Cabrera et al., 1999; Kontiola et al.,
2001). Measurements of intraocular pressure using a
rebound tonometer have been found to correlate closely
with those obtained manometrically, whereas measure-
ments using an electronic tonometer were found to un-
derestimate intraocular pressure (Goldblum et al.,
2002). Selected anatomic parameters of the rat eye are
presented in Table 4.1.
The iris arises from the anterior portion of the ciliary
body and is a rostral continuation of the choroid. It is
completely devoid of pigment in the albino rat and con-
sists of loose, highly vascular connective tissue. As in
other species, the pupil dilates and constricts to regulate
the amount of light entering the eye. The iris of an albino
rat is almost transparent with the vessels being easily
visible. Care must be taken since albino rats are suscep-
tible to retinal damage because of how thin the iris is
(Beaumont, 2002).
The recommended light level for rat housing is be-
tween 350 and 400 lux. Both pigmented and albino rats
have shown a preference of lighting less than 100 lux
compared to 100e380 lux (Blom et al., 1995). Albino
rats will even seek areas with a light intensity of only
25 lux. Rats in the top cages are more sensitive to
98
TABLE 4.1 Selected Parameters for the Rat Eye.a
Intraocular pressure
(mmHg)
Globe diameter axial
(mm)
Globe diameter
equatorial (mm)
Corneal diameter (mm)
Corneal thickness (mm)
Anterior chamber
depth (mm)
Lens diameter axial
(mm)
Lens diameter
equatorial (mm)
Vitreous chamber
depth (mm)
Vitreous volume (mL)
a
Data are approximations only and vary significantly by strain, age, sex, health status,
diet, as well as by the scientific methods used for measurements. For examples, see the
manuscripts cited (Massof and Chang, 1972; Hughes, 1979; Cabrera et al., 1999; Sha
and Kwong, 2006; Kontiola et al., 2001; Lozano and Twa, 2013).
light-induced toxicities compared to rats on the bottom
row. Rats that are susceptible to light-induced damage
should be kept in light levels of 130e325 lux (Clough,
1982). Light levels below 160 lux are less likely to cause
damage (Rao, 1991). Rats exposed to a light level of only
200 lux, 24 h a day for 10 days will develop significant
retinal damage. Rats raised in low-light housing are
more susceptible to light-induced injury versus those
raised in higher levels (Schlingmann et al., 1993a). Al-
bino rats are shown to be more susceptible to phototoxic
injury than pigmented ones (Heywood, 1973; Lanum,
1978; Contin et al., 2013). Albino rats can develop retinal
damage in as little as 80 lux light (Penn et al., 1985). It is
important to keep in mind that there needs to be a min-
imum light level in a room of 210 lux for the best perfor-
mance from personnel and their safety (Schlingmann
et al., 1993b).
The lens is a transparent, biconvex, spherical body
that occupies approximately two-thirds of the intraoc-
ular cavity (Heywood, 1973). The lens thickness is be-
tween 3.71 and 4.57 mm and is 4.23e4.5 mm wide
(Hughes, 1979; Lozano and Twa, 2013). It is attached to
the ciliary body by suspensory ligaments and changes
its shape during the process of visual accommodation.
Compared to other animals, the rat has poorly devel-
oped ciliary muscles. Because of this, there is little to
no accommodation (LeVere, 1978). The rate of lens
growth in the rat follows an asymptotic curve (Norrby,
1958). At birth, the rat lens is relatively flat. However,
4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
it becomes increasingly spherical in shape as it ages.
With advancing age, the rate of growth of the lens and
10e16.5
density of the lens nucleus increases. A critical period
in lens maturation in the rat occurs about 12e16 days af-
6.29 ter gestation (Carper et al., 1985; Groth-Vasselli and
Farnworth, 1986). By day 16 it occupies much of the
6.41 intraocular space (Sivak and Dovrat, 1984). The refrac-
tive components of the rat eye seem similar in appear-
5.64 ance and quality to those of a diurnal mammal at
birth, but they assume the characteristics associated
0.25
with nocturnal vision during an early period of
0.87 postnatal development. At birth, the lens is a vascular
structure supplied by the hyaloid vessels. The hyaloid
3.71e3.9 vessels form two distinct entities, the anterior and poste-
rior tunica vasculosa lentis. There are central hyaloid
4.23e4.5 vessels that consist of three to five arteries running
from the optic disc to the caudal pole of the lens. Closure
1.51 of the hyaloid vessels normally occurs between 7 and
22 days old (Cairns, 1959; Vrolyk et al., 2017).
The vitreous body fills the posterior segment between
54
the lens and the retina. This material consists of a color-
less, transparent, amorphous, gelatinous mass (Hey-
wood, 1973). Almost 99% of the vitreous consists of
water, the remainder being hydrophilic polysaccharide,
especially hyaluronic acid. The depth of the vitreous
chamber is 1.32e1.52 mm (Hughes, 1979; Lozano and
Twa, 2013). The volume of vitreous in an adult rat is
only 54 mL (Sha and Kwong, 2006). Approximately 5%
of aged Sprague-Dawley rats have small, globular vitre-
ous opacities that can be observed by routine slit lamp
eye examination (Ruttimann and Daicker, 1989).
The retina is the innermost of the three coats of the
eye and is the tissue responsible for the reception and
transduction of light stimuli and the transmission of
these signals in the form of nerve impulses to the brain.
The retina has 10 distinct layers: retinal pigmented
epithelium, photoreceptor cell layer, external limiting
membrane, outer nuclear layer, outer plexiform layer, in-
ner nuclear layer, inner plexiform layer, ganglionic cell
layer, optic nerve fiber layer, and inner limiting mem-
brane. Because it is derived from the prosencephalon,
the retina is usually considered to be part of the brain.
The rat retina is classified as holangiotic with vessels
radiating outward (Fig. 4.6) from the optic nerve to the
periphery like spokes on a wheel (Heywood, 1973; Wil-
liams, 2002).
Many mammals have an area within the retina with a
high concentration of photoreceptors. In humans it is the
macula. In dogs it is the area centralis. In birds it is called
the fovea. Rats have a less defined horizontal band
called the visual streak. The maximum photoreceptor
density of this area is 6774 cells/mm2 in the rat, as
compared to the densest area of the human retina, which
has up to 38,000 cells/mm2 (Curcio and Allen, 1990;
Heffner and Heffner, 1992).
BIOLOGY AND CARE
 II. GENERAL APPEARANCE
FIGURE 4.6 Image of rat retina showing holangiotic vessel pattern.
Courtesy of David L. Williams, MA Med, VetMD, PhD, DECAWBM, cert
VOphthal cert WEL. FHEA, FSRB, FRCVS.
In rats, the peripapillary choroid plays a significant
role in both blood supply and venous drainage of the
optic nerve head (Sugiyama et al., 1999). Likewise, the
central retinal artery also contributes to the circulation
of the optic nerve head. The posterior ciliary artery
travels along the inferior side of the optic nerve sheath,
directly enters the optic head, and divides into three
branches: the central retinal artery, and the medial and
lateral long posterior ciliary arteries, which provide
several short branches to the choroids.
DORSAL OPHTHALMIC VEIN
ANGULARIS OCULI VEIN
INFRAORBITAL VEIN ENTERING
INFRAORBITAL FISSURE
SPHENOPALATINE VEIN
ENTERING SPHENOPALATINE
FORAMEN
FIGURE 4.7 Rat orbital veins and venous plexus (lateral aspect). From Constantinescu, G.M., 2011. Comparative Anatomy of the Mouse and the
Rat: A Color Atlas and Text. American Association for Laboratory Animal Science, Memphis, TN, courtesy of the American Association for Laboratory Animal
Science.]
BIOLOGY AND CARE
99
The rat has a retro-orbital venous plexus located
dorsolaterally to the eye, in contrast to mice and
hamsters that have a retro-orbital venous sinus at this
similar anatomic location (Timm, 1979; Constantinescu,
2011). The plexus is formed by the external dorsal
ophthalmic vein, external ventral ophthalmic vein, and
numerous anastomoses between these veins as shown
in Fig. 4.7 (Constantinescu, 2011). Although it is possible
to collect blood at this site, due to the relatively small
size of the retro-orbital venous plexus in the rat, the
orbital tissues and Harderian gland can be easily
damaged. Use of alternative blood collection sites are
recommended for this reason (Williams, 2002).
The eyes of a rat have a wide field of view but only 76
degrees of binocular overlap (Williams, 2012). Although
rats were once considered to be color blind, they have
two classes of retinal cones: one type contains an
ultraviolet-sensitive photopigment at 358 nm and the
other contains a pigment maximally sensitive in the
middle wavelengths of the visible spectrum at 510 nm
(Jacobs et al., 2001). Tests of wavelength discrimination
provide evidence that rats may have dichromatic color
vision (Szel and Rohlich, 1991; Jacobs et al., 2001;
Koolhaas, 2010). Both types of cones have photopig-
ments that absorb light in the blue and green spectrum.
Rats have a low visual acuity compared to the human
eye. This is determined by both the optics of the eye as
well as neurologically by the retina. Compared to
normal 20/20 vision in a person, the pigmented rats
have 20/600 vision and albino rats are closer to 20/
1200. Similarly, the visual acuity of pigmented rats is
approximately 1.0e1.5 cycles per degree (CPD)
compared to albino rats at 0.5 CPD (Prusky et al., 2000,
RETRO-ORBITAL VENOUS PLEXUS
OPHTHALMIC VEIN
ENTERING ROSTRAL
FORAMEN LACERUM
VENTRAL
OPHTHALMIC VEIN
100 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
2002). CPD is a unit of measurement based on how well
alternating black and white lines can be differentiated
from each other within one degree of vision. Humans
see 30 CPD while dogs only see 12 CPD (Prusky et al.,
2000, 2002; Artal et al., 1998).
The use of the color red in rat caging structures for
lighting is a controversial subject. Changing lighting
intensity, duration, wavelength, and timing can alter
circadian rhythms in rats. Light will stimulate photobio-
logical changes through the photopigment melanopsin
that is located in the intrinsically photosensitive retinal
ganglion cells (Wren et al., 2014; Dauchy et al., 2015). In-
formation from the eyes is transmitted via the retinohy-
pothalamic tract, which projects to the suprachiasmatic
nuclei (SCN). The signals from the SCN to the pineal
gland regulate the nocturnal production of the hormone
melatonin. Recent studies determined that the transmit-
tance of light (blue, amber, or red) through rodent cages
can influence the circadian patterns of plasma mela-
tonin, total fatty acid, glucose, lactic acid, corticosterone,
pO2, and pCO2 levels in both pigmented and nonpig-
mented rats (Dauchy et al., 2015; Wren-Dail et al.,
2016). Therefore caution should be used with red safety
lights, tinted animal room viewing windows, or colored
caging components to avoid possible unintended effects
on physiologic responses and circadian rhythm (McCor-
mack and Sontag, 1980; Wren et al., 2014; Dauchy et al.,
2015; Wren-Dail et al., 2016).
2. Olfaction
The rat nose anatomy is complex serving multiple
functions, including olfaction and protection of the
lower respiratory tract by filtering, humidifying, and
controlling the temperature of incoming air. Interest-
ingly, the rat is an obligate nasal breather, but the most
important function of the nose is olfaction. Various so-
cial and behavior cues between rats, including determi-
nation of social standing, kinship, and stage of estrus in
females, are communicated by odor (Otto et al., 2015).
Both inhaled and exhaled air are directed laterally by
each nare. This feature decreases mixing of odorant
intake. The consequence of this is that rats are able to
take independent, bilateral samples of the odor environ-
ment (Wilson and Sullivan, 1999). The nasal passageway
is the entrance to the respiratory system, protecting the
lower airways by regulating the temperature and hu-
midity of the incoming air, and filtering inhaled parti-
cles. Despite respiration being a secondary function to
olfaction, rats are obligate nasal breathers due to the
close apposition of the epiglottis to the soft palate
(Harkema et al., 2018). The nasal turbinates are complex,
with a relative surface area approximately five times
greater than in humans. The nose, whiskers, and head
movement act in a coordinated, rhythmic manner to
BIOLOGY AND CARE
explore the surroundings with olfactory and tactile
senses (Kurnikova et al., 2017; Severson and O’Connor,
2017).
Inhaled air passes through the nasal passageway
over four distinct nasal epithelial cell types: squamous
epithelium in the nasal vestibule, respiratory epithe-
lium in the chamber and nasopharynx, transitional
epithelium in the proximal aspect of the main chamber,
and the olfactory epithelium, which accounts for about
50% of the surface area, in the dorsal aspect of the nasal
cavity (Harkema et al., 2018). The mucous, or goblet,
cells in the surface epithelium secrete mucus, which is
moved along rapidly by the cilia on the surface of the
epithelial cells toward the oropharynx and then
swallowed.
The olfactory epithelium contains three principal cell
types: olfactory sensory neurons, basal cells, and suste-
nacular cells (Harkema et al., 2018). The olfactory sen-
sory neurons have short, thick dendrites with
expanded ends called olfactory rods. From these rods,
nonmotile cilia project to the surface of the mucosa.
The membranes of the cilia contain the odorant recep-
tors, responsible for the initial detection of inhaled odors
via the chemical interaction with those molecules. There
are approximately 2 million olfactory sensory neurons in
the rodent nasal cavity (Harkema et al., 2018). The axons
of the olfactory receptor neurons join together to form
nerve bundles. These bundles pierce the cribriform plate
of the ethmoid bone and enter the olfactory bulb of the
brain. From the olfactory bulb, neurons project to struc-
tures of the limbic system, including the amygdala,
septal nuclei, prepyriform cortex, entorhinal cortex, hip-
pocampus, and subiculum. To digress slightly from the
laboratory rat, the sensitive olfactory powers of the
cousin to the laboratory rat, the African pouched rat
(Cricetomys gambianus), have been used to detect land-
mines and human tuberculosis (Edwards et al., 2015;
Poling et al., 2015; Ellis et al., 2017).
In addition to the sensory epithelium, there are Bow-
man’s glands in the nasal mucosa; these glands produce
a secretion that bathes the surface of the sensory receptors
with an aqueous solution containing mucopolysaccha-
rides, immunoglobulins, and enzymes. There are three
other accessory olfaction organs in the nasal passageway
in addition to the olfactory epithelium: the vomeronasal
organ (VNO), the septal organ of Masera, and the septal
organ of Grüneberg (Harkema et al., 2018). The VNO is a
chemoreceptor organ enclosed in a cartilaginous capsule
and separated from the main olfactory epithelium
(Keverne, 1999; Harkema et al., 2018). Vomeronasal sen-
sory neurons resemble the main olfactory epithelium by
light microscopy but are important for pheromone detec-
tion from other individuals of the same species (Kashi-
wayanagi, 2014; Brennan and Keverne, 2015). Rat social
 II. GENERAL APPEARANCE
behavior, including reproduction, maternal care, aggres-
sion, alarm responses, and anxiety-like behavior, can be
influenced by signals detected by the VNO (Swaney
and Keverne, 2009; Bind et al., 2013; Kiyokawa et al.,
2013). In the example of maternal care, dams detect the
pheromone released by pups, dodecyl proprionate,
which stimulates maternal anogenital licking of the
pups. Disruption of the VNO in dams results in poor
maternal care, including inadequate licking and stimula-
tion of the pups to urinate and defecate (Bind et at., 2013).
When stimulated, sensory neuron receptors activate
inositol 1,4,5-triphosphate signaling as opposed to cyclic
adenosine monophosphate. Stimulation of the VNO
leads to activation of the hypothalamus by way of the
accessory olfactory bulb and amygdala (Keverne, 1999,
2008). The septal organ of Masera is an additional chemo-
sensory structure lined with olfactory epithelium. It is
located bilaterally in the ventral nasal septum and ac-
counts for about 1% of the olfactory epithelium in the
nose (Harkema et al., 2018). The function of this organ
may include sensing odors during resting and breathing,
and also detecting odors from food in the mouth. The
septal organ of Grüneberg is located in the dorsorostral
tip of the nasal septum. Its exact function has not been
defined (Harkema et al., 2018).
As in many mammals, the olfactory epithelium of the
rat retains the capacity to recover after damage. Basal
cells in the VNO and olfactory epithelium retain the ca-
pacity to generate new neurons throughout life (Brann
and Firestein, 2014).
3. Taste
Taste buds, the sense organs for taste, are ovoid
bodies located on the tongue, the hard and soft palates,
and the pharynx in the rat (Miller and Spangler, 1982;
Iida et al., 1983; Travers and Nicklas, 1990; Harada
et al., 2000; El-Sharaby et al., 2001; Treuting et al.,
2018d). In general, they measure 50e70 mm in diam-
eter and 50e60 mm in height. Each taste bud is made
up of connective tissue and various numbers of hair
cells, the gustatory receptors (Iida et al., 1983). In addi-
tion, basal cells, which are derived from surrounding
epithelium, are present to differentiate into new recep-
tor cells. The receptor cells each have a number of hairs
projecting into the taste pore, the opening at the epithe-
lial surface of the taste bud. The sense of taste may
decline with age (Whiddon et al., 2017). At least three
different cell types are found in mammalian taste
buds, each with slightly different structures and pur-
poses. Type I cells are glial-like supporting cells in the
taste bud and may be responsible for detecting salt
(Naþ). Type II (receptor) and Type III (presynaptic) cells
are sensory cells for main tastes: Type II for sweet,
bitter, or umami tastes, and Type III for sour, sweet,
bitter, and umami tastes (Roper, 2013).
BIOLOGY AND CARE
101
Primary gustatory fibers synapse in the medulla. In-
formation is subsequently relayed to the somatosensory
cortex, hypothalamus, amygdala, and insula. Interest-
ingly, adrenergic transmission and cholecystokinin
signaling within the taste bud may play a paracrine
role in rat taste physiology (Herness et al., 2002; Zhang
et al., 2010). Saliva plays a major role in some aspects
of taste, as the taste stimuli are dissolved in salivary se-
cretions. The proteins in saliva interact with the taste
bud receptors and/or the taste stimuli to alter the
perception of taste for the animal (Martin et al., 2018).
4. Hearing and Vestibular Function
Like other mammals, the ear of the rat includes an
external ear, a middle ear, and an inner ear. The pinna
and external acoustic meatus, or external ear canal,
make up the external ear. This portion of the ear receives
sound from the environment. The pinna serves to funnel
sound to the external auditory canal and on to the mid-
dle ear. The external ear is largely covered by stratified
squamous epithelium with interspersed glands. At the
base of the external ear is the Zymbal’s gland, which is
grossly visible in the rat. This gland is a modified seba-
ceous gland and secretes into the auditory canal. The
junction between the external ear and the middle ear is
the tympanic membrane. The middle ear is located
within the tympanic cavity, or bulla. The tympanic
membrane converts sound waves into mechanical en-
ergy transmitted to the ossicles. These three bones are
named the malleus, incus, and stapes. The tympanic
membrane in rats is about 11 mm2 (Treuting et al.,
2018c). The malleus is attached to the tympanic mem-
brane and the incus and stapes transmit the energy to
the oval window of the cochlea of the inner ear and
cause waves in the fluid of the cochlea. Surgical access
to the stapes and/or tympanic membrane is difficult
due to the stapedial artery (or carotid artery, depending
on the reference) that runs through the base of the co-
chlea (Pinilla et al., 2001; Albuquerque et al., 2009; Ber-
gin et al., 2013). The mucosa of the middle ear consists
primarily of simple epithelium that transforms into
pseudostratified columnar ciliated epithelium near the
entrance to the Eustachian tube. The inner ear is located
in the temporal bone within the bony labyrinth. The
components include the vestibule, the semicircular ca-
nals, and the cochlea. The cochlea is responsible for
the sense of hearing. The vestibule and semicircular ca-
nals are responsible for the sense of balance and equilib-
rium. The cochlea in rats makes 2.5 turns and is about
11 mm long (Treuting et al., 2018). The organ of Corti,
which lies within the cochlea, contains fluid. As the os-
sicles transmit waves in the fluid, this generates action
potentials in the nerve fibers via hair cells in the organ
of Corti. Nerve impulses are then carried to various re-
gions of the brain, including the inferior colliculi and
102 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
the auditory cortex (Treuting et al., 2018). The cortex has
been shown to be a necessary component for normal
audition (King et al., 2015). There is a direct correlation
between the hair cell density and the auditory threshold
in rats (Burda and Voldrick, 1980). This threshold is
diminished by exposure to ototoxic substances,
including aminoglycoside antibiotics (McKinney et al.,
2015) and chemotherapy agents (Harrison et al., 2016).
Loss of hair cells occurs as part of the aging process,
and may vary depending on strain (Cai et al., 2018).
The range of hearing in the rat is approximately
250e80,000 Hz at 70 dB, although the greatest sensitivity
is for sounds between 8000 and 32,000 Hz (Kelly and
Masterton, 1977; Heffner et al., 1994). In contrast, a hu-
man being can hear sounds from approximately
16,000e20,000 Hz (Jilek et al., 2014). The ultrasonic range
of hearing and vocalization (22e80 kHz) is important for
a variety of social behaviors, including pup communica-
tion to dam, and adult animals during sexual or aggres-
sive behavior (Otto et al., 2015). Rat vocalizations can
be categorized into three types, which are produced by
the animal depending on age, environmental conditions,
and affective state (Brudzynski, 2007; Portfors, 2007). Rat
pups emit a vocalization at 40 kHz in response to separa-
tion from the dam, reflecting a negative affective state.
When adult rats are in a negative affective state, such as
in advance of a known aversive stimuli, they will pro-
duce a 50 kHz vocalization. Adult rats emit short chirps
at 50 kHz in many positive affective states, including
play, sexual behaviors, and tickling by humans (Portfors,
2007). The Guide for the Care and Use of Laboratory Animals
(NRC, 2011) recommends monitoring facilities and
equipment for noise and vibration. Environmental noise
has been documented to have adverse effects on rats,
including disruptions in endocrine, reproductive, and
cardiovascular function, sleep/wake cycles, and social
interaction between animals (Turner et al., 2005, 2007),
which may, in turn, have deleterious effects on research
results. In addition, noise exposure or acoustic trauma
in young animals may result in lasting alteration in audi-
tory processing (Rybalko et al., 2015).
The vestibular organ is located in the inner ear in all
mammals and functions to maintain equilibrium.
Specifically, the vestibule, which contains the utricle
and saccule, which sense motion in relation to gravity,
and three semicircular canals, which sense rotational
motion, are responsible for vestibular function. Briefly,
increases or decreases in the velocity of circular move-
ment stimulate a flow of liquid in the semicircular
canals. The flow induces lateral movement of the conic
cup that covers the sensory area of the vestibular organ.
Either bending or tensile forces on the sensory cells elicit
nerve impulses. The vestibular branch and the eighth
cranial nerve innervates these sensory cells
(Treuting et al., 2018).
BIOLOGY AND CARE
5. Touch
The main tactile organs in the rat are the vibrissae,
used in navigation, object recognition, and social in-
teractions (Berg and Kleinfeld, 2003; Sofroniew and
Svoboda, 2015). The most apparent vibrissae are the
mystacial vibrissae, though additional, nonmystacial
vibrissae are present in supraorbital, postero-orbital,
lateral cervical, median cervical, submental, and carpal
forelimb locations. Each vibrissa is sunken in a follicle
that is sealed within a blood sinus. When a vibrissa is
touched, it bends and pushes the blood against the
opposite side of the sinus, triggering a nerve impulse
to the barrel cortex in the brain. The barrel cortex oc-
cupies a relatively large portion of the somatosensory
cortex in rats. Innervation of the mystacial vibrissae is
via the trigeminal nerve (Kurnikova et al., 2017).
Rats use their vibrissae to navigate, orient, and bal-
ance. The biomechanics of sensory perception by the
vibrissae are actively studied for many research
purposes, not only in the use of rats in biomedical
neurophysiology research, but in the field of biomi-
metics, object detection in robotics, and the develop-
ment of human haptic sensory systems (Diamond
and Arabzadeh, 2013). The vibrissae of rats have rhyth-
mic motor activity that is used for the tactile localiza-
tion of objects; this motor activity is under active
muscular control (Diamond and Arabzadeh, 2013).
The surface of the rat snout pad is ridged in a fashion
similar to the dermatoglyphic pattern found in primate
digital skin. These epidermal and dermal ridges almost
certainly play a role in sensory discrimination. The nose
and whiskers are the major portal for olfactory and
tactile sensory information in the rat (Kurnikova
et al., 2017).
III. DIGESTIVE SYSTEM
The digestive and absorptive functions of the
gastrointestinal tract hinge on several processes that
soften food, propel it along, mix it with bile, and add
digestive enzymes secreted by auxiliary glands. Some
processes arise from the intrinsic nature of smooth mus-
cle. Others are comprised of reflexes associated with
neurons in the gut or deriving in the central nervous
system as well as the paracrine effects of chemical
messengers and gastrointestinal hormones (Senoo,
2000).
The rat is one of the most popular experimental ani-
mals for studying the physiology of digestion. Rats are
nocturnal rodents and typically feed semicontinuously
when they are active at night. They are coprophagous
and some part of the orally ingested food and its metab-
olites remains in the feces to be reingested (Senoo, 2000).
 III. DIGESTIVE SYSTEM
Rats consume approximately 5 g per 100 g body weight
in a 24-h period. Water consumption in 24 h is approxi-
mately 8e11 mL per 100 g body weight (Bivin et al.,
1979). The following is a description of the digestive
system from the oral cavity to the anus and rectum
and a discussion of the accessory organs associated
with the alimentary tract. Some important differences
between rats and other laboratory animal species
include lack of tonsils and gallbladder, an extremely
diffuse pancreas, and many visceral accessory glands.
A. Mouth and Buccal Cavity
A cleft upper lip, the philtrum, and an intact lower lip
are the rostral boundaries of the mouth. The space be-
tween the lips, cheeks, and teeth is the vestibule. Both
jaws have a pair of well-developed incisor teeth. The in-
cisors grow continuously and the pulp cavity is open, so
it is essential that the teeth are aligned to maintain a
sharp cutting edge. Canine teeth are absent, but the
open space where they would be is called the diastema.
Folds of cheek mucosa fill the diastema and serve to
separate the gnawing machinery from the caudal buccal
cavity. The dental formula, characteristic for rodents, is
2(I 1/1, C 0/0, Pm 0/0, M 3/3) ¼ 16.
Along with many mammals, rats have four types of
lingual papillae: filiform, fungiform, circumvallate, and
foliate, on the dorsal or lateral surface of the tongue
(Iwasaki et al., 1997). The circumvallate papilla, located
on the posterior portion of the tongue, contains a large
number of taste buds and is surrounded by a trench
(Mistretta and Baum, 1984). Underlying the papilla is a
tubuleeacinar salivary gland, the von Ebner’s gland,
whose secretory ducts open into the trench surrounding
the papilla (Sbarbati et al., 1999). An important function
of the von Ebner’s gland is the production of lipase for
fat digestion in neonatal rats (Hamosh and Hand,
1978). More recent work has identified a closer relation-
ship between the papilla and associated gland and de-
scribes the circumvallate papilla/von Ebner’s gland
complex as an example of a specialized sensory/secre-
tory unit for tasting and digestion (Sbarbati et al., 1999,
2002; Sohn et al., 2011). Each fungiform papilla in the
rat has a single taste bud, resulting in a spatial distribu-
tion of fungiform papillae equivalent to the location of
taste buds on the rostral portion of the tongue. A mean
total number of 187 fungiform papillae per tongue
have been described for an average density of 3.4
papillae/mm (Miller and Preslar, 1975). Investigators
have long used the rat fungiform papillae as a model
system of the mammalian taste receptor (Beidler and
Smallman, 1965). There is no medial frenum, but two
lateral ones extend from near the tip of the band, which
ties the lower lip to the gum. There are no sublingual
BIOLOGY AND CARE
103
papillae; however, a small pair of salivary papillae lie
close to the median line behind the incisors.
The hard and soft palates form the roof of the oral
cavity. The hard palate extends from the incisors to
the posterior third molars and has eight rows of pala-
tine ridges composed of dense connective tissue
(Kutuzov and Sicher, 1952) with an overlying stratified
squamous epithelium. Sensory nerve fibers identified
in the anterior hard palate of the rat are thought to be
important for monitoring mechanical properties of
food (Chan and Byers, 1985; Halata and Baumann,
1999). Although mechanoreceptors are present in the
oral mucosa of all mammals, the type and location of
these receptors varies from species to species, including
those found in rats and other rodents (Tachibana et al.,
1991). The soft palate extends from the caudal border of
the hard palate to the nasopharyngeal hiatus, where it
merges with the ventral wall of the pharynx. Like the
hard palate, it is covered by stratified squamous epithe-
lium, which is replaced every 3.25e4.5 days (Hamilton
and Blackwood, 1974). Laterally the soft palate is
continuous with the cheeks and lateral wall of the phar-
ynx (Cleaton-Jones, 1971). At the caudal extremity,
there is no obvious tonsil, no uvula, and no rostral or
caudal pillars of the fauces.
An unusual feature in the rat is the relationship of
the larynx to the soft palate and nasopharyngeal hiatus.
The epiglottis lies 2e3 mm rostral to the nasopharyn-
geal hiatus, whereas the caudal border of the larynx,
namely the arytenoid cartilages, lies within the naso-
pharyngeal hiatus rostral to its caudal border. A muscle
called the nasopharyngeal sphincter surrounds the
nasopharyngeal hiatus and is closely related to the
cartilage plates on either side of it. There are no levator
palati, musculus unulae, or palatoglossus muscles
(Cleaton-Jones, 1972).
The pharyngeal region has no other unusual features
and is rather typical of most mammalian species. The
esophagus begins just dorsal to the glottis and extends
caudally to connect the oral cavity with the stomach.
Saliva consists of water plus amylase, mucin, electro-
lytes, immunoglobulin, and other trace components.
However, secretion from the parotid gland is unique. It
has a protein concentration of about 2%. Removing the
salivary gland or ligating the salivary duct brings out
the many influences that these glands have on
numerous endocrine and exocrine functions. For
example, parotid hormone stimulates dental fluid trans-
port in teeth and may prevent tooth decay (Senoo, 2000).
B. Esophagus
The esophagus is accessible caudal to the diaphragm,
permitting relatively easy esophagealeintestinal anasto-
mosis and gastrectomy (Bivin et al., 1979). As in all
104 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
rodents, the epithelium of the esophagus is covered with
a layer of keratin. The esophagus enters the stomach at
the inner curvature through a fold of the limiting ridge
that separates the forestomach from the glandular stom-
ach. The anatomy of the stomach as well as a lack of
some of the neurologic components necessary to induce
a vomiting reflex makes it impossible for a rat to vomit
(Horn et al., 2013).
C. Stomach
An excellent review of the anatomy and physiology of
structures affecting gastrointestinal absorption in rats is
in DeSesso and Jacobson (2001). The stomach is located
in the left proximal portion of the abdomen and is in
contact with the liver. Attaching it and other organs of
the digestive tract to the dorsal body wall is a prominent,
highly vascularized mesentery. The sac-like mesentery
that attaches to the greater curvature of the stomach
and drapes like an apron over the stomach and intes-
tines is called the omentum.
The gastric mucosa is divided into two distinct re-
gions: the forestomach and the glandular stomach. The
glandular stomach (Fig. 4.8) is further divided into three
regions: the small cardia, the fundus, and the antrum
(Treuting et al., 2018a). A histologic description of a
rat’s stomach would not differ significantly from that
of most rodents. The nonglandular forestomach has
FIGURE 4.8 Stomach. The interior structure of the rat stomach has
two distinctive regions separated by a prominent limiting ridge, which
precludes vomition. Food entering the stomach goes into the forest-
omach, a nonsecretory region with a hardy epithelium. The portion of
the stomach with an exit to the duodenum is the glandular stomach
and is characterized by a delicate secretory epithelium and prominent
folds (rugae). From Treuting, P.M., Arends, M.J., Dintzis, S.M., 2018a.
Upper gastrointestinal tract. In: Treuting, P.M., Dintzis, S.M., Montine,
K.S. (Eds.), Comparative Anatomy and Histology: A Mouse, Rat, and Hu-
man Atlas, second ed. Academic Press, London, pp. 191e211.
BIOLOGY AND CARE
rumen-like mucosal folds covered with stratified squa-
mous epithelium and serves as a reservoir. The glan-
dular region is characterized by gastric pits with
simple columnar epithelium. The gastric pits are
composed primarily of mucous neck cells, parietal cells,
and chief cells. The gastric pits are connected to gastric
glands located in the lamina propria. These glands are
often dilated in aging rats (Komárek et al., 2000). In addi-
tion to cell types found in the gastric pits, enteroendo-
crine cells can also be found in this region and include
enterochromaffin-like cells, A-like cells, and D cells
(Uehara et al., 2018). The pyloric portion of the stomach
is again characterized by a mucosa of simple columnar
epithelium lining the elongated gastric epithelium. Pylo-
ric glands present in this region contain mucous cells
and enteroendocrine cell types G and D that produce
gastrin and somatostatin, respectively (Uehara et al.,
2018). The gastric mucosa of most mammals secretes
four distinct aspartic proteases: pepsinogen A, pepsin-
ogen C, cathepsin D, and cathepsin E. That of the rat se-
cretes only pepsinogen C and cathepsins D and E
(Senoo, 2000).
D. Small Intestine
A comprehensive review of the development of intes-
tinal transport in mammals can be found in Pacha
(2000). The small intestine is the major site of digestion
and absorption of nutrients. It is the longest portion of
the gastrointestinal tract and is comprised of the duo-
denum, jejunum, and ileum. The mucosal surface is
covered by villi with intestinal crypts, crypts of Lieber-
kühn, located at their base. Villous height and shape
are variable and can make identification of the regions
of the small intestine difficult. Furthermore, villous
height can increase during lactation and after partial
resection. Villous height and morphology can also
change in response to certain diets (Nakatsuji et al.,
2018). The epithelium of the small intestine is composed
of several different types of cells comprising a multitude
of functions. Enterocytes are tall columnar absorptive
cells with surface microvilli that produce brush border
hydrolases. Goblet cells produce mucin that lubricates
intestinal contents and protects the epithelium
(Young and Heath, 2000). Stem cells are rapidly dividing
cells and are responsible for replenishing the small intes-
tinal epithelium, which is renewed every 2e3 days in ro-
dents (Treuting et al., 2018a). Paneth cells are found in
larger numbers in the ileum and secrete substances
important for immunity and host-defense systems.
Enteroendocrine cells are important for regulating intes-
tinal physiology and secrete hormones and peptides
(Senoo, 2000). Gut-associated lymphoid tissue is present
through the intestinal tract. The largest foci of lymphatic
 III. DIGESTIVE SYSTEM
tissue are Peyer’s patches. They are diffusely distributed
along the antimesenteric border and are present in
greater numbers in the distal small intestine in rats
(Nakatsuji et al., 2018). The mucosa overlying Peyer’s
patches contain M cells that are responsible for
antigen sampling of the intestinal contents and transport
of antigens and bacteria from the lumen to immune
cells.
The submucosa of the small intestine contains coiled
tubuloalveolar glands called Brunner’s glands. These
glands are thought to be modified extensions of the
crypts of Lieberkühn and are located near the pylorus
in the first 6e8 mm of the duodenum (Nakatsuji et al.,
2018). They secrete a mucinous alkaline fluid that pro-
tects the gastric epithelium and the proximal duodenal
mucosa by neutralizing acidic chyme entering from
the stomach (Leeson and Leeson, 1966).
Most nutrients are absorbed through the apices of the
epithelial cells in the small intestine facing the lumen. A
conspicuous specialization of the apical surface of each
epithelial cell is large numbers of microvilli, outward
projections from the apical surface that vary in number
and density. Microvilli create the appearance of a brush
border and increase the surface area for absorption. Ab-
sorption can be through active transport, pinocytosis, or
diffusion. The length and surface area of the absorptive
gut are well documented. The young rat, most often
used in absorption and nutrition experiments, has a
mucosal area per unit of gut length ratio of about 2:1
(Boyne et al., 1966; Permezel and Webling, 1971).
Monosaccharides glucose, galactose, and fructose are
absorbed by the intestine via specific translocators after
the digestion of ingested carbohydrates (Stumpel et al.,
2000). Glucose and galactose are taken up by sodium-
dependent glucose cotransporter-1 and fructose by
sodium-independent glucose transporter-5. Both are
located in the apical plasma membrane of mature enter-
ocytes. On the basolateral membrane of the enterocytes,
all three carbohydrates share the same translocator and
enter the circulation via the sodium-independent
glucose transporter-2.
The absorptive capacity for carbohydrates is not con-
stant. It responds to long-term changes in physiologic
conditions. Commonly, changes in intestinal glucose
transport come about through modulation of both the
sodium-dependent glucose cotransporter-1 and
sodium-independent glucose transporter-5 protein con-
centrations (Stumpel et al., 2000). Transport of intact
peptides and proteins from the intestinal lumen into
the blood differs from the regular process of food diges-
tion and absorption. Intestinal absorption of minute
amounts of proteins via transcytotic transport through
the enterocyte is considered a routine physiologic pro-
cess (Ziv and Bendayan, 2000).
BIOLOGY AND CARE
105
Protein digestion begins in the stomach where they
are hydrolyzed to polypeptides. Digestion continues in
the duodenum and jejunum by proteolytic enzymes pro-
duced in the pancreas and intestinal mucosa. Most small
oligopeptides and amino acids are then transported
across the apical surface of enterocytes and then across
the basolateral membrane to the bloodstream for distri-
bution (Senoo, 2000; Jando et al., 2017). Most neutral
amino acids are transported across the apical brush-
border membrane by the broad neutral amino acid
transporter B0AT1. In rats it has been shown that
B0AT1-mediated absorption is adapted to the diurnal
rhythm and long term to the amount of dietary proteins
and amino acids present in the proximal small intestine
(Jando et al., 2017). Lipid and fat digestion begins in the
duodenum via pancreatic lipase hydrolysis. Lipids are
then emulsified in the small intestine by bile salts, leci-
thin, and monoacylglycerol (Senoo, 2000). Maximal fat
absorption occurs at the base of the enterocyte microvilli
by lacteals (DeSesso and Jacobson, 2001). Intestinal ab-
sorption of selected vitamins and minerals is reviewed
by Thomson et al. (2001).
E. Cecum
The cecum is a large, thin-walled, blind pouch con-
sisting of an apical and a basal portion. The base of the
cecum includes the ileocecal and colocecal junctions.
The apical portion contains a distinct mass of gut-
associated lymphoid tissue. The size of the rat cecum re-
flects its omnivorous nature. It is smaller than the cecum
of herbivores, such as the rabbit, and larger than that of
carnivores with a small and less developed cecum. The
presence of bacteria in the cecum supports its function
as a fermentation vat, a compartmentalized area for
the breakdown of plant material (Snipes, 1981). Absorp-
tion of substances, including water, electrolytes, and
minerals, also occurs in the cecum (Nakatsuji et al.,
2018).
F. Large Intestine
The rat colon is shaped like an inverted V, dividing it
into ascending and descending regions (Nakatsuji et al.,
2018). From the cecum, the colon ascends cranially,
transverses across the duodenum, and then descends,
finally forming the rectum in the pelvic region. The
proximal and distal regions of the colon contain mucosal
folds that assist in distinguishing the regions histologi-
cally. The mucosa contains crypts of Lieberkühn, tubular
glands lined by absorptive colonocytes, goblet cells, and
enteroendocrine cells. Goblet cells are important
because they produce mucin that lubricates fecal mate-
rial. Fecal pellets can be seen in the distal colon giving
106 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY

it a segmented appearance that should not be confused

with haustra present in the colon of other species (Treut-
ing et al., 2018b).

G. Rectum and Anus

The rectum is straight and short and its appearance
indistinct from the distal colon. There is an abrupt tran-
sition from the glandular mucosa of the rectum to the
squamous mucosa lining the anal canal (Treuting
et al., 2018b). Modified sebaceous glands, called cir-
cumanal glands, are located around the anus, which
may help provide important olfactory cues (Kairali
et al., 1984). These glands are much larger than seba-
ceous glands located in other areas of the skin (Nakat-
suji et al., 2018).

H. Accessory Organs
The accessory organs are the exocrine pancreas and
the liver. The rat pancreas is not a singular mass but is
diffuse and extends from the end of the duodenal loop
to the left into the gastrosplenic omentum. Although
diffuse, three regions of the rat pancreas can be identi-
fied. Naming of these regions differs but many use
duodenal, gastric, and splenic or left, middle, and right
(Senoo, 2000; Liggitt and Dintzis, 2018). The pancreas
plays an important role in digestion by synthesizing
and secreting enzymes. Digestive enzymes are stored
in zymogen granules that are released into the common FIGURE 4.9 Liver. The four major lobes of the rat liver. From Rogers,
bile duct or directly into the duodenum by way of excre- A.B., Dintzis, S.M., 2018. Hepatobiliary system. In: Treuting, P.M., Dintzis,
tory ducts. The number of pancreatic ducts in rats is var- S.M., Montine, K.S. (Eds.), Comparative Anatomy and Histology: A Mouse,
Rat, and Human Atlas, second ed. Academic Press, London, pp. 229e239.
iable with the number of main ducts ranging from two to
eight (Senoo, 2000).
The main functions of the liver are processing nutri- mesorchium that covers the testicle of the male; mesova-
ents, producing protein, maintaining energy homeosta- rium, to the ovaries of the female; and broad ligament, to
sis, and clearing toxins. It has an important role in the fallopian tubes and uterus of the female.
immunosurveillance. The liver (Fig. 4.9) spans the sub-
diaphragmatic space and is divided into four lobes:
right, median, left, and caudate (Rogers and Dintzis, IV. RESPIRATORY SYSTEM
2018). The rat has no gallbladder. Bile ducts from each
lobe come together to form the common bile duct that A. Upper Respiratory System
empties into the descending duodenum approximately
25 mm from the pyloric sphincter (Bivin et al., 1979). The upper respiratory system of the rat does not
These ducts are unable to concentrate bile as occurs in differ in any great way from that of the typical mammal.
the gallbladder of other rodents (McMaster, 1922). The external nares are located rostrolaterally and open
The mesentery in the rat is a double layer of perito- caudally through the caudal nares into the nasopharynx.
neal membrane extending from the dorsal body wall The Eustachian tubes open on the dorsolateral wall of
to the viscera. It is given a specific name according to the nasopharynx.
the particular visceral organ to which it is attached The epiglottis lies in the oropharynx where it covers
and thus supports: mesogastrium, to the stomach; mes- the opening to the larynx. The beginning of the trachea
oduodenum, to the duodenum; true mesentery or mes- lies ventral to the esophagus and extends caudally to
entery proper, to all of the small intestine exclusive of form the two main branches, the primary bronchi, each
the duodenum; mesocolon, to the large intestine; of which enters a lung. The inner diameter of the trachea

BIOLOGY AND CARE

 IV. RESPIRATORY SYSTEM
is approximately 3e1.5 mm in the adult rat (Schulz and
Muble, 2000; Monteiro, 2014), and the shape is main-
tained by 18e24 rigid C-shaped cartilage structures
(Valerius, 1996) that form the framework of the trachea.
The cellular morphology of the trachea and upper
airway reaches full development by approximately
postnatal day 21 (Greeley, 2016). As in other species,
tracheal epithelium is predominantly pseudostratified
with cilia, though basal cells and serous cells also are
present (Reynolds et al., 2015). Ciliated cells perform
a critical function in the respiratory tract to help to
remove mucus and any entrapped material. It is theo-
rized that only the tips of the cilia, which are described
as having a claw-like structure, penetrate the periciliary
fluid and “claw” the mucus forward. Basal cells have a
role in cellular adhesion and may serve as progenitors
for other respiratory cell types (Evans et al., 2001). Se-
rous cells are a type of secretory cell. The rat has a
higher amount of serous cells in its respiratory epithe-
lium than other common laboratory animal species
(Barthold et al., 2016; Meyerholz et al., 2018). Goblet
(or mucous) cells are situated in the epithelium of con-
ducting airways at all levels, but comprise less than 1%
of the total cells under normal conditions (Jeffery and
Reid, 1975; Mercer et al., 1994b; Cesta et al., 2014). In
response to inhaled airway insult, a number of prod-
ucts are secreted by goblet cells, including mucins
and glycoproteins (Rogers, 1994). Mucous glands are
most common in the larynx and proximal portion of
the trachea where they are located between the ventral
aspects of the cartilaginous rings (Widdicombe et al.,
2001) and are part of the mucociliary apparatus. The
mucociliary apparatus consists of a mucous layer, fluid,
and cilia for transportation, which work together as
part of the body’s innate defense system to trap and
rhythmically move materials such as particulates up-
ward where they can then be expelled (Van Winkle
et al., 2018). Rats are an often studied species in inhala-
tion toxicology work, and represent a model to evaluate
nasal mucociliary function and drug absorption
(Morgan et al., 1984; Harkema, 1990; Inoue et al., 2013).
B. Lower Respiratory System
There are five lung lobes in the rat: one left lobe and
four on the right (cranial, middle, accessory, and caudal
lobes). The middle lobe lies in contact with the dia-
phragm and apex of the heart and is notched to accom-
modate the caudal vena cava. For this reason, the middle
lobe is sometimes referred to as the postcaval lobe. Bron-
chial branching follows a monopodial pattern in rats
where each main intrapulmonary longitudinal airway
has much smaller side branches (Monteiro, 2014). The
respiratory bronchioles are relatively short and rudi-
mentary (Boorman, 1990), resulting in terminal
BIOLOGY AND CARE
107
bronchioles almost immediately connecting into alve-
olar ducts, each of which subdivides four or five times.
The lung in the newborn rat is immature. It contains
no alveoli or alveolar ducts; instead, gas exchange oc-
curs in smooth-walled channels and saccules, and the
prospective alveolar structures (Burri, 1974). Once the
rat reaches 4 days old, a rapid restructuring of lung pa-
renchyma occurs as transition from the saccular stage
into the alveolarization stage begins (Greeley, 2016).
The total number of acini formed in the lung is consid-
ered complete by this time (Barre et al., 2016). Respira-
tory bronchioles are not present at birth, but by day 10
they are easily identified. After day 13, the primary
and secondary septa expand and thin to form true alve-
olar septa (Burri, 1974). Bronchial airway growth paral-
lels alveolar development in juvenile rats (Lee et al.,
2011). Apoptosis contributes to lung maturation by
reducing the number of fibroblasts and type II epithelial
cells in the third postnatal week (Schittny et al., 1998;
Bruce et al., 1999).
In the intrapulmonary bronchi, the epithelium be-
comes shorter and columnar rather than pseudostrati-
fied. At this level of the respiratory tract, ciliated cells
predominate (Chang et al., 1986; Souma, 1987; Miller
et al., 1993); however, nonciliated cells are also present
and include brush cells (type III pneumocytes), club
(Clara) cells, and secretory cells. The function of pulmo-
nary brush cells is not well understood. They can be dis-
cerned from other nonciliated respiratory epithelial cells
in rats by electron microscopy and immunohistochem-
ical staining properties (Yamamoto et al., 2018) and
may be involved in immune surveillance or act as che-
mosensors (Chang et al., 1986; Reid et al., 2005; Reynolds
et al., 2015). Club cells assist with protection and repair
of the respiratory epithelium (Rokicki et al., 2016). For
example, they may have a role in differentiating into
alveolar type I and II epithelial cells (Zheng et al., 2017).
The lung of the average adult rat contains an esti-
mated 975,000,000 cells, of which 74% are in alveolar tis-
sues and 26% in nonalveolar tissues (Stone et al., 1992).
Basal cells decrease and virtually disappear from the
small airways and, at all airway levels, the remaining
nonciliated cells form a high proportion (about 40%) of
the total cells present (Miller et al., 1993; Mercer et al.,
1994b; Rogers, 1994). Septal cells in the alveolar intersti-
tium contain contractile filaments containing actin, des-
min, and vimentin (Aoki et al., 1995). This feature
suggests that septal cells can contract and change the ar-
chitecture of the aireblood barrier, thereby influencing
the regulation of the ventilation/perfusion ratio.
The alveoli are lined by large, flat type I pneumocytes
and by round type II pneumocytes; both are epithelial
cells. Type I pneumocytes constitute part of the
extremely thin gaseous diffusion barrier, whereas type
II pneumocytes secrete surfactant. Type I cells cover
108 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
the majority of the surface area of the alveoli in rats
although type II pneumocytes predominate by cell count
(Crapo et al., 1983; Dormans, 1983). The alveolar wall
consists of three layers: the epithelial layer lining the
alveolar space; a basement membrane; and the endothe-
lial cell lining of the capillary lumen (Kikkawa, 1970). All
three layers are relatively thin and continuous
(Crapo et al., 1983; Bastacky et al., 1995). The alveolar
spaces are normally clear of fluid or debris. Changes
can occur in the respiratory tract with advancing age.
For example, with age the ratio of type II cells to type I
cells lining the alveolar surfaces can decrease (Pinkerton
et al., 1982) and the size of the terminal airways may
expand (Yamamoto et al., 2003).
Surfactant, a lipid surface tension-lowering agent,
coats the alveoli and helps to maintain the patency of
conducting airways (Enhorning et al., 1995). Phospho-
lipids, particularly phosphatidylcholine, are essential
components of surfactant. Although surfactant is
composed of mostly monounsaturated phospholipids
in many mammals, rat surfactant has a high content of
polyunsaturated phospholipids (Postle et al., 2001). Sev-
oflurane, a commonly used inhalant anesthetic agent,
can negatively impact surfactant biochemical properties
in rats (Malacrida et al., 2014) as well as cause antiin-
flammatory effects (Lee et al., 2015).
Pulmonary arteries and bronchial arteries supply
blood to the lung (Greene, 1963). The left bronchial ar-
tery originates from the internal thoracic artery, while
the right may have a variable origin (Ferreira et al.,
2001). There are two types of pulmonary arteries in the
rat: elastic arteries and muscular arteries (Hislop and
Reid, 1978). The elastic artery has an abundance of extra-
cellular matrix in the media and an oblique arrangement
of smooth muscle cells connecting to neighboring elastic
laminae. The muscular artery has a paucity of extracel-
lular matrix in the media and a circumferential arrange-
ment of smooth muscle cells enclosing the lumina
(Sasaki et al., 1995). In the conscious resting rat, blood
flow preferentially distributes to the central, hilar re-
gions of the lung lobes, with less blood flow to the pe-
ripheral regions (Kuwahira et al., 1994).
The pulmonary vein of the rat is thicker than in most
other species because of the presence of striated muscle
fibers that are contiguous with those of the heart. These
muscle fibers are especially apparent in the longer intra-
pulmonary branches of the vessel. Both smooth and car-
diac muscle may be present in variable amounts
depending on the location in the vein. Cardiomyocytes
in rats extend from the atrium and continue past the
hilus of the lungs (Ludatscher, 1968; Mueller-Hoecker
et al., 2008; Townsley, 2012). Noncardiomyocyte-lined
segments in the periphery of the rat lung are thought
to be responsible for the regulation of total pulmonary
vascular resistance due to the anatomical location of
BIOLOGY AND CARE
the smooth muscle cells and their functions within the
pulmonary vein (Hosoyamada et al., 2010). Precapillary
anastomoses between the bronchial and pulmonary
arteries have been demonstrated in the rat (Rakshit,
1949), as they have been in humans and guinea pigs
(Verloop, 1948). These anastomoses are limited to the hi-
lar region in the rat.
Pulmonary lymphatics are critical to clearing lung
fluid. A most important site for pulmonary edema forma-
tion, the pulmonary capillary is just upstream from small
veins that have focal, smooth muscle tufts termed venous
sphincters (Schraufnagel and Patel, 1990). Because of
their constricting potential, these sphincters may control
lung perfusion and cause edema. Increased numbers of
lymphatics are adjacent to the venous sphincters, thus
helping to moderate edema (Aharinejad et al., 1995).
Innervation of the lung is complex. The rat does not have
adrenergic nerve supply to the smooth muscle of the intra-
pulmonary arteries (Hebb, 1969; McLean et al., 1985).
Instead, bronchoconstriction is controlled by vagal tone.
The lung weight is related to body size, but the sur-
face area of the lung is related to O2 consumption. In
this regard, the alveolar diameter is related to metabolic
rate as measured by the O2 used per unit of body weight
(Tenney and Remmers, 1963). The comparative dimen-
sions of alveolar septal wall components for the rat
lung have been reviewed (Townsley, 2012). The alveolar
diameter for an adult rat is approximately 90e98 mm, in
contrast to an approximate alveolar diameter of
210e240 mm for a human (Mercer et al., 1994a). The total
surface area of the lung in an adult rat is approximately
0.4 m2, compared with about 62 m2 in humans (Oller
and Oberdörster, 2010). Relatively wider airways and a
decline in airway resistance with declining body mass
result in a relatively high ventilatory dead space that is
compensated by a higher breathing frequency compared
with larger mammals (Gomes et al., 2000).
Respiration is regulated, as in other mammals, in
response to tissue CO2 changes in the medullary respira-
tory center, though the carotid bodies also play a role.
The carotid bodies are located on each side of the
neck, in the bifurcation of the common carotid artery.
The carotid bodies are composed of nerve tissue and
arise as branches of the glossopharyngeal and vagus
trunks and the cranial cervical ganglion, and are accom-
panied by sympathetic ganglion cells (Atanasova et al.,
2011). The carotid bodies function as chemoreceptors,
responding when the arterial partial pressure of oxygen
decreases to maintain rate and regularity of respirations
(Sheikhbahaei et al., 2017). Similar chemoreceptors
located in the aorta are called aortic bodies; the aortic
body afferents travel via the vagi to the brain. The sub-
clavian aortic bodies and the vagal paraganglia, which
are located near the recurrent laryngeal nerve, are
commonly studied in the rat (Piskuric et al., 2011).
 V. CARDIOVASCULAR SYSTEM
V. CARDIOVASCULAR SYSTEM
A. Heart
The heart is located between the second and sixth
intercostal space with its longitudinal axis at an angle
of 30e40 degrees with the sternum (Constantinescu,
2011). The left side of the heart is easily accessible
through the thoracic wall for blood collection due to
the anatomical configuration. The heart is four cham-
bered with two atria and two ventricles. Similar to
most domestic mammal species, the aortic and pulmo-
nary valves each have three leaflets along with the right
atrioventricular (tricuspid) valve, whereas the left
109
atrioventricular (mitral) valve has two leaflets (Dyce
et al., 1987; Constantinescu, 2011). Compared to human
anatomy, valve leaflets of rodents are less individually
distinct and more like a continuous curtain (Buetow
and Laflamme, 2018). Early development of the rat heart
in utero has been reviewed as well as the histologic car-
diac maturation in juvenile rats (Marcela et al., 2012;
Greeley and White-Hunt, 2016).
A schematic of the major blood vessels in the female
rat is shown in Fig. 4.10. The figure emphasizes areas
frequently targeted in research studies. The aortic arch
bends to the left, as usual in other mammals, and di-
verges into the brachiocephalic trunk, the left common
carotid, and the left subclavian arteries. The

FIGURE 4.10 Schematic of the major arteries of the female rat. Redrawn from Bivin, W.S., Crawford, P., Brewer, N.R., 1979. Morphophysiology. In:
Baker, H.J., Lindsey, J.R., Weisbroth, S.H. (Eds.), The Laboratory Rat, first ed. Academic Press, New York, NY, pp. 73e103, by G. Carlson.

BIOLOGY AND CARE

110 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
brachiocephalic trunk divides at the sternoclavicular
joint into right common carotid and right subclavian ar-
teries. There are good illustrations of the aorta and its
systemic branches elsewhere (Greene, 1963; Constanti-
nescu, 2011). One notable idiosyncrasy is the presence
of a retained accessory extracoronary myocardial blood
supply originating from the internal mammary or sub-
clavian arteries (Halpern, 1957). The right coronary ar-
teries provide a large blood supply to both right and
left atria, but the left coronary arteries supply only a
small portion of the left atrium (Halpern, 1957). This
makes the blood supply in the rat cardiovascular system
more similar to that found in some fish than to other do-
mestic mammalian species, but useful to study since the
blood supply to the sinoatrial and atrioventricular nodes
is effectively separate (Halpern, 1957).
The rat vena cava looks different from that of other
mammals as well. There are two precavae. The right cra-
nial vena cava joins the right atrium directly (Fig. 4.11);
however, the left cranial vena cava extends caudally,
joins the left azygous vein, unites with the caudal vena
cava, and finally joins the right atrium (Popesko et al.,
2002; Constantinescu, 2011). Variations in venous
drainage of the rat heart have been reported both within
individual rats and also by strain (Kresáková; et al.,
2015).
Cardiac output, total peripheral resistance, and
venous capacity are regulated moment-to-moment to
keep blood pressure and volume nearly constant. This
regulation is critical to maintaining an ample blood
supply to varied and various tissues. To maintain blood
pressure and adjust flow efficiently, the central nervous
system processes peripheral information on blood
pressure, blood gases, pH, volume, and temperature
(Dampney, 1994). The information is conveyed by
afferent neurons arising from sets of receptors:
baroreceptors, chemoreceptors, and cardiopulmonary
receptors. This information is integrated by different
areas and at different levels of the central nervous sys-
tem to change the sympathetic and parasympathetic
tone to the main effectors of circulatory control, the
heart and blood vessels, appropriately (Palma and
Benarroch, 2014).
The rat is widely used as an experimental model to
investigate the electrophysiology of both normal and
pathophysiologic conditions. Studies with the
Langendorf-perfused rat heart have provided much of
the basis for current understanding (Lateef et al., 2015).
Advances in cardiovascular testing and imaging have
allowed phenotyping the rat heart in even greater detail
to further expand knowledge in this research area. Ultra-
sound echocardiography is most commonly used,
although other modalities such as X-ray microcomputed
BIOLOGY AND CARE
tomography, magnetic resonance microscopy, and
radionuclide studies have also been used to evaluate
cardiac morphology and function (Watson et al., 2004;
Badea et al., 2006; Cicone et al., 2017; Teh et al., 2016).
A few examples of surgical models of heart disease in
the rat include aortic banding and creation of aortacaval
shunts for studying cardiac hypertrophy; coronary ar-
tery narrowing or ligation, blockage of intramyocardial
vessels, and renal artery occlusion for induction of heart
failure; and heterotrophic heart transplantation to eval-
uate ventricular volume unloading and recovery (Dog-
grell and Brown, 1998; Benke et al., 2017; Chen et al.,
2018; Fu et al., 2016). Although the regulation of the car-
diovascular system will not be further covered here, a
good general review of cardiac physiology can be found
in Muir (2015) and in basic physiology textbooks.
Table 4.2 gives selected hemodynamic parameters for
the rat.
B. Peripheral Circulation
Rats are well suited for a wide variety of cardiovascu-
lar research applications due to similarities in anatomy
and physiology to the human, as well as their small
size and ease of handling. Because the rat genome has
been fine mapped, rat models are proving to be a valu-
able tool for identifying the genetic origin of complex
traits related to cardiovascular disease (Dillmann, 2008;
Bader, 2010; Wang et al., 2016). In modeling hyperten-
sion, rats are the most popular species studied (Pinto
et al., 1998); the spontaneously hypertensive rat and
salt-loaded stroke-prone rat are classic models (d’Uscio
et al., 2000; Mullins et al., 2016). The field is now also
poised for increases in cardiovascular research with
transgenic rats due to advances in and increased acces-
sibility to gene editing tools such as the CRISPR/Cas
system (Meek et al., 2017).
The peripheral circulatory and lymphatic system of
the rat differs little from that of other small mammals.
Knowledge of lymphoid anatomy and lymphatic routes
of drainage can be important for biological investiga-
tions. Suami et al. (2011) have described microinjection
techniques to visualize the lymphatic system of rats us-
ing color contrast agents and radiography. An overview
of lymphatic system drainage is illustrated in Fig. 4.12. A
review of the use of the common animal models for
studying drug transport via the intestinal lymphatic sys-
tem that describes the conscious rat and dog models in
detail is in Edwards et al. (2001). In addition, there are
reviews covering the lymphatic system of the head
and neck region (Dunne et al., 2004), as well as the medi-
astinal lymph nodes of the rat (Pasierbek, 2014).
 VI. URINARY AND REPRODUCTIVE SYSTEMS 111
RIGHT CRANIAL VENA CAVA
(A) LEFT CRANIAL VENA CAVA
COMMON CAROTID ARTERIES
APEX
RIGHT SUBCLAVIAN A. LEFT SUBCLAVIAN A.

BRACHIOCEPHALIC LEFT CRANIAL VENA CAVA RIGHT VENTRICLE

LEFT VENTRICLE
TRUNK
AORTA
LEFT AURICULA
RIGHT AURICULA
RIGHT CRANIAL
VENA CAVA PULMONARY TRUNK
LEFT AURICULA
RIGHT ATRIUM
LEFT VENTRICLE
LEFT ATRIUM
RIGHT AURICULA

LEFT CRANIAL VENA CAVA

RIGHT CRANIAL
VENA CAVA

RIGHT VENTRICLE CAUDAL

APEX VENA CAVA AZYGOUS V.
CAUDAL VENA CAVA
ESOPHAGUS THORACIC AORTA
ESOPHAGUS
THORACIC AORTA

Ventral Aspect of the Heart Dorsal Aspect of the Heart (Reflected towards the Head)

Heart and Great Vessels

LEFT SUBCLAVIAN A.
(B)
LEFT COMMON CAROTID A.
AORTA
RIGHT COMMON CAROTID A.
CHORDAE TENDINEAE
RIGHT SUBCLAVIAN A.
LEFT AZYGOUS V.

BRACHIOCEPHALIC TRUNK PULMONARY TRUNK

PULMONARY Vv.

CRANIAL LEFT LEFT ATRIUM

VENAE CAUDAL VENA
CAVAE RIGHT CAVA
PECTINATE MUSCLES
OF LEFT AURICULA
PECTINATE MUSCLES OF AURICLAE
PARIETAL CUSP BICUSPID
RIGHT ATRIUM
SEPTAL CUSP VALVE
SEMILUNAR
VALVULES MUSCULUS PAPILLARIS
PARIETAL CUSP SUBATRIALIS
TRICUSPID
SEPTAL CUSP CHORDAE TENDINEAE
VALVE
ANGULAR CUSP
MUSCULUS PAPILLARIS
MUSCULUS PAPILLARIS SUBAURICULARIS
MAGNUS
INTERVENTRICULAR
MUSCULUS PAPILLARIS SEPTUM
SUBAPTERIOSUS
LEFT VENTRICLE
RIGHT VENTRICLE TRABECULAE
CARNEAE
MUSCULI PAPILLARIS PARVI
TRABECULA
SEPTOMARGINALIS

FIGURE 4.11 Rat heart. (A) Heart in situ (ventral aspect) and reflected cranially (dorsal aspect). (B) Longitudinal cross-section through the rat
heart (atrial aspect). From Constantinescu, G.M., 2011. Comparative Anatomy of the Mouse and the Rat: A Color Atlas and Text. American Association
for Laboratory Animal Science, Memphis, TN, courtesy of the American Association for Laboratory Animal Science.

BIOLOGY AND CARE

112 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY

TABLE 4.2 Selected Hemodynamic and Respiratory Parameters

for the Rat.a Distal Convoluted
Tubule
Blood volume (mL/kg body wt) 54.3

Cortex
Macula Densa
Macula
Arterial blood pressure (mmHg) 105e114 Densa Cortical
Segment
Systolic (mmHg) 116e145
Outer Ascending
Diastolic (mmHg) 76e97 Stripe Thick

Outer
Limb
Heart rate (beats/min) 250e450 Medullary
Inner Segment
Respiration rate (breaths/min) 70e115 Stripe

Medulla
Tidal volume (mL/100 g body wt) 0.2e0.3
Thin Loop of Henle
Cardiac output (mL/min) 50 Collecting Duct

Inner
a
Data are approximations only and vary significantly by strain, age, sex, P1
health status, diet, as well as by the scientific methods used for measurements.
P2 Proximal
For examples, see the manuscripts cited (Strohl et al., 1997; d’Uscio et al., 2000; Tubule
Tabrizchi and Pugsley, 2000; Diehl et al., 2001; Hrapkiewicz et al., 2013). P3

FIGURE 4.13 Schematic showing location of nephron segments

within renal medulla and cortex. Modified from Tisher, C.C., 1981.
Anatomy of the kidney. In: Brenner, B.M., Rector, F.C., (Eds.), The Kidney.
W.B. Saunders Co., Philadelphia, PA; From Boorman, G.A., 1990. Pathology of
the Fischer Rat: Reference and Atlas, first ed. Academic Press, San Diego, CA.

VI. URINARY AND REPRODUCTIVE

SYSTEMS

FIGURE 4.12 Lymphatic drainage. A schematic diagram to show
the lymphatic system in a rat: (1) axillary node, (2) accessory axillary
node, (3) thoracic duct, (4) cisterna chyli, (5) intestinal lymph trunk, (6)
renal node, (7) lumber node, (8) hypogastric node, (9) lateral sacral
node, and (10) popliteal node. From Suami, H., Chang, D.W., Matsu-
moto, K., Kimata, Y., 2011. Demonstrating the lymphatic system in rats with
microinjection. Anat. Rec. 294, 1566e1573, courtesy of John Wiley and
Sons, Ltd., © 2011 Wiley-Liss, Inc.
A. Kidneys
The mammalian kidney is responsible for many crit-
ical biological functions such as filtering blood and
excreting waste products, and maintenance of the
renineangiotensinealdosterone system. As with other
mammals, the rat’s urinary system is composed of
paired kidneys, ureters, and the bladder. The right kid-
ney and the adrenal gland are more cranial than the
left in the rat and are located in the retroperitoneal space
in the abdomen. A corresponding difference is present
in the branching patterns of the renal vasculature in rela-
tion to the aorta and caudal vena cava (Fuller and
Huelke, 1973; Popesko et al., 2002). Although it is
possible to palpate the kidneys in young animals, it is
difficult in mature specimens because the outlines are
lost in fat.
The rat kidney has a single papilla and calyx that con-
nect to the ureter. The unipapillate structure makes it
easily accessible by cannulation techniques. The overall
structure of the kidney consists of the renal pelvis, me-
dulla, and cortex. The medulla (Fig. 4.13) is further
divided into inner and outer zones, with the latter sub-
divided into the inner and outer stripe (Boorman, 1990).

BIOLOGY AND CARE

 VI. URINARY AND REPRODUCTIVE SYSTEMS
The medullary renal pyramid is well developed, and in-
cludes a strong zonation of vascular and tubular ele-
ments (Pannabecker et al., 2004). The rat kidney has
specialized fornices that are long evaginations of the
renal pelvis with epithelium similar to collecting duct
epithelium (Schmidt-Nielsen et al., 1980; Tomonari
et al., 2016). The fornices are in close association with
the thin loops of Henle and function to build up the
urea concentration in the papilla (Bankir and de Rouffi-
gnac, 1985; Tomonari et al., 2016).
The nephron is the functional unit of the kidney. The
components of the nephron include the renal corpuscle
(glomerulus and Bowman’s capsule), the proximal tu-
bule, thin limb of the loop of Henle, distal tubule, and
the connecting tubule, or early part of the cortical collect-
ing duct (Pfaller, 1982). There are both long- and short-
looped nephrons in the laboratory rat. Short-looped
nephrons predominate (Ichii et al., 2006) and arise
from the tufts in the middle and outer zone of the cortex.
Humans have seven times more short-looped than long-
looped nephrons, whereas the rat has about two times
more (Tisher and Madsen, 2000; Wüthrich, 2000; Chris-
tensen et al., 2012). While descending, the thin segment
of short loops changes to the broad thick segment, such
that the bend of the loop is formed by the latter and the
bend occurs in the outermost zone of the medulla or in
the medullary ray of the cortex. In the rat’s renal cortex,
most groups of short nephrons possess no ascending
thin segment (Christensen et al., 2014). The straight
descending parts of the proximal tubules join the thick
segments directly.
113
The glomerulus is lobulated, and there are a limited
number of connective tissue cells between the vessels
near the vascular pole. Within Bowman’s capsule, the
wall is thin and lined with flattened parietal epithelium
that may become slightly thicker and cuboidal at the uri-
nary pole (Jakowski, 1982) before it becomes the prox-
imal tubule. Although the presence of cuboidal
parietal epithelium can occasionally be seen in females,
it is more commonly observed in male rats and mice as a
feature of sexual dimorphism (Delaney et al., 2018; Seely
et al., 2018) as shown in Fig. 4.14. The visceral layer
covers the glomerulus, whereas the parietal layer
covers Bowman’s capsule. The visceral cells are charac-
terized by their foot processes, called podocytes, which
interdigitate with each other creating filtration
slits. The glomerular endothelium, basement mem-
brane, and visceral epithelial cell layers compromise
the barrier for glomerular ultrafiltration (Kriz and Kais-
sling, 2013).
The rat proximal tubule is characteristic for most ro-
dents and its main roles include resorption of water,
electrolytes, and solutes (Bachmann and Kriz, 1998).
Like most mammals, the cells lining the proximal convo-
luted tubule are cuboidal with a rounded central nu-
cleus, have a brush border, and show mitochondria
arranged perpendicular to the basement membrane as
demonstrated by electron microscopy (Maunsbach and
Christensen, 2011). Proximal tubules can be morpholog-
ically divided into three distinct segments (P1eP3,
Fig. 4.13) based on cell structure characteristics such as
height of brush border, number and position of

FIGURE 4.14 Kidney, glomeruli-sexual dimorphism parietal epithelium. (A) Male rat with cuboidal parietal epithelium. (B) Female rat
with thin parietal epithelium. From Delaney, M.A., Kowalewska, J., Treuting, P.M., 2018. Urinary system. In: Treuting, P.M., Dintzis, S.M., Montine,
K.S. (Eds.), Comparative Anatomy and Histology: A Mouse, Rat, and Human Atlas, second ed. Academic Press, London, pp. 275e302.

BIOLOGY AND CARE

114 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
mitochondria, and organization of apical and basolateral
membranes relative to the segment location within the
tubule (Maunsbach, 1966; Bachmann and Kriz, 1998;
Christensen et al., 2012). The transition to S3 occurs
more abruptly in the rat compared to some other species
(Bachmann and Kriz, 1998; Greaves, 2012). The cells of
the S3 segment have reduced numbers of endosomes, ly-
sosomes, and mitochondria, which result in functional
changes (Bachmann and Kriz, 1998; Verlander, 1998).
The proximal tubule is an important site to evaluate his-
tologically for damage from renal insults such as toxins
and hypoxia, with the S3 site being particularly sensitive
to injury (Trevisan et al., 1999; Greaves, 2012; Seely et al.,
2018). Adult male rats have some degree of hyaline
droplets in the tubules normally, but an abnormal accu-
mulation (or observing them in females) may suggest a
response to injury, especially when other lesions are pre-
sent (Greaves, 2012; Seely and Brix, 2014; Seely et al.,
2018).
As the S3 segment of the proximal straight tubule
transitions into the descending thin limb of the loop of
Henle, the cuboidal epithelium of the proximal segment
is replaced by a flattened epithelium. The thin limb has
multiple different epithelial cell types that possess few
organelles and have a simpler membrane structure;
they function in urine concentrating mechanisms (Bach-
mann and Kriz, 1998; Verlander, 1998; Pannabecker,
2012). The thick segment of the ascending limb of the
loop of Henle joins the distal convoluted tubule at the
macula densa. At this point, the structure of the neph-
rons changes remarkably; the distal convoluted tubule
is distinguished by the width of its lumen and increased
cell height (Bachmann and Kriz, 1998; Pannabecker
et al., 2004). The distal convoluted tubule and collecting
tubules are lined by cuboidal epithelium of similar
height and can be distinguished based on staining and
ultrastructural properties (Bachmann and Kriz, 1998;
Verlander, 1998; Maunsbach and Christensen, 2011).
The ureter expands within the renal sinus to create the
renal pelvis. The collecting ducts empty into the renal
pelvis, and the ureter carries the urinary waste products
to the bladder for storage prior to excretion via the ure-
thra. In the male, the urethra extends through the penis.
In the female, the urethra opens on the perineum sepa-
rately from the vagina.
The ability of the laboratory rat to concentrate its
urine is about twice that of humans. This difference in
concentrating ability is the result of the functional
anatomical differences between the kidney anatomy of
the two species. There is a significant osmotic gradient
in the medulla, rising from the corticomedullary junc-
tion to the tip of the papilla, where it approximates
that of the urine (Sands and Layton, 2009; Dantzler
et al., 2014). Measure of urine density is often considered
the best way to determine urine concentrating ability to
BIOLOGY AND CARE
assess tubule function (Braun and Lefebvre, 2008). Urine
osmolality is considered the gold standard, and mea-
sures the number of dissolved particles in solution
(Chau et al., 2016). In the normal rat, when allowed an
adequate supply of drinking water, the urine osmolality
is in the region of 1000e1500 mOsm kg1 (Pennell et al.,
1974; Yang and Bankir, 2005) as compared with humans
at approximately 500 mOsm kg1 (Perrier et al., 2015).
Osmolality and urine specific gravity are usually pro-
portional and can be predictive (Chau et al., 2016).
Normal urine specific gravity for rats and humans often
overlaps in a similar range in a nonrestricted state
(generally about 1.003e1.030); for the water-restricted
rat, specific gravity is often around 1.040e1.060, but sig-
nificant variations between individuals can exist in
either state (Heller, 1949; Kasiske and Keane, 2000;
Kulick et al., 2005; Car et al., 2006; Otto et al., 2015).
These values can be used as a rough guide but should
not be strictly interpreted as a standard reference inter-
val. In the rat, sodium depletion and local amino acid
metabolism control the amount of protein in the urine
(Tobian and Nason, 1966; Herrero et al., 1997; Weinstein,
1998). In humans, proteinuria and albuminuria usually
increase with decreases in renal function (Saleh et al.,
2012). In rats, the evaluation of total urine protein as
an assessment of renal function can be complicated by
normal proteinuria, especially in young intact male
rats where proteinuria due to a2u-globulin is significant
(Perry, 1965; Alt et al., 1980; Seely et al., 2018). Care
should be taken in the selection of assay methods and
interpretation of results based on test limitations (Braun
and Lefebvre, 2008; Chau et al., 2016). Significant varia-
tion in clinical pathology parameters can also occur due
to strain, age, health status, and other factors for the best
way to determine appropriate reference intervals for
renal parameters, possibly to test control animals within
a study (Loeb, 1999; Everds and Ramaiah, 2018).
Selected renal anatomic and excretory parameters are
presented in Tables 4-3 and 4-4, respectively. Reviews
of urine concentrating mechanisms and overall mamma-
lian renal physiology can be found in Alpern et al. (2013)
and Skorecki et al. (2016).
Rats are a valuable model for translational studies of
renal pathology. For example, surgical models such as ne-
phrectomy or clamping of the renal pedicle are used to
evaluate acute and chronic renal disease and effects of
ischemia along with streptozotocin-induced diabetic ne-
phropathy models (Mullins et al., 2016). Superficial neph-
rons in the cortex of the rat kidney provide the model for
most micropuncture work examining the individual
transport process across the nephrons (Vallon, 2009).
This approach offers the most direct method for evalu-
ating tubular function in vivo. Some strains of rat, such
as Munich-Wistar, have superficial glomeruli that facili-
tate this analysis (Shea and Raskova, 1985). A
 VI. URINARY AND REPRODUCTIVE SYSTEMS 115
TABLE 4.3 Relation of Body Weight, Kidney Dimensions, and diagnostic techniques, such as diffusion-weighted mag-
Thickness of Kidney Regions.a netic resonance imaging and multiphoton microscopy,
provide alternate methods to evaluate renal physiology
Body weight (g) 200e300
(London et al., 1983; Yang et al., 2004). Intravital photon
Weight of left kidney (g) 0.8e1.4 microscopy allows real-time imaging with direct evalua-
Dimensions (mm) 10  6  4 tion of subcellular processes at submicron resolution
(Peti-Peterdi et al., 2015; Small et al., 2016) and offers a
Cortical thickness (mm) 4.0
unique approach to improving the understanding of the
Outer zone of medulla (mm) 2.2 roles of the glomerular filtration barrier and proximal tu-
Inner zone of medulla (mm) 6.0 bule in albumin filtration and reabsorption (Saleh et al.,
2012).
Nephrons 30,000e40,000
Cortical (%) 8.2
B. Male Reproductive System
Short (%) 44.7
Medullary (%) 18.6
The rat is one of the most widely used research
animals in reproductive physiology. The rat is also
Long (%) 28.5 useful in assessment of toxicologic insult to the repro-
a
Data are approximations only and vary significantly by strain, age, sex, health
ductive tract.
status, diet, as well as by the scientific methods used for measurements. For The testes of the adult male lie in two separate
examples, see the manuscripts cited (Abdallah and Tawfik, 1969; Lohr et al., 1991; thin-walled scrotal sacs located between the anus and
Christiansen et al., 1997; Wüthrich, 2000; Obineche et al., 2001).
the prepuce. In early life they begin their intraabdominal
descent in two embryonic phases: the first at approxi-
TABLE 4.4 Selected Renal Excretory Parameters.a mately E16e21 where the testes are at the level of the
kidney, and the second phase during E22epostnatal
Blood urea nitrogen (mmol/L) <20
day 1, where the testis move past the caudal pole of
Urine volume (mL/24 h/100 g 5.5e6.2 the kidney toward the bladder (Fiegel et al., 2010). The
bw) testes fully descend between the 30th and 40th day of
Naþ excretion (mmol/h) 12e52 life and are able to travel between the scrotal sacs and
the abdominal cavity throughout life through the open
Kþ excretion (mmol/h) 31e130
inguinal canal. Maturation of the testes occurs around
Protein concentration (g/L) 0.09e1.57 postnatal day 46, when sperm are released from the
Urine osmolarity (mOsm/kg of 205e2118 seminiferous tubules (Picut and Remick, 2016a). Prior
H2O) to testicular descent, measurement of the anogenital dis-
Specific gravity 1.050e1.062 tance is necessary for sexing. The anogenital distance is
longer in males than in females.
Glomerular filtration rate (mL/ 1.01e1.236
The testicular artery and the pampiniform venous
min/100 g bw)
plexus are surrounded by fat as they enter the inguinal
Urine/Plasma insulin (mg/mL) 431 canal. Within the scrotum, several epididymal branches
Clearance of inulin (mL/min/ 857 are given off from the internal spermatic artery to pro-
100 g) vide blood supply to the testes and the epididymis
Clearance of para- 1.341 (Greene, 1963; Constantinescu, 2011).
aminohippurate (mL/min/100 g) The epididymis consists of three sections: the
enlarged caput epididymis on the proximal end of the
Filtration fraction 35%e45%
testis, nearly completely embedded in fat; the slender
Urine flow rate (mL/min/100 g) 4.8e5.2 corpus epididymis lying along the dorsomedial aspect
a of the testis; and cauda epididymis on the distal pole.
Data are approximations only and vary significantly by strain, age, sex, health
status, diet, as well as by the scientific methods used for measurements. For The cauda epididymis doubles upon itself and distally
examples, see the manuscripts cited (Perry, 1965; Flamenbaum et al., 1974; Zabel develops into the ductus deferens (Popesko et al., 2002).
and Schiebler, 1980; Remuzzi, 1988; Loeb, 1999; Wüthrich, 2000; Sutherland, 2016;
The ductus deferens is supplied by the deferential
Everds and Ramaiah, 2018).
blood vessels and runs proximally through the inguinal
canal and crosses the ureter to enter the urethra. The
micropipette can be used to collect from single nephrons gland of the ductus deferens surrounds the duct close
under conditions of free flow. The collected fluid is to its opening into the urethra. The ampullary glands
analyzed and the tubular collection site is identified by originate from the ampullae of the ductus deferens
microdissection (Morsing et al., 1988). Advances in (Whitney, 2018a).

BIOLOGY AND CARE

116 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY

absence of its formation, but it is suspected to act as a

reservoir for the gradual release of sperm or to prevent
the outflow of sperm from the vagina (Sofikitis et al.,
1992; Whitney, 2018b).
The penis lies within a loose prepuce with a single
cartilaginous or bony process, the os penis, on the
ventral wall. A pair of slender and flattened preputial
glands are located beneath the skin of the prepuce
(Popesko et al., 2002).

C. Female Reproductive System

In the female, the ovaries are oriented along the
lateral border of psoas muscle and embedded in fat
near the kidneys. Maturation of the female rat reproduc-
tive tract occurs by about postnatal day 42; by this time
the ovary has completed several ovulatory cycles (Picut
and Remick, 2016b). The mature ovary appears as a
mass of follicles. The convoluted oviduct has its open
end applied to the ovary and its distal end into the
bicornuate uterus. The oviduct is surrounded by the
oviductal mesentery (mesosalpinx) forming the ovarian
bursa. Although the uterine horns appear to be fused
distally, there are two distinct ossa uteri opening into
the vagina. Each ossa uteri has an ostium interim and
FIGURE 4.15 Male urogenital system, ventral view. externum and cervical canal (Fig. 4.16).

The rat has five types of accessory sex glands located

within the pelvis and surrounding the bladder
(Fig. 4.15): the glands of the ductus deferens (ampullary
glands); the prostate, oriented dorsal and ventral to the
ductus deferens; one pair of large scythe-shaped and
convoluted vesicular glands; and one pair of coagulating
glands in close association to the vesicular glands. The
paired bulbourethral glands (Cowper’s glands) are in
association with the bulboglandular muscle. There is
variation in the literature regarding the number of pros-
tatic lobes depending on whether this is defined by gross
anatomical appearance, histology, function, or other spe-
cific morphologic features (Sharma et al., 2008). Multiple
references support dividing the prostate into three or
four paired lobes (sometimes referred to as dorsocranial;
dorsal and lateral, or dorsolateral; and ventral) on the
basis of microscopy (Jesik et al., 1982; Lee and Holland,
1987; Komárek et al., 2000; Whitney, 2018a). However,
incongruity in classification or naming convention still
exists and may in part depend on whether the coagu-
lating gland is counted as a prostatic lobe or as a sepa-
rate gland (Greene, 1963).
The seminal vesicles and coagulating glands are
important for fertility in rats. Both organs secrete fluids
that are necessary for appropriate formation of a vaginal
plug. The role of the vaginal plug is not well understood
beyond the observation that pregnancy is rare in the FIGURE 4.16 Female urogenital system.

BIOLOGY AND CARE

 VII. ENDOCRINE SYSTEM
The only genital structure of the female connected to
the urinary system is the clitoris. This organ is located in
a prepuce with clitoral glands, analogous to the prepu-
tial glands of the male. The bladder empties into the ure-
thra that opens to the perineum at the urethral orifice
located at the base of the clitoris. The vaginal opening
is located dorsal to the urethra. The urethra does not
enter the vagina or vestibule, as is seen in other domestic
mammals (Popesko et al., 2002).
The estrous cycle of the rat is approximately 4e5 days
in duration. During proestrus, serum estrogen and pro-
lactin levels increase until just before ovulation, trig-
gering anatomical changes in the vaginal and uterine
linings and behavioral changes consistent with mating
behavior acceptance. Estrogen also stimulates the
release of follicle stimulating hormone (FSH) to concur-
rently initiate the maturation of the follicles. The estro-
gen secretion continues until the luteinizing hormone
(LH) surge is released on estrus, and ovulation occurs
within 8e14 h. This LH release is closely tied to the
time of day as defined by the light/dark cycle (light on
0500, off 1900). The estrus phase of the cycle is character-
ized by acceptance of the male and superficial squamous
cells in the vagina. This LH surge, in addition to causing
ovulation, also terminates the ongoing estrogen secre-
tion and starts progesterone secretion by the ovary. Pro-
gesterone acts through the nervous system and helps
induce mating behavior. As a result of the lowering of
estrogen secretion and its negative feedback effect on
FSH, the FSH secretion levels are freed to begin
increasing, thus initiating the maturation of the follicles
for the next cycle. A review of hormonal and neurogenic
factors impacting ovarian function and associated feed-
back mechanisms can be found in Ojeda and Skinner
(2006). Hormonal analysis and vaginal cytology are use-
ful when determining the phase of the estrous cycle
(Karim et al., 2003; Westwood, 2008; Paccola et al.,
2013). Vaginal impedance has also been used as an aid
for predicting estrus. This method relies on use of an
impedance probe to measure increases in electrical
resistance of the vaginal wall, and can help optimize
timing of breeder pair set-up and be used to track repro-
ductive aging (Bartos, 1977; Ramos et al., 2001; Single-
tary et al., 2005; Ichihashi et al., 2010; Jaramillo et al.,
2012). A disadvantage of methods that involve stimula-
tion of the vaginal wall is the possible induction of
pseudopregnancy. Implantation of the blastocyst nor-
mally occurs starting on the fifth day postfertilization
but can be delayed in nursing dams (Dickmann and
De Feo, 1967). The gestation period of the rat is approx-
imately 21e23 days.
BIOLOGY AND CARE
117
VII. ENDOCRINE SYSTEM
The endocrine system of the rat has been studied
extensively and is a valuable animal model for explora-
tion of multiple endocrine systems (Eisenbarth and Jasin-
ski, 2004; Hess and Zimmermann, 2004; Makara et al.,
2004; Wong et al., 2004). More specifically, the rat is an
important animal model in the study of diabetes, one of
the most common human endocrine disorders. Several
rat models of diabetes have been described (King,
2012). Commonly used rat models of type 1 diabetes
involve chemical induction with streptozotocin or
alloxan as well as the use of spontaneous autoimmune
models such as BB rats (Srinivasan et al., 2005; Wallis
et al., 2009; Lucchesi et al., 2015). Zucker fatty rats and
Zucker diabetic fatty rats are commonly used rat models
of type 2 diabetes (Király et al., 2007; Schmidt et al., 2013).
A. Hypothalamus
The hypothalamus is typical for mammals. It sur-
rounds the third ventricle at the base of the dienceph-
alon. The hypothalamus is a senso-neuroendocrine
organ that converts neural input into endocrine output
by producing hormones to act upon the pituitary gland.
The hormones produced by the hypothalamus include
gonadotropin-releasing hormone, thyrotropin-releasing
hormone, corticotropin-releasing hormone, growth
hormone-releasing hormone, somatostatin, and
prolactin-releasing and prolactin-inhibiting factors,
including dopamine (Ohkura et al., 2000).
B. Pituitary Gland
The pituitary gland, or hypophysis, is situated within
a bony cavitation called the sella turcica and is sur-
rounded by a meningeal fold. This orientation makes
removal of the hypophysis with the brain difficult. At
about 40e50 days old, the hypophysis of the female be-
comes heavier than that of the male. This difference
tends to increase with age (Dada et al., 1985).
The pituitary gland is divided into the anterior lobe,
the intermediate lobe, and the posterior lobe. The ante-
rior lobe secretes several hormones, including LH;
FSH; thyroid stimulating hormone (TSH); growth hor-
mone; prolactin; and adrenocorticotropic hormone
(ACTH). The intermediate lobe produces melanocyte-
stimulating hormone. The posterior lobe secretes
oxytocin and arginine vasopressin (Ohkura et al., 2000).
118 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
C. Thyroid and Parathyroid
The thyroid gland consists of two lobes connected by
a thin isthmus located on either side of the trachea, just
caudal to the larynx, and extending over four to five
tracheal rings (Komárek et al., 2000). The glands are
characterized histologically by the presence of thyroid
follicles. Colloid is present in the lumen of the follicles
and parafollicular or C cells are located between them
(Komárek et al., 2000).
The thyroid glands secrete hormones important for
metabolism, reproduction, and development. The two
primary hormones are thyroxine (T4) and triiodothyro-
nine (T3) under stimulation by TSH from the pituitary
gland. The C cells of the thyroid secrete calcitonin,
which is important in the regulation of calcium deposi-
tion in bone (Yamamoto et al., 1995).
The parathyroid glands are located on the dorsolat-
eral surface of each lobe of the thyroid and secrete para-
thyroid hormone, which is an antagonist of calcitonin
and plays an important role in calcium homeostasis
(Yamamoto et al., 1995; Mallette, 1991).
D. Adrenals
Adrenal glands in the domesticated laboratory rat are
much smaller than those found in wild rats and are
located at the craniomedial pole of each kidney. The ad-
renal cortex of the gland of the female is also consistently
larger than that of the male (Majchrzak and Malendo-
wicz, 1983). The adrenal gland consists of a cortex and
a medulla. The adrenal cortex is further divided into
three zones: the zona glomerulosa, zona fasciculata,
and zona reticularis (Mulrow, 1986).
Glucocorticoids are steroid hormones secreted by the
zona fasciculata and zona reticularis of the adrenal cortex
in response to release of ACTH from the anterior pitui-
tary during times of physical or psychological stress
(Mulrow, 1986; Sorrells et al., 2009; Milot et al., 2012).
Corticosterone is the primary glucocorticoid of the rat
and can be a useful measure of the stress response in
that species (Mizoguchi et al., 2001; Milot et al., 2012).
Glucocorticoids have effects on many physiological pro-
cesses, including immune and inflammatory responses
(Sorrells et al., 2009; Milot et al., 2012). Additionally, rat
models have been used to investigate the effects of stress
and glucocorticoids on aging, mood, and cognition (McE-
wen and Sapolsky, 1995; Mizoguchi et al., 2001, 2009).
Mineralocorticoids are secreted by the zona glomerulosa
of the adrenal cortex. They are responsible for sodium and
potassium regulation in body fluids. Aldosterone is the
most potent of the mineralocorticoids (Ohkura et al., 2000).
The catecholamines, norepinephrine and epineph-
rine, are produced by the adrenal medulla under direct
neurologic and hormonal control (Mulrow, 1986).
BIOLOGY AND CARE
E. Pancreas
The rat pancreas has a mesenteric pattern and is rela-
tively diffusely dispersed within the duodenal mesen-
tery (Liggitt and Dintzis, 2018). It is a combined
endocrine and exocrine gland that plays an important
role in metabolism and digestion (Ohkura et al., 2000).
In addition to its exocrine functions important for diges-
tion, the islets of Langerhans of the pancreas are impor-
tant in the hormonal control of metabolism. Insulin is
secreted by the B cells of the pancreatic islet cells and
stimulates the uptake of blood glucose into adipose or
muscle cells. Glucagon is secreted by the A cells of the
pancreatic islet cells and stimulates glycogenolysis to in-
crease blood glucose concentrations. Somatostatin is
secreted by the D cells of the pancreatic islets and is
important in metabolic control, but the regulatory mech-
anisms are not fully identified (Ohkura et al., 2000).
F. Reproductive Organs
The reproductive organs also play a role in the
endocrine system. Specifically, the gonads, the uterus,
and the placenta secrete hormones important in regula-
tion of physiologic function.
The gonads secrete steroid hormones, including the
androgens (e.g., testosterone), the estrogens (e.g.,
estrone), and the progestins (e.g., progesterone). The
secretion of these hormones is controlled through feed-
back by the pituitary gland and aid in the coordination
of reproductive events ranging from ovulation to main-
tenance of pregnancy and formation of sperm. The
ovaries also secrete several nonsteroidal hormones:
inhibin, activin, and follistatin.
The uterus secretes prostaglandins and oxytocin,
which play important roles in luteolysis and parturition.
The placenta has been shown to secrete lactogens, which
stimulate progesterone and insulin secretions during
pregnancy (Ohkura et al., 2000).
G. Miscellaneous
Various other organs, not traditionally classified as
endocrine, also are associated with endocrine functions.
Adipose tissue secretes leptin, a hormone that has been
shown to play a role in appetite control and obesity (Pel-
leymounter et al., 1995). The kidney secretes two hor-
mones, renin and angiotensin, which play an important
role in the control of blood pressure (Vallotton et al.,
1990). Melatonin, important in regulation of daily and
seasonal endocrine activity, is secreted by the pineal
gland (Reiter, 1991). The gastrointestinal tract is associ-
ated with four hormones. Gastrin is secreted by the G
cells in the antral stomach and stimulates gastric acid
secretion. Secretin is secreted by the duodenum and
 VIII. NERVOUS SYSTEM
stimulates the release of alkaline juice from the pancreas.
Motilin is secreted by the duodenum and stimulates
gastrointestinal tract motility. Cholecystokinin stimulates
pancreatic enzyme and bile release (Ohkura et al., 2000).
VIII. NERVOUS SYSTEM
The rat has a long and significant history of being a
useful experimental animal model for studies involving
the nervous system. The intent of the discussion pre-
sented here is to summarize major anatomical features
of the nervous system, not to provide in-depth anatom-
ical descriptions or specific model details. The reader is
referred to alternate references (Heidbreder and Groene-
wegen, 2003; Çavdar et al., 2011; Paxinos and Watson,
2013; Jaumard et al., 2015; Paxinos, 2015; Snyder et al.,
2018) for additional detailed anatomical descriptions.
The nervous system is made up of the central nervous
system, brain and spinal cord, and the peripheral ner-
vous system, ganglia and nerves. The central nervous
system and peripheral nervous system together control
both voluntary and involuntary (or autonomic) func-
tions of the body.
A. Central Nervous System
For researchers and scientists studying the brain, the
use of an atlas for a source of stereotaxic coordinates and
anatomic information is essential (Paxinos and Watson,
2013). A detailed, visual atlas will demonstrate impor-
tant anatomic landmarks, such as bregma and lambda
on the skull, and anatomic locations of specific brain re-
gions. The central nervous system is composed of the
brain and spinal cord. A three-layered meninges covers
both structures. The outermost layer is the dura mater.
On the brain, the dura mater is folded between the cere-
bral hemispheres as the falx cerebri and between the ce-
rebrum and cerebellum as the tentorium cerebelli. Along
the spinal cord, the dura mater is the tough outer fibrous
coat that closely invests or surrounds each spinal nerve
for a distance as it branches off from the spinal cord. The
other two layers are difficult to differentiate grossly. The
innermost layer of the meninges is the thin and delicate
pia mater. It adheres to the brain and the spinal cord and
dips into all grooves and depressions. The nonvascular
arachnoid covers the pia mater. This layer does extend
into most of the depressions in the brain (Walker and
Homberger, 1997). The subarachnoid space is the thin
cerebrospinal fluid (CSF)-filled space between the two
meninges. CSF is produced by the vascular pia mater
and drains into venous sinuses within the dura mater.
The brain consists of two large lissencephalic
(smooth; no sulci or gyri) cerebral hemispheres, the
BIOLOGY AND CARE
119
cerebellum, and the medulla oblongata. The two cere-
bral hemispheres are separated by a median fissure.
There is no demarcation between the frontal lobes and
the larger and more caudal temporal lobes. Two large ol-
factory bulbs project from the rostral end of the brain
and are connected to the hippocampal lobes via the ol-
factory tracts. The olfactory nerves terminate at the large
olfactory bulbs after passing through the fenestrated
ethmoid plate from the nasal epithelium (Tran et al.,
2008; Huilgol and Tole, 2016). The convoluted cere-
bellum occupies the major portion of the caudal end of
the brain. It consists of the vermis and two lateral hemi-
spheres (Walker and Homberger, 1997). Between the ce-
rebral hemispheres and the vermis are two pairs of
rounded bodies: the corpora quadrigemina, also known
as the superior and inferior colliculi. The caudal pair (su-
perior colliculi) is associated with acute hearing; the
rostral pair (inferior colliculi) is associated with vision.
The pineal gland is located between the two cerebral
hemispheres and cerebellum. This gland plays a role
in diurnal and seasonal cycles. Melatonin is the hor-
mone secreted by this structure. The most caudal
portion of the brain is composed of the medulla
oblongata as it tapers back and merges into the spinal
cord.
On the ventral aspect of the brain are the origins of the
cranial nerves. The cranial nerves are considered a part
of the peripheral nervous system. Their origins and rela-
tions to the brain are illustrated in Figs. 4.17 and 4.18. A
brief description of each of these nerves is given in
Table 4.5.
Other structures of importance include the pituitary
gland, or hypophysis, consisting of the stalk, the
neurohypophysis, and adenohypophysis (discussed
earlier in this chapter). The hypothalamus (also dis-
cussed earlier in this chapter) is positioned around
the third ventricle caudal to the optic chiasma. On
either side of the infundibulum are fiber tracts, the pen-
dunculi cerebri, which connect the cerebrum and the
medulla oblongata. The fiber tracts and nuclei of the
pons are located caudal to the hypophysis. These tracts
serve as relay centers to connect the cerebellar hemi-
spheres and the cerebral cortex. The pyramids extend
caudally from the pons and carry information from
the cerebral cortex to centers within the spinal cord
(Travers, 2015).
A median sagittal plane view of the brain (Fig. 4.19)
reveals a prominent corpus callosum or middle commis-
sure. This is a white band of fibers linking the two cere-
bral hemispheres. A very small white fiber tract lies
rostral to the intermediate mass and is the rostral
(anterior) commissure. Also identifiable are the crura
cerebri, thickened masses of fibers that lie on the floor
of the brain and link the fore- and hindbrains. Other
structures of importance include the corpora
120 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY

FIGURE 4.17 Lateral view of brain.

FIGURE 4.18 Ventral view of brain.

quadrigemina, the pineal body, the optic chiasm, the me-
dulla oblongata, the arbor vitae of the cerebellum, and
the ventricles of the brain.
The ventricular system of the rat consists of one cen-
tral ventricle (the third) connected with two lateral ones
(first and second), and a caudal one (the fourth). Each
lateral ventricle communicates with the third ventricle
through the interventricular foramen that is on the
ventral side of the anterior horn about 1 mm from its
caudal end (Ozdemir et al, 2005). The cerebral aqueduct
is about 3 mm long and connects the third and fourth
ventricles. The ventricular system communicates with
the cerebral subarachnoid space by two lateral
apertures. This system collects and circulates the CSF
and interstitial fluid. The foramen of Magendie is a me-
dian aperture connecting the fourth ventricle to the
subarachnoid space in humans. The rat brain has
been noted to lack this opening (Levinger, 1971), which
is also true in the mouse (Oda and Nakanishi, 1987),
dog, cat, rabbit, and goat (Coben, 1967). The CSF is pro-
duced by the choroid plexus in the lateral and fourth
ventricles (Snyder et al., 2018). The walls of the third
ventricle contain the subfornical organ, the vascular or-
gan of the lamina terminalis, the pineal body, the sub-
commissural organ, and the median eminence
(associated with the neurohypophysis).

BIOLOGY AND CARE

 VIII. NERVOUS SYSTEM 121
TABLE 4.5 Chart of the Cranial Nerves

Foramen of exit from, or

Name Superficial origin on brain entrance to. cranial cavity Action Distribution

I. Olfactory Olfactory bulb Cribiform plate of ethmoid Sensory Nasal epithelium

II. Optic Anterior corpora bigemina Optic foramen Sensory Retina of eye
and thalamus

III. Oculomotor Pedunculi cerebri
IV. Trochlear Posterior to posterior
corpora bigemina
V. Trigeminal Pons
VI. Abducens Anterior medulla oblongata
VII. Facial Medulla oblogata near V
VIII. Vestibulochlear Medulla oblongata,
posterior to VII
Anterior lacerated foramen
Anterior lacerated foramen
Anterior lacerated foramen
(ophthalmic and dorsal maxillary
branches) and foramen ovale
(ventral maxillary- branch)
Anterior lacerated foramen
Facial canal to stylomstoid
foramen
Internal acoustic meatus
Motor Dorsal, ventral and medical
recti and ventral oblique muscles
Motor Dorsal oblique muscle
Motor and Skin, vibrissae. tongue, teeth,
sensory muscles of mastication
Motor Laterall rectus muscle
Sensory and Facial muscles, tongue,
motor salivary and lacrimal glands
Sensory Organs of equilibrium and
hearing in inner ear

IX. Glossopharyngeal Medulla oblongata near X Posterior lacerated foramen Sensory and Pharynx, tongue, carotid sinus
motor and parotid gland

X. Vagus Medulla oblongata
posterior to VIII
XI. Spinal accessory Medulla oblongata and
anterior end of spinal cord
XII. Hypoglossal Medulla oblongata
posterior to X
Posterior lacerated foramen Sensory and Pharynx, larynx, heart, lungs,
motor diaphragm and stomach
Posterior lacerated foramen Motor Muscles of neck and pharyngeal
viscera with vagus
Hypoglossal canal Motor Intrinsic, extrinsic tongue
muscles

FIGURE 4.19 Median sagittal view of brain.

B. Peripheral Nervous System
The peripheral nervous system is composed of 34
pairs of spinal nerves: 7 cervical, 13 thoracic, 6 lumbar,
4 sacral, and 27e30 caudal (Greene, 1949; Snyder et al.,
2018). The true spinal cord ends at the level of the inter-
vertebral disc between the third and fourth lumbar
vertebrae (Gelderd and Chopin, 1977). The paired spinal
nerves arise from the spinal cord through the interverte-
bral foramina (Gelderd and Chopin, 1977). Each nerve is
formed by dorsal and ventral roots. The dorsal root is
sensory and carries impulses into the spinal cord. The
ventral root carries most fibers away from the spinal
cord. The vasculature of the spinal cord includes the
ventral artery and the bilateral dorsal spinal arteries
(Snyder et al., 2018).

BIOLOGY AND CARE

122 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
The nerves of the peripheral nervous system relay in-
formation in two directions: from the central nervous
system to the periphery, or from the periphery to the
central nervous system. The anatomic components of
the peripheral nervous system include the dorsal and
ventral spinal nerve roots, the ganglia (spinal, dorsal
root, and other sensory), sensory and motor nerves,
and the cranial nerves IIIeXII.
The first cervical nerve lacks a ganglion; the ganglion
of the second cervical nerve lies dorsal to the bifurcation
of the carotid artery. The ganglion of the third cervical
nerve and the first few thoracic ganglia contribute to
the stellate ganglion, located at the level of the first
two thoracic vertebrae. All other spinal ganglia are
enclosed within the vertebral canal. From the stellate
ganglion to the first sacral nerves, the bilateral commu-
nicating ramus connects the spinal nerves with the sym-
pathetic ganglia. Ventral divisions of the nerves form
typical plexuses in the cervical, brachial, and lumbosa-
cral regions. Detailed descriptions of the distribution
of these terminal branches are described elsewhere
(Hebel and Stromberg, 1976).
The brachial plexus gives rise to five major nerves
that supply the forelimb. These include the ulnar nerve
that serves the caudal portion of the forearm, the median
nerve that serves the medial surface of the forelimb, the
axillary nerve that serves the shoulder and lateral sur-
face of the forelimb, the musculocutaneous nerve that
serves the shoulder and upper brachium, and the radial
nerve that serves the upper caudal muscles of the fore-
limb and the lower cranial surface of the forelimb.
The lumbar plexus is formed by the 13th thoracic and
the first four or five lumbar nerves. The major nerves
arising from the lumbar plexus include the femoral
nerve that serves the medial surface of the thigh and
the saphenous nerve that serves the medial surface of
the thigh.
The pelvic plexus arises from the last lumbar and first
sacral nerves. This plexus provides the neural connec-
tions to the genitourinary tract.
The spinal cord terminates in a slender filum termi-
nale. The caudal spinal nerves and the filum terminale
are collectively called the cauda equina (Hebel and
Stromberg, 1976; Snyder et al., 2018).
The autonomic nervous system carries signals con-
trolling involuntary functions. It is composed of two
sympathetic trunks bearing 24 ganglia oriented parallel
bilaterally on the vertebral column. Each trunk commu-
nicates to the ventral root of the spinal nerves. The
eighth, ninth, and tenth thoracic and the first lumbar
sympathetic ganglia give rise to four branches that unite
to form the greater splanchnic nerves on either side.
These two nerves pierce the diaphragm to reach the un-
paired celiac ganglion supplying branches to the dia-
phragm, cranial mesenteric artery, and adjacent viscera.
BIOLOGY AND CARE
The lesser splanchnic arises at the level of the third
lumbar ganglion and supplies additional branches to
the celiac ganglion. The most caudal branches arise
from the third and fourth lumbar ganglia and supply
the aortic and caudal mesenteric plexuses (Hebel and
Stromberg, 1976).
Acknowledgments
This chapter builds upon the related chapter in the 2nd edition of this
text. Portions of text from the previous edition have been retained,
updated and added to. The authors of the present chapter are greatly
indebted to the authors of the previous editions, 2nd edition authors:
John Hofstetter, Mark A. Suckow and Debra L. Hickman. We are also
grateful to the American Association of Laboratory Animal Science
for generously allowing use of selected anatomical diagrams for inclu-
sion in this work.
References
Abdallah, A., Tawfik, J., 1969. The anatomy and histology of the kidney
of sand rats (Psammomys obesus). Z. Versuchstierk 11, 261e275.
Adams, D.J., Ackert-Bicknell, C.L., 2015. Genetic regulation of bone
strength: a review of animal model studies. BoneKEy Rep. 8, 714.
Addison, W., How, H.W., 1921. The development of the eyelids of the
albino rat, until the completion of disjunction. Am. J. Anat. 29,
1e31.
Aharinejad, S., Bock, P., Firbas, W., Schraufnagel, D.E., 1995. Pulmo-
nary lymphatics and their spatial relationship to venous
sphincters. Anat. Rec. 242, 531e544.
Alam, I., Sun, Q., Liu, L., Koller, D.L., Fishburn, T., Carr, L.G.,
Econs, M.J., Foroud, T., Turner, C.H., 2006. Identification of a quan-
titative trait locus on rat chromosome 4 that is strongly linked to
femoral neck structure and strength. Bone 39, 93e99.
Alam, I., Carr, L.G., Liang, T., Liu, Y., Edenberg, H.J., Econs, M.J.,
Turner, C.H., 2010. Identification of genes influencing skeletal
phenotypes in congenic P/NP rats. J. Bone Miner. Res. 25,
1314e1325.
Albuquerque, A.A.S., Rossato, M., Oliveira, J.A.A., Hyppolito, M.A.,
2009. Understanding the anatomy of ears from guinea pigs and
rats and its use in basic otologic research. Braz. J. Otorhinolaryngol.
75, 43e49.
Alev, K., Vain, A., Aru, M., Pehme, A., Purge, P., Kaasik, P., Seene, T.,
2018. Glucocorticoid-induced changes in rat skeletal muscle biome-
chanical and viscoelastic properties: aspects of aging. J. Manip.
Physiol. Ther. 41, 19e24.
Allen, M.R., Newman, C.L., Smith, E., Brown, D.M., Organ, J.M., 2014.
Variability of in vivo reference point indentation in skeletally
mature inbred rats. J. Biomech. 47, 2504e2507.
Almeida, M., Laurent, M.R., Dubois, V., Claessens, F., O’Brien, C.A.,
Bouillon, R., Vanderschueren, D., Manolagas, S.C., 2017. Estrogens
and androgens in skeletal physiology and pathophysiology. Phys-
iol. Rev. 97, 135e187.
Alpern, R.J., Caplan, M.J., Moe, O.W., 2013. Seldin and Giebisch’s the
Kidney Physiology and Pathophysiology, fifth ed. Academic Press,
London.
Alt, J.M., Hackbarth, H., Deerberg, F., Stolte, H., 1980. Proteinuria
in rats related to age-dependent renal changes. Lab. Anim. 14,
95e101.
Amano, O., Iseki, S., 2001. Expression and localization of cell growth
factors in the salivary gland: a review. Kaibogaku Zasshi 76,
201e212.
 REFERENCES
Amano, O., Mizobe, K., Bando, Y., Sakiyama, K., 2012. Anatomy and
histology of rodent and human major salivary glands: doverview
of the Japan Salivary Gland Society-sponsored workshop. Acta His-
tochem. Cytoc. 45, 241e250.
Aoki, T., Taira, K., Shibasaki, S., Fujimoto, T., 1995. The cytological and
immunohistochemical study of septal cells in the rat lung. Acta His-
tochem. Cytoc. 28, 349e355.
Artal, P., Herreros de Tejada, P., Muñoz Tedó, C., Green, D.G., 1998.
Retinal image quality in the rodent eye. Vis. Neurosci. 15, 597e605.
Atanasova, D.Y., Iliev, M.E., Lazarov, N.E., 2011. Morphology of the rat
carotid body. Biomed. Rev. 22, 41e55.
Bachmann, S., Kriz, W., 1998. Histology, cytology, ultrastructure:
nephron and collecting duct structure in the kidney, rat. In:
Jones, T.C., Hard, G.C., Mohr, U. (Eds.), Urinary System [Mono-
graphs on Pathology of Domestic Animals], second ed. Springer-
Verlag, Heidelberg, pp. 3e36.
Badea, C.T., Bucholz, E., Hedlund, L.W., Rockman, H.A.,
Johnson, G.A., 2006. Imaging methods for morphological and func-
tional phenotyping of the rodent heart. Toxicol. Pathol. 34, 111e117.
Bader, M., 2010. Rat models of cardiovascular diseases. Methods Mol.
Biol. 597, 403e414.
Bagi, C.M., Berryman, E., Moalli, M.R., 2011. Comparative bone anat-
omy of commonly used laboratory animals: implications for drug
discovery. Comp. Med. 61, 76e85.
Bankir, L., de Rouffignac, C., 1985. Urinary concentrating ability: in-
sights from comparative anatomy. Am. J. Physiol. 249, 643e666.
Barre, S.F., Haberthur, D., Cremona, T.P., Stampanoni, M., Schittny, J.C.,
2016. The total number of acini remains constant throughout post-
natal rat lung development. Am. J. Physiol. Lung Cell Mol. Physiol.
311, 1082e1089.
Barthold, S.W., Percy, D.H., Griffey, S.M., 2016. Pathology of Labora-
tory Rodents and Rabbits, fourth ed. Wiley Blackwell, Ames, IA.
Bartos, L., 1977. Vaginal impedance measurement used for mating in
the rat. Lab. Anim. 11, 53e55.
Bastacky, J., Lee, C.Y., Goerke, J., Koushafar, H., Yager, D., Kenaga, L.,
Speed, T.P., Chen, Y., Clements, J.A., 1995. Alveolar lining layer is
thin and continuous: low-temperature scanning electron micro-
scopy of rat lung. J. Appl. Physiol. 79, 1615e1628.
Beaumont, S., 2002. Ocular disorders of pet mice and rats. Vet. Clin.
Exot. Anim. 5, 311e324.
Beidler, L.M., Smallman, R.L., 1965. Renewal of cells within taste buds.
J. Cell Biol. 27, 263e272.
Benke, K., Sayour, A.A., Mátyás, C., Ágg, B., Németh, B.T., Oláh, A.,
Ruppert, M., Hartyánszky, I., Szabolcs, Z., Radovits, T.,
Merkely, B., Szabó, G., 2017. Heterotopic abdominal rat heart trans-
plantation as a model to investigate volume dependency of
myocardial remodeling. Transplantation 101, 498e505.
Berg, R.W., Kleinfeld, D., 2003. Rhythmic whisking by rat: retraction as
well as protraction of the vibrissae is under active muscular control.
J. Neurophysiol. 89, 104e117.
Bergin, M., Vlajkovic, S., Bird, P., Thorne, P., 2013. Systematic review of
animal models of middle ear surgery. World J. Otorhinolaryngol. 3,
71e88.
Bind, R.H., Minney, S.M., Rosenfeld, S., Hallock, R.M., 2013. The role of
pheromonal responses in rodent behavior: future directions for the
development of laboratory protocols. J. Am. Assoc. Lab. Anim. Sci.
52, 124e129.
Bivin, W.S., Crawford, P., Brewer, N.R., 1979. Morphophysiology. In:
Baker, H.J., Lindsey, J.R., Weisbroth, S.H. (Eds.), The Laboratory
Rat, first ed. Academic Press, New York, NY, pp. 73e103.
Blazsek, J., Varga, G., 1999. Secretion from minor salivary glands
following ablation of the major salivary glands in rats. Arch. Oral
Biol. 44, 45e48.
Blom, H.J.M., Van Tintelen, G., Baumans, V., Van den Broek, J.,
Beynen, A.C., 1995. Development and application of a preference
BIOLOGY AND CARE
123
test system to evaluate housing conditions for laboratory rats.
Appl. Anim. Behav. Sci. 43, 279e290.
Boorman, G.A., 1990. Pathology of the Fischer Rat: Reference and
Atlas, first ed. Academic Press, San Diego, CA.
Boyd, K.L., Muehlenbach, A., Rendi, M.H., Garcia, R.L., Gibson-
Corley, K.N., 2018. Female reproductive system. In:
Treuting, P.M., Dintzis, S.M., Montine, K.S. (Eds.), Comparative
Anatomy and Histology: A Mouse, Rat, and Human Atlas, second
ed. Academic Press, London, pp. 303e334.
Boyne, R., Fell, B.F., Robb, I., 1966. The surface area of the intestinal mu-
cosa in the lactating rat. J. Physiol. 183, 570e575.
Brann, J.H., Firestein, S.J., 2014. A lifetime of neurogenesis in the olfac-
tory system. Front. Neurosci. 8, 182.
Braun, J.P., Lefebvre, H.P., 2008. Kidney function and damage. In:
Kaneko, J.J., Harvey, J.W., Bruss, M.L. (Eds.), Clinical Biochemistry
of Domestic Animals, sixth ed. Academic Press, Burlington, MA,
pp. 485e528.
Brennan, P., Keverne, E.B., 2015. Biological complexity and adapt-
ability of simple mammalian olfactory memory systems. Neurosci.
Biobehav. Rev. 50, 29e40.
Bruce, M.C., Honaker, C.E., Cross, R.J., 1999. Lung fibroblasts undergo
apoptosis following alveolarization. Am. J. Respir. Cell Mol. Biol.
20, 228e236.
Brudzynski, S.M., 2007. Ultrasonic calls of rats as indicator variables of
negative or positive states: acetylcholine-dopamine interaction and
acoustic coding. Behav. Brain Res. 182, 261e273.
Buetow, B.S., Laflamme, M.A., 2018. Cardiovascular. In: Treuting, P.M.,
Dintzis, S.M., Montine, K.S. (Eds.), Comparative Anatomy and His-
tology: A Mouse, Rat, and Human Atlas, second ed. Academic
Press, London, pp. 163e188.
Burda, H., Voldrick, L., 1980. Correlation between the hair cell density and
the auditory threshold in the white rat. Hear. Res. 3, 91e93.
Burri, P.H., 1974. The postnatal growth of the rat lung. 3. Morphology.
Anat. Rec. 180, 77e98.
Cabrera, C.L., Wagner, L.A., Schork, M.A., Bohr, D.F., Cohan, B.E., 1999.
Intraocular pressure measurement in the conscious rat. Acta Oph-
thalmol. Scand. 77, 33e36.
Cai, R., Montgomery, S.C., Graves, K.A., Caspary, D.M., Cox, B.C.,
2018. The FBN rat model of aging: investigation of ABR waveforms
and ribbon synapse changes. Neurobiol. Aging 62, 53e63.
Cairns, J.E., 1959. Normal development of the hyaloid and retinal ves-
sels in the rat. Br. J. Ophthalmol. 43, 385e393.
Car, B.D., Eng, V.M., Everds, N.E., Bounouns, D.I., 2006. Clinical pa-
thology of the rat. In: Sukow, M.A., Weisbroth, S.H.,
Franklin, C.L. (Eds.), The Laboratory Rat, second ed. Academic
Press, San Diego, CA, pp. 127e146.
Cardiff, R.D., Jindal, S., Treuting, P.M., Going, J.J., Gusterson, B.,
Thompson, H.J., 2018. Mammary gland. In: Treuting, P.M.,
Dintzis, S.M., Montine, K.S. (Eds.), Comparative Anatomy and His-
tology: A Mouse, Rat, and Human Atlas, second ed. Academic
Press, London, pp. 487e509.
Carper, D., Russell, P., Shinohara, T., Kinoshita, J.H., 1985. Differential
synthesis of rat lens proteins during development. Exp. Eye Res. 40,
85e94.
Çavdar, S., Hacio glu, H., Sirvanci, S., Keskinöz, E., Onat, F., 2011. Syn-
aptic organization of the rat thalamus: a quantitative study. Neurol.
Sci. 32, 1047e1056.
Cesta, M.F., Dixon, D., Herbert, R.A., Staska, L.M., 2014. Lung - meta-
plasia, goblet cell. In: Cesta, M.F., Herbert, R.A., Brix, A.,
Malarkey, D.E., Sills, R.C. (Eds.), National Toxicology Program
Nonneoplastic Lesion Atlas. https://ntp.niehs.nih.gov/nnl/
respiratory/lung/metapgc/index.htm.
Chan, K.Y., Byers, M.R., 1985. Sensory nerve endings of the incisive
papilla of rat hard palate studied by peroxidase cytochemical
methods. J. Comp. Neurol. 234, 192e200.
124 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
Chang, L.Y., Mercer, R.R., Crapo, J.D., 1986. Differential distribution of
brush cells in the rat lung. Anat. Rec. 216, 49e54.
Chau, K., Hutton, H., Levin, A., 2016. Laboratory assessment of kidney
disease: glomerular filtration rate, urinalysis, and proteinuria. In:
Skorecki, K., Chertow, G.M., Marsden, P.A., Taal, M.W., Yu, S.L.A.
(Eds.), Brenner & Rector’s the Kidney, tenth ed. Elsevier, Philadel-
phia, pp. 780e803.
Chen, H.B., Yamabayashi, S., Ou, B., Tanaka, Y., Ohno, S., Tsukahara, S.,
1997. Structure and composition of rat precorneal tear film. A study
by an in vivo cryofixation. Investig. Ophthalmol. Vis. Sci. 38,
381e387.
Chen, J., Ceholski, D.K., Turnbull, I.C., Liang, L., Hajjar, R.J., 2018.
Ischemic model of heart failure in rats and mice. Methods Mol.
Biol. 1816, 175e182.
Chiasson, R.B., 1958. Laboratory Anatomy of the White Rat. W.C.
Brown, Dubuque, IA.
Chowdhury, P., Long, A., Harris, G., Soulsby, M.E., Dobretsov, M.,
2013. Animal model of simulated microgravity: a comparative
study of hindlimb unloading via tail versus pelvic suspension.
Phys. Rep. 1, e00012. https://doi.org/10.1002/phy2.12.
Christiansen, T., Rasch, R., Stodkilde-Jorgensen, H., Flyvbjerg, A., 1997.
Relationship between MRI and morphometric kidney measure-
ments in diabetic and non-diabetic rats. Kidney Int 51, 50e56.
Christensen, E.I., Wagner, C.A., Kaissling, B., 2012. Uriniferous tubule:
structural and functional organization. Comp. Physiol. 2, 805e861.
Christensen, E.I., Grann, B., Kristoffersen, I.B., Skriver, E.,
Thomsen, J.S., Andreasen, A., 2014. Three-dimensional recon-
struction of the rat nephron. Am. J. Physiol. Renal. Physiol. 306,
664e671.
Cicone, F., Viertl, D., Pousa, A.M.Q., Denoel, T., Gnesin, S.,
Scopinaro, F., Vozenin, M.C., Prior, J.O., 2017. Cardiac radionuclide
imaging in rodents: a review of methods, results and factors at play.
Front. Med. 4, 1e11.
Cleaton-Jones, P., 1971. Histological observations in the soft palate of
the albino rat. J. Anat. 110, 39e47.
Cleaton-Jones, P., 1972. Anatomical observations in the soft palate of
the albino rat. Anat. Anzeiger 131, 419e424.
Clough, G., 1982. Environmental effects on animals used in biomedical
research. Biol. Rev. 57, 487e523.
Coben, L.A., 1967. Absence of a foramen of Magendie in the dog, cat,
rabbit, and goat. Arch. Neurol. 16, 524e528.
Constantinescu, G.M., 2011. Comparative Anatomy of the Mouse and
the Rat: A Color Atlas and Text. American Association for Labora-
tory Animal Science, Memphis, TN.
Contin, M., Arietti, M., Benedetto, M., Bussi, C., Guido, M., 2013.
Photoreceptor damage induced by low-intensity light: model of
retinal degeneration in mammals. Mol. Vis. 19, 1614e1625.
Crapo, J.D., Young, S.L., Fram, E.K., Pinkerton, K.E., Barry, B.E.,
Crapo, R.O., 1983. Morphometric characteristics of cells in the alve-
olar region of mammalian lungs. Am. Rev. Respir. Dis. 128 (2 Pt 2),
42e46.
Curcio, C.A., Allen, K.A., 1990. Topography of ganglion cells in human
retina. J. Comp. Neurol. 300, 5e25.
Dada, M.O., Rodriguez-Sierra, J.F., Blake, C.A., 1985. Sex differences in
the anterior pituitary gland. In: Gilles, R., Balthazart, J. (Eds.),
Neurobiology: Current Comparative Approaches. Springer-
Verlag, Berlin and Heidelberg, pp. 220e247.
Dampney, R.A., 1994. Functional organization of central pathways
regulating the cardiovascular system. Physiol. Rev. 74, 323e364.
Dantzler, W.H., Layton, A.T., Layton, H.E., Pannabecker, T.L., 2014.
Urine-concentrating mechanism in the inner medulla: function of
the thin limbs of the loops of Henle. Clin. J. Am. Soc. Nephrol. 9,
1781e1789.
Dauchy, R., Wren, M., Dauchy, E., Hoffman, A., Hanifin, J., Warfield, B.,
Jablonski, M., Brainard, G., Hill, S., Mao, L., Dobek, G., Dupepe, L.,
Blask, D., 2015. The influence of red light exposure at night on
BIOLOGY AND CARE
circadian metabolism and physiology in Sprague-Dawley rats.
J. Am. Assoc. Lab. Anim. Sci. 54, 40e50.
de Bakker, C.M., Altman-Singles, A.R., Li, Y., Tseng, W.J., Li, C.,
Liu, X.S., 2017a. Adaptations in the microarchitecture and load dis-
tribution of maternal cortical and trabecular bone in response to
multiple reproductive cycles in rats. J. Bone Miner. Res. 32,
1014e1026.
de Bakker, C.M.J., Tseng, W.J., Li, Y., Zhao, H., Altman-Singles, A.R.,
Jeong, Y., Robberts, J., Han, L., Kim, D.G., Sherry Liu, X., 2017b.
Reproduction differentially affects trabecular bone depending on
its mechanical versus metabolic role. J. Biomech. Eng. 139,
1110061e11100610.
Delaney, M.A., Kowalewska, J., Treuting, P.M., 2018. Urinary system.
In: Treuting, P.M., Dintzis, S.M., Montine, K.S. (Eds.), Comparative
Anatomy and Histology: A Mouse, Rat, and Human Atlas, second
ed. Academic Press, London, pp. 275e302.
DeSesso, J.M., Jacobson, C.F., 2001. Anatomical and physiological pa-
rameters affecting gastrointestinal absorption in humans and rats.
Food Chem. Toxicol. 39, 209e228.
Diamond, M.E., Arabzadeh, E., 2013. Whisker sensory system - from
receptor to decision. Prog. Neurobiol. 103, 28e40.
Dickmann, Z., De Feo, V.J., 1967. The rat blastocyst during normal
pregnancy and during delayed implantation, including an
observation on the shedding of the zona pellucida. J. Reprod. Fertil.
13, 3e9.
Diehl, K.H., Hull, R., Morton, D., Pfister, R., Rabemampianina, Y.,
Smith, D., Vidal, J.M., van de Vorstenbosch, C., 2001. A good prac-
tice guide to the administration of substances and removal of blood,
including routes and volumes. J. Appl. Toxicol. 21, 15e23.
Dillmann, W.H., 2008. The rat as a model for cardiovascular disease.
Drug Discov. Today Dis. Model. 5, 173e178.
Doggrell, S.A., Brown, L., 1998. Rat models of hypertension, cardiac
hypertrophy and failure. Cardiovasc. Res. 39, 89e105.
Dormans, J.A., 1983. The ultrastructure of various cell types in the lung
of the rat: a survey. Exp. Pathol. 24, 15e33.
Driskell, R.R., Giangreco, A., Jensen, K.B., Mulder, K.W., Watt, F.M.,
2009. Sox2-positive dermal papilla cells specify hair follicle type
in mammalian epidermis. Development 136, 2815e2823.
Dunn, D.G., Baker, J., Sorden, S.D., 2018. Eye and associated glands. In:
Suttie, A.W. (Ed.), Boorman’s Pathology of the Rat, second ed. Ac-
ademic Press, London, pp. 253e254.
Dunne, A.A., Steinke, L., Teymoortash, A., Kuropkat, C., Folz, B.J.,
Werner, J.A., 2004. The lymphatic system of the major head and
neck glands in rats. Otolaryngol. Pol. 58, 121e130.
Dyce, K.M., Sack, W.O., Wensing, C.J.G., 1987. Textbook of Veterinary
Anatomy, second ed. W.B. Saunders Company, Philadelphia, PA.
d’Uscio, L.V., Kilo, J., Lı̈scher, T.F., Gassmann, M., 2000. Circulation. In:
Krinke, G.J. (Ed.), The Laboratory Rat. Academic Press, London,
pp. 345e357.
Ebeling, P.R., 2010. Androgens and osteoporosis. Curr. Opin. Endocri-
nol. Diabetes Obes. 17, 284e292.
Edwards, G.A., Porter, C.J., Caliph, S.M., Khoo, S.M., Charman, W.N.,
2001. Animal models for the study of intestinal lymphatic drug
transport. Adv. Drug Deliv. Rev. 50, 45e60.
Edwards, T.L., Cox, C., Weetjens, B., Tewelde, T., Poling, A., 2015. Giant
African pouched rats (Cricetomys gambianus) that work on tilled soil
accurately detect landmines. J. Appl. Behav. Anal. 48, 696e700.
Eisenbarth, G.S., Jasinski, J.M., 2004. Disease prevention with islet
autoantigens. Endocrinol Metab. Clin. N. Am. 33, 59e73.
El Sharaby, A., Ueda, K., Kurisu, K., Wakisaka, S., 2001. Development
and maturation of taste buds of the palatal epithelium of the rat:
histological and immunohistochemical study. Anat. Rec. 263,
260e268.
Ellis, H., Mulder, C., Valverde, E., Poling, A., Edwards, T., 2017. Repro-
ducibility of African giant pouched rats detecting Mycobacterium
tuberculosis. BMC Infect. Dis. 17, 298.
 REFERENCES
Emmelin, N., 1981. Nervous control of mammalian salivary glands.
Philos. Trans. R. Soc. Lond. B Biol. Sci. 296, 27e35.
Enhorning, G., Duffy, L.C., Welliver, R.C., 1995. Pulmonary surfactant
maintains patency of conducting airways in the rat. Am. J. Respir.
Crit. Care Med. 151, 554e556.
Esau, P.J., Gittemeier, E.M., Opoku-Acheampong, A.B., Rollins, K.S.,
Baumfalk, D.R., Poole, D.C., Musch, T.I., Behnke, B.J., Copp, S.W.,
2017. Prostate cancer reduces endurance exercise capacity in associ-
ation with reductions in cardiac and skeletal muscle mass in the rat.
Am. J. Cancer Res. 7, 2566e2576.
Evans, M.J., Van Winkle, L.S., Fanucchi, M.V., Plopper, C.G., 2001.
Cellular and molecular characteristics of basal cells in airway
epithelium. Exp. Lung Res. 27, 401e415.
Everds, N.E., Ramaiah, L., 2018. The laboratory rat. In: Kurtz, D.M.,
Travlos, G.S. (Eds.), The Clinical Chemistry of Laboratory Animals,
third ed. CRC Press, Boca Raton, FL, pp. 33e78.
Everson, C.A., Folley, A.E., Toth, J.M., 2012. Chronically inadequate
sleep results in abnormal bone formation and abnormal bone
marrow in rats. Exp. Biol. Med. 237, 1101e1109.
Farris, E.J., Griffith, J.Q., 1949. The Rat in Laboratory Investigation. Lip-
pincott, Philadelphia, PA.
Ferreira, P.G., Silva, A.C., Aguas, A.P., Pereira, A.S., Grande, N.R., 2001.
Detailed arrangement of the bronchial arteries in the Wistar rat: a
study using vascular injection and scanning electron microscopy.
Eur. J. Anat. 5, 67e76.
Festing, M.F.W., Lutz, C., 2011. Laboratory animal genetics and genetic
quality control. In: Hau, J.S., Schapiro, S.J. (Eds.), Handbook of Lab-
oratory Animal Science, Essential Principles and Practices, third
ed., vol. 1. CRC Press, Boca Raton, FL, pp. 209e249.
Fiegel, H.C., Rolle, U., Metzger, R., Geyer, C., Till, H., Kluth, D., 2010.
The testicular descent in the rat: a scanning electron microscopic
study. Pediatr. Surg. Int. 26, 643e647.
Fitts, R.H., Troup, J.P., Witzmann, F.A., Holloszy, J.O., 1984. The effect
of ageing and exercise on skeletal muscle function. Mech. Ageing
Dev. 27, 161e172.
Flamenbaum, W., Huddleston, M.L., McNeil, J.S., Hamsburger, R.J.,
1974. Uranyl nitrate-induced acute renal failure in the rat: micro-
puncture and renal hemodynamic studies. Kidney Int 6, 408e418.
Fu, X., Segiser, A., Carrel, T.P., Tevaearai Stahel, H.T., Most, H., 2016.
Rat heterotopic heart transplantation model to investigate
unloading-induced myocardial remodeling. Front. Cardiovasc.
Med. 3, 1e12.
Fukuoka, C.Y., Simoes, A., Uchiyama, T., Arana-Chavez, V.E.,
Abiko, Y., Kuboyama, N., Bhawal, U.K., 2017. The effects of low-
power laser irradiation on inflammation and apoptosis in subman-
dibular glands of diabetes-induced rats. PLoS One 12, e0169443.
https://doi.org/10.1371/journal.pone.0169443.
Fuller, P.M., Huelke, D.F., 1973. Kidney vascular supply in the rat, cat
and dog. Acta Anat. 84, 516e522.
Gelderd, J.B., Chopin, S.F., 1977. The vertebral level of origin of spinal
nerves in the rat. Anat. Rec. 188, 45e47.
Gipson, I.K., Yankauckas, M., Spurr-Michaud, S.J., Tisdale, A.S.,
Rinehart, W., 1992. Characteristics of a glycoprotein in the ocular
surface glycocalyx. Investig. Ophthalmol. Vis. Sci. 33, 218e227.
Goldblum, D., Kontiola, A.I., Mittag, T., Chen, B., Danias, J., 2002. Non-
invasive determination of intraocular pressure in the rat eye. Com-
parison of an electronic tonometer (TonoPen), and a rebound
(impact probe) tonometer. Graefes Arch. Clin. Exp. Ophthalmol.
240, 942e946.
Gomes, R.F.M., Shen, X., Ramchandani, R., Tepper, R.S., Bates, J.H.,
2000. Comparative respiratory system mechanics in rodents.
J. Appl. Physiol. 89, 908e916.
Goutianos, G., Tzioura, A., Kyparos, A., Paschalis, V.,
Margaritelis, N.V., Veskoukis, A.S., Zafeiridis, A., Dipla, K.,
Nikolaidis, M.G., Vrabas, I.S., 2015. The rat adequately reflects hu-
man responses to exercise in blood biochemical profile: a
BIOLOGY AND CARE
125
comparative study. Phys. Rep. 3, e12293. https://doi.org/10.
14814/phy2.12293.
Greaves, P., 2012. Histopathology of Preclinical Toxicity Studies: Inter-
pretation and Relevance in Drug Safety Studies, fourth ed. Aca-
demic Press, London.
Greeley, M.A., 2016. Respiratory system. In: Parker, G.A., Picut, C.A.
(Eds.), Atlas of Histology of the Juvenile Rat. Academic Press, Lon-
don, pp. 89e125.
Greeley, M.A., White-Hunt, S.J., 2016. Cardiovascular system. In:
Parker, G.A., Picut, C.A. (Eds.), Atlas of Histology of the Juvenile
Rat. Academic Press, London, pp. 423e437.
Greene, E.C., 1935. Anatomy of the Rat, vol. 27. American Philosoph-
ical Society, Philadelphia, PA.
Greene, E.C., 1949. Gross anatomy. In: Farris Jr., E.J., Griffin, Q.J. (Eds.),
The Rat in Laboratory Investigation. J.B. Lippincott Co., Philadel-
phia, PA, pp. 24e50.
Greene, E.C., 1963. Anatomy of the Rat, vol. 27. Hafner Pub. Co., New
York.
Groth-Vasselli, B., Farnworth, P.N., 1986. A critical maturation period
in neonatal-rat-lens development. Exp. Eye Res. 43, 1057e1066.
Halata, A., Baumann, K.I., 1999. Sensory nerve endings in the hard pal-
ate and papilla incisive of the rhesus monkey. Anat. Embryol. 199,
427e437.
Hall, H.D., Schneyer, C.A., 1964. Paper electrophoresis of rat salivary
secretions. Proc. Soc. Exp. Biol. Med. 115, 1001e1005.
Halpern, M.H., 1957. The dual blood supply of the rat heart. Am. J.
Anat. 101, 1e16.
Hamilton, A.I., Blackwood, H.J., 1974. Cell renewal of oral mucosal
epithelium of the rat. J. Anat. 117, 313e327.
Hamosh, M., Hand, A.R., 1978. Development of secretory activity in se-
rous cells of the rat tongue: cytological differentiation and accumu-
lation of lingual lipase. Dev. Biol. 65, 100e113.
Hand, A.R., Pathmanathan, D., Field, R.B., 1999. Morphological fea-
tures of the minor salivary glands. Arch. Oral Biol. 44 (Suppl. 1),
3e10.
Harada, S., Yamaguchi, K., Kanemaru, N., Kasahara, Y., 2000. Matura-
tion of taste buds on the soft palate of the postnatal rat. Physiol.
Behav. 68, 333e339.
Harkema, J.R., 1990. Comparative pathology of the nasal mucosa in
laboratory animals exposed to inhaled irritants. Environ. Health
Perspect. 85, 231e238.
Harkema, J.R., Carey, S.A., Wagner, J.G., Dintzis, S.M., Liggitt, D., 2018.
Nose, sinus, pharynx, and larynx. In: Treuting, P.M., Dintzis, S.M.,
Montine, K.S. (Eds.), Comparative Anatomy and Histology: A
Mouse, Rat, and Human Atlas, second ed. Academic Press, Lon-
don, pp. 89e114.
Harrison, R.T., Seiler, B.M., Bielefeld, E.C., 2016. Ototoxicity of 12 mg/
kg cisplatin in the Fischer 344/NHsd rat using multiple dosing
strategies. Anti Canccer Drugs 27, 780e786.
Hatakeyama, S., Sashima, M., Suzuki, A., 1987. A sexual dimorphism
of mucous cells in the submandibular salivary gland of rat. Arch.
Oral Biol. 32, 689e693.
Hebb, C., 1969. Motor innervation of the pulmonary blood vessels of
mammals. In: Fishman, A.P., Hecht, H.H. (Eds.), The Pulmonary
Circulation and Interstitial Space. University of Chicago Press, Chi-
cago, IL, pp. 195e222.
Hebel, R., Stromberg, M.W., 1976. Anatomy of the Laboratory Rat. The
Williams & Wilkins Co., Baltimore, MD.
Heffner, R., Heffner, H., 1992. Visual factors in sound localization in
mammals. J. Comp. Neurol. 317, 219e232.
Heffner, H.E., Heffner, R.S., Contos, C., Ott, T., 1994. Audiogram of the
hooded Norway rat. Hear. Res. 73, 244e247.
Heidbreder, C.A., Groenewegen, H.J., 2003. The medial prefrontal cor-
tex in the rat: evidence for a dorso-ventral distinction based upon
functional and anatomical characteristics. Neurosci. Biobehav.
Rev. 27, 555e579.
126 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
Heller, H., 1949. Effects of dehydration on adult and newborn rats.
J. Physiol. 108, 303e314.
Herness, S., Zhao, F.L., Kaya, N., Lu, S.G., Shen, T., Sun, X.D., 2002.
Adrenergic signaling between rat taste receptor cells. J. Physiol.
543, 601e614.
Herrero, M.C., Remesar, X., Blade, C., Arola, L., 1997. Amino acid meta-
bolism in the kidneys of genetic and nutritionally obese rats. Bio-
chem. Mol. Biol. Int. 42, 261e269.
Hess, S.Y., Zimmermann, M.B., 2004. The effect of micronutrient defi-
ciencies on iodine nutrition and thyroid metabolism. Int. J. Vitam.
Nutr. Res. 74, 103e115.
Heywood, R., 1973. Some clinical observations on the eyes of Sprague-
Dawley rats. Lab. Anim. 7, 19e27.
Hillier, M.L., Bell, L.S., 2007. Differentiating human bone from animal
bone: a review of histological methods. J. Forensic Sci. 52, 249e263.
Hislop, A., Reid, L., 1978. Normal structure and dimensions of the pul-
monary arteries in the rat. J. Anat. 125 (Pt 1), 71e83.
Hofstetter, J., Suckow, M.A., Hickman, D.L., 2006. Morphophysiology.
In: Suckow, M.A., Weisbroth, S., Franklin, C. (Eds.), The Laboratory
Rat, second ed. Academic Press, Burlington, MA, pp. 93e125.
Horn, C.C., Kimball, B.A., Wang, H., Kaus, J., Daniel, S., Nagy, A., et al.,
2013. Why can’t rodents vomit? A comparative behavioral, anatom-
ical, and physiological study. PLoS One 8, e60537. https://doi.org/
10.1371/journal.pone.0060537.
Hosoyamada, Y., Ichimura, K., Koizumi, K., Sakai, T., 2010. Structural
organization of pulmonary veins in the rat lung, with special
emphasis on the musculature consisting of cardiac and smooth
muscles. Anat. Sci. Int. 85, 152e159.
Hrapkiewicz, K., Colby, L., Denison, P., 2013. Clinical Laboratory Ani-
mal Medicine, fourth ed. Wiley-Blackwell, Ames, IA.
Hughes, A., 1979. A schematic eye for the rat. Vis. Res. 19, 569e588.
Hughes, P.C., Tanner, J.M., 1970a. A longitudinal study of the growth of
the black-hooded rat: methods of measurement and rates of growth
for skull, limbs, pelvis, nose-rump and tail lengths. J. Anat. 106,
349e370.
Hughes, P.C., Tanner, J.M., 1970b. The assessment of skeletal maturity
in the growing rat. J. Anat. 106, 371e402.
Huilgol, D., Tole, S., 2016. Cell migration in the developing rodent ol-
factory system. Cell. Mol. Life Sci. 73, 2467e2490.
Hukkanen, R.R., Dintzis, S.M., Treuting, P.M., 2018. Salivary glands. In:
Treuting, P.M., Dintzis, S.M., Montine, K.S. (Eds.), Comparative
Anatomy and Histology: A Mouse, Rat, and Human Atlas, second
ed. Academic Press, London, pp. 135e145.
Ichihashi, M., Hasegawa, M., Imahie, H., Nishida, A., Kitamura, K.,
2010. Effects of Nanpao, a kampo medicine, on the decline in
estrous cyclicity with advancing age in female rats, as measured
by vaginal impedance methods. Exp. Anim. 59, 85e93.
Ichii, O., Yabuki, A., Ojima, T., Matsumoto, M., Suzuki, S., 2006. Species
specific differences in the ratio of short to long loop nephrons in the
kidneys of laboratory rodents. Exp. Anim. 55, 473e476.
Iida, M.I.Y., Yoshioka, I., Muto, H., 1983. Taste bud papillae on the ret-
romolar mucosa of the rat, mouse and golden hamster. Acta Anat.
117, 374e381.
Inomata, T., Eguchi, Y., Nakamura, T., 1985. Development of the
external genitalia in rat fetuses. Jikken Dobutsu 34, 439e444.
Inoue, D., Furubayashi, T., Ogawara, K., Kimura, T., Higaki, K.,
Shingaki, T., Kimura, S., Tanaka, A., Katsumi, H., Sakane, T.,
Yamamoto, A., Higashi, Y., 2013. In vitro evaluation of the ciliary
beat frequency of the rat nasal epithelium using a high-speed dig-
ital imaging system. Biol. Pharm. Bull. 36, 966e973.
Ito, K., Morikawa, M., Inenaga, K., 2001. The effect of food consistency
and dehydration on reflex parotid and submandibular salivary
secretion in conscious rats. Arch. Oral Biol. 46, 353e363.
Iwasaki, S., Yoshizawa, H., Kawahara, I., 1997. Study by scanning elec-
tron microscopy of the morphogenesis of three types of lingual
papilla in the rat. Anat. Rec. 247, 528e541.
BIOLOGY AND CARE
Jacobs, G.H., Fenwick, J.A., Williams, G.A., 2001. Cone-based vision
of rats for ultraviolet and visible lights. J. Exp. Biol. 204,
2439e2446.
Jakowski, R.M., 1982. Renal tubular epithelium lining parietal layer of
Bowman’s capsule in adult Long Evans rats. Vet. Pathol. 19,
212e215.
Jando, J., Camargo, S.M.R., Herzog, B., Verrey, F., 2017. Expression and
regulation of the neutral amino acid transporter B0AT1 in rat small
intestine. PLoS One 12, e0184845. https://doi.org/10.1371/journal.
pone.0184845.
Jaramillo, L.M., Balcazar, I.B., Duran, C., 2012. Using vaginal wall
impedance to determine estrous cycle phase in Lewis rats. Lab.
Anim. 41, 122e128.
Jaumard, N.V., Leung, J., Gokhale, A.J., Guarino, B.B., Welch, W.C.,
Winkelstein, B.A., 2015. Relevant anatomic and morphological
measurements of the rat spine: considerations for rodent models
of human spine trauma. Spine 40, 1084e1092.
Jeffery, P.K., Reid, L., 1975. New observations of rat airway epithelium:
a quantitative and electron microscopic study. J. Anat. 120 (Pt 2),
295e320.
Jerome, C., Hoch, B., Carlson, C.S., 2018. Skeletal system. In:
Treuting, P.M., Dintzis, S.M., Montine, K.S. (Eds.), Comparative
Anatomy and Histology: A Mouse, Rat, and Human Atlas, second
ed. Academic Press, London, pp. 67e88.
Jesik, C.J., Holland, J.M., Lee, C., 1982. An anatomic and histologic
study of the rat prostate. Prostate 3, 81e97.
Jilek, M., Suta, D., Syka, J., 2014. Reference hearing thresholds in an
extended frequency range as a function of age. J. Acoust. Soc.
Am. 136, 1821e1830.
Kairali, R., Rani, P., Alexander, K.M., 1984. Specialized integumentary
glands of house rat, Rattus rattus. Proc. Indian Acad. Sci. 93, 535e542.
Karim, B.O., Landolfi, J.A., Christian, A., Ricart-Arbona, R., Qiu, W.,
McAlonis, M., Eyabi, P.O., Khan, K.A., Dicello, J.F., Mann, J.F.,
Huso, D.L., 2003. Estrous cycle and ovarian changes in a rat mam-
mary carcinogenesis model after irradiation, tamoxifen chemo-
prevention, and aging. Comp. Med. 53, 532e538.
Kashiwayanagi, M., 2014. Molecular and neural mechanisms of phero-
mone reception in the rat vomeronasal system and changes in the
pheromonal reception by the maturation and sexual experiences.
In: Mucignat-Caretta, C. (Ed.), Neurobiology of Chemical
Communication. CRC Press/Taylor & Francis, Boca Raton, FL.
https://www.ncbi.nlm.nih.gov/books/NBK200989/.
Kasiske, B.L., Keane, W.F., 2000. Laboratory assessment of renal dis-
ease: clearance, urinalysis, and renal biopsy. In: Brenner, B.M.
(Ed.), Brenner & Rector’s the Kidney. W.B. Saunders, Philadelphia,
PA, pp. 1129e1170.
Kelly, J.B., Masterton, B., 1977. Auditory sensitivity of the albino rat.
J. Comp. Physiol. Psychol. 91, 930e936.
Keune, J.A., Philbrick, K.A., Branscum, A.J., Iwaniec, U.T., Turner, R.T.,
2016. Spaceflight-induced vertebral bone loss in ovariectomized
rats is associated with increased bone marrow adiposity and no
change in bone formation. NPJ Microgravity 2, 16016. https://dx.
doi.org/10.1038/npjmgrav.2016.16.
Keverne, E.B., 1999. The vomeronasal organ. Science 286, 716e720.
Keverne, E.B., 2008. Visualisation of the vomeronasal pheromone
response system. Bioessays 30, 802e805.
Kikkawa, Y., 1970. Morphology of alveolar lining layer. Anat. Rec. 167,
389e400.
King, A.J.F., 2012. The use of animal models in diabetes research. Br. J.
Pharmacol. 166, 877e894.
King, J., Insanally, M., Jin, M., Martins, A.R., D’Amour, J.,A.,
Froemke, R.C., 2015. Rodent auditory perception: critical band lim-
itations and plasticity. Neuroscience 296, 55e65.
Király, M.A., Bates, H.E., Yue, J.T., Goche-Montes, D., Fediuc, S.,
Park, E., Matthews, S.G., Vranic, M., Riddell, M.C., 2007. Attenua-
tion of type 2 diabetes mellitus in the male Zucker diabetic fatty
 REFERENCES
rat: the effects of stress and non-volitional exercise. Metabolism 56,
732e744.
Kirkeby, O.J., 1991. Bone metabolism and repair are normal in athymic
rats. Acta Orthop. Scand. 62, 253e256.
Kiyokawa, Y., Kodama, Y., Kubota, T., Takeuchi, Y., Mori, Y., 2013.
Alarm pheromone is detected by the vomeronasal organ in male
rats. Chem. Senses 38, 661e668.
Knoblaugh, S.E., True, L., Tretiakova, M., Hukkanen, R.R., 2018. Male
reproductive system. In: Treuting, P.M., Dintzis, S.M.,
Montine, K.S. (Eds.), Comparative Anatomy and Histology: A
Mouse, Rat, and Human Atlas, second ed. Academic Press, Lon-
don, pp. 335e363.
Komárek, V., Gembart, C., Krinke, A., Mahrous, T.A., Schaetti, P., 2000.
Synopsis of the organ anatomy. In: Krinke, G.J. (Ed.), The Labora-
tory Rat. Academic Press, London, pp. 283e319.
Kontiola, A.I., Goldblum, D., Mittag, T., Danias, J., 2001. The induc-
tion/impact tonometer: a new instrument to measure intraocular
pressure in the rat. Exp. Eye Res. 73, 781e785.
Koolhaas, J.M., 2010. The laboratory rat. In: Hubrecht, R., Kirkwood, J.
(Eds.), The UFAW Handbook on the Care and Management of Lab-
oratory and Other Research Animals, eighth ed. Wiley-Blackwell,
Oxford, UK, pp. 311e326.
Kregel, K.C., 2006. Resource Book for the Design of Animal Exercise
Protocols. American Physiological Society. http://www.the-aps.
org/mm/SciencePolicy/AnimalResearch/Publications/Animal-
Exercise-Protocols/book14824.pdf.
Kresáková, L., Purzyc, H., Schusterová, I., Fulton, B., Maloveská, M.,
Vdoviaková, K., Kravcová, Z., Boldizár, M., 2015. Variability in
the cardiac venous system of Wistar rats. J. Am. Assoc. Lab.
Anim. Sci. 54, 10e16.
Kriz, W., Kaissling, B., 2013. Structural organization of the mammalian
kidney. In: Alpern, R.J., Caplan, M., Moe, O. (Eds.), Seldin and Gie-
bisch’s the Kidney: Physiology and Pathophysiology, fifth ed., vol.
1. Academic Press, London, pp. 595e691.
Kulick, L.J., Clemons, D.J., Hall, R.L., Koch, M.A., 2005. Refinement of
the urine concentration test in rats. Contemp. Top. Lab. Anim. Sci.
44, 46e49.
Kurimoto, Y., Saruta, J., To, M., Yamamoto, Y., Kimura, K.,
Tsukinoki, K., 2016. Voluntary exercise increases IgA concentration
and polymeric Ig receptor expression in the rat submandibular
gland. Biosci. Biotechnol. Biochem. 80, 2490e2496.
Kurnikova, A., Moore, J.D., Liao, S.M., Deschenes, M., Kleinfeld, D.,
2017. Coordination of orofacial motor actions into exploratory
behavior by rat. Curr. Biol. 27, 688e696.
Kutuzov, H., Sicher, H., 1952. Anatomy and function of the palate in the
white rat. Anat. Rec. 114, 67e84.
Kuwahira, I., Moue, Y., Ohta, Y., Mori, H., Gonzalez, N.C., 1994. Distri-
bution of pulmonary blood flow in conscious resting rats. Respir.
Physiol. 97, 309e321.
Lanum, J., 1978. The damaging effects of light on the retina. Empirical
findings, theoretical and practical implications. Surv. Ophthalmol.
22, 221e249.
Lateef, R.U., Al-Masri, A.A., Alyahya, A.M., 2015. Langendorff’s iso-
lated perfused rat heart technique: a review. Int. J. Basic Clin. Phar-
macol. 4, 1314e1322.
Lee, C., Holland, J.M., 1987. Anatomy, histology, and ultrastructure
(correlation with function), prostate, rat. In: Jones, T.C.,
Mohr, U., Hunt, R.D. (Eds.), Genital System (Monographs on Pa-
thology of Laboratory Animals). Springer-Verlag, Berlin,
pp. 239e251.
Lee, M.M., Chu, P.C., Chan, H.C., 1969. Effects of cold on the skeletal
growth of albino rats. Am. J. Anat. 124, 239e249.
Lee, D., Srirama, P.K., Wallis, C., Wexler, A.S., 2011. Postnatal growth of
tracheobronchial airways of Sprague-Dawley rats. J. Anat. 218,
717e725.
BIOLOGY AND CARE
127
Lee, Y.M., Song, B.C., Yeum, K.J., 2015. Impact of volatile anesthetics on
oxidative stress and inflammation. BioMed Res. Int. article ID
242709, 8 pages https://doi.org/10.1155/2015/242709.
Leeson, C.R., Leeson, T.S., 1966. The fine structure of Brunner’s glands
in the rat. Anat. Rec. 156, 253e268.
LeVere, T.E., 1978. The primary visual system of the rat: a primer of its
anatomy. J. Comp. Physiol. Psychol. 6, 142e169.
Levinger, I.M., 1971. The cerebral ventricles of the rat. J. Anat. 108,
447e451.
Liggitt, D., Dintzis, S.M., 2018. Pancreas. In: Treuting, P.M.,
Dintzis, S.M., Montine, K.S. (Eds.), Comparative Anatomy and His-
tology: A Mouse, Rat, and Human Atlas, second ed. Academic
Press, London, pp. 241e250.
Loeb, W.F., 1999. The rat. In: Loeb, W.F., Quimby, F. (Eds.), The Clinical
Chemistry of Laboratory Animals, second ed. Taylor & Francis,
London, pp. 33e48.
Lohr, J., Mazurchuk, R.J., Acara, M.A., Nickerson, P.A., Fiel, R.J., 1991.
Magnetic resonance imaging (MRI) and pathophysiology of the rat
kidney in streptozotocin-induced diabetes. Magn. Reson. Imaging
9, 93e100.
London, D.A., Davis, P.L., Williams, R.D., Crooks, L.E., Sheldon, P.E.,
Gooding, C.A., 1983. Nuclear magnetic resonance imaging of
induced renal lesions. Radiology 148, 167e172.
Lozano, D.C., Twa, M.D., 2013. Development of a rat schematic eye
from in vivo biometry and the correction of lateral magnification
in SD-OCT imaging. Investig. Ophthalmol. Vis. Sci. 54, 6446e6455.
Lucchesi, A.N., Cassettari, L.L., Spadella, C.T., 2015. Alloxan-induced
diabetes causes morphological and ultrastructural changes in rat
liver that resemble the natural history of chronic fatty liver disease
in humans. J. Diabetes Res. Article ID 494578, 11 pages https://doi.
org/10.1155/2015/494578.
Ludatscher, R.M., 1968. Fine structure of the muscular wall of rat pul-
monary veins. J. Anat. 103 (Pt 2), 345e357.
Majchrzak, M., Malendowicz, K.K., 1983. Sex differences in adrenocor-
tical structure and function. Cell Tissue Res. 232, 457e469.
Makara, G.B., Mergl, Z., Zelena, D., 2004. The role of vasopressin in
hypothalamo-pituitary-adrenal axis activation during stress: an
assessment of the evidence. Ann. N. Y. Acad. Sci. 1018, 151e161.
Malacrida, L., Reta, G., Piriz, H., Rocchiccioli, F., Botti, H., Denicola, A.,
Briva, A., 2014. Sevoflurane anesthesia deteriorates pulmonary sur-
factant promoting alveolar collapse in male Sprague-Dawley rats.
Pulm. Pharmacol. Therapeut. 28, 122e129.
Mallette, L.E., 1991. The parathyroid polyhormones: new concepts in
the spectrum of peptide hormone action. Endocr. Rev. 12, 110e117.
Marcela, S.G., Cristina, R.M., Angel, P.G., Manuel, A.M., Sofia, D.C.,
Patricia de, L.R., Bladimir, R.R., Concepcion, S.G., 2012. Chronolog-
ical and morphological study of heart development in the rat. Anat.
Rec. 295, 1267e1290.
Martin, L.E., Nikonova, L.V., Kay, K., Paedae, A.B., Contreras, R.J.,
Torregrossa, A.M., 2018. Salivary proteins alter taste-guided behav-
iors and taste nerve signaling in rat. Physiol. Behav. 184, 150e161.
Martorell, J., 2017. Reproductive disorders in pet rodents. Vet. Clin.
North Am. Exot. Anim. Pract. 20, 589e608.
Massof, R.W., Chang, F.W., 1972. A revision of the rat schematic eye.
Vis. Res. 12, 793e796.
Matsuo, R., Kobashi, M., Mitoh, Y., Fujita, M., 2015. Role of the lateral
hypothalamus in submandibular salivary secretion during feeding
in rats. Brain Res. 1596, 99e107.
Maunsbach, A.B., 1966. Observations on the segmentation of the prox-
imal tubule in the rat kidney. Comparison of results from phase
contrast, fluorescence and electron microscopy. J. Ultrastruct. Res.
16, 239e258.
Maunsbach, A.B., Christensen, E.I., 2011. Functional ultrastructure of
the proximal tubule. Comp. Physiol. (Suppl. 25), 41e107. https://
doi.org/10.1002/cphy.cp080102.
128 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
McCormack, C., Sontag, C., 1980. Entrainment by red light of running
activity and ovulation rhythms of rats. Am. J. Physiol. 239,
450e454.
McEwen, B., Sapolsky, R.M., 1995. Stress and cognitive function. Curr.
Opin. Neurobiol. 5, 205e216.
McKinney, W., Yonovitz, A., Smolensky, M.H., 2015. Circadian variation
of gentamicin toxicity in rats. The Laryngoscope 125, 252e256.
McLean, J.R., Twarog, B.M., Bergofsky, E.H., 1985. The adrenergic
innervation of pulmonary vasculature in the normal and pulmo-
nary hypertensive rat. J. Auton. Nerv. Syst. 14, 111e123.
McMaster, P.D., 1922. Do species lacking a gallbladder possess it’s
functional equivalent? J. Exp. Med. 35, 127e140.
Meek, S., Mashimo, T., Burdon, T., 2017. From engineering to editing
the rat genome. Mamm. Genome 28, 302e314.
Meng, Q., Mongan, M., Carreira, V., Kurita, H., Liu, C., Kao, W., Xia, Y.,
2014. Eyelid closure in embryogenesis is required for ocular adnexa
development. Investig. Ophthalmol. Vis. Sci. 55, 7652e7661.
Mercer, R.R., Russell, M.L., Crapo, J.D., 1994a. Alveolar septal structure
in different species. J. Appl. Physiol. 77, 1060e1066.
Mercer, R.R., Russell, M.L., Roggli, V.L., Crapo, J.D., 1994b. Cell num-
ber and distribution in human and rat airways. Am. J. Respir. Cell
Mol. Biol. 10, 613e624.
Mercurio, A.R., Mitchell, O.G., 1987. Submandibular duct salivary
bladder of the rat. J. Morphol. 192, 247e256.
Meyerholz, D.K., Suarez, C.J., Dintzis, S.M., Frevert, C.W., 2018.
Respiratory system. In: Treuting, P.M., Dintzis, S.M.,
Montine, K.S. (Eds.), Comparative Anatomy and Histology: A
Mouse, Rat, and Human Atlas, second ed. Academic Press, Lon-
don, pp. 147e162.
Miller Jr., I.J., Preslar, A.J., 1975. Spatial distribution of rat fungiform
papillae. Anat. Rec. 181, 679e684.
Miller Jr., I.J., Spangler, K.M., 1982. Taste bud distribution and innerva-
tion on the palate of the rat. Chem. Senses 7, 99e108.
Miller, F.J., Mercer, R.R., Crapo, J.D., 1993. Lower respiratory tract
structure of laboratory animals and humans: dosimetry
implications. Aerosol Sci. Technol. 18, 257e271.
Milot, M.R., James, J.S., Merali, Z., Plamondon, H., 2012. A refined
blood collection method for quantifying corticosterone. Lab.
Anim. 41, 77e83.
Mintz, G.A., Mooradian, A.D., 1987. Age-related changes in rat sublin-
gual salivary gland morphology. Gerodontology 6, 137e144.
Mistretta, C.M., Baum, B.J., 1984. Quantitative study of taste buds in
fungiform and circumvallate papillae of young and aged rats.
J. Anat. 138, 323e332.
Mizoguchi, K., Yuzurihara, M., Ishige, A., Sasaki, H., Chui, D.H.,
Tabira, T., 2001. Chronic stress differentially regulates glucocorti-
coid negative feedback response in rats. Psychoneuroendocrinol-
ogy 26, 443e459.
Mizoguchi, K., Ikeda, R., Shoji, H., Tanaka, Y., Maruyama, W.,
Tabira, T., 2009. Aging attenuates glucocorticoid negative feedback
in rat brain. Neuroscience 159, 259e270.
Moe, H., Bojsen-Moller, F., 1971. The fine structure of the lateral
nasal gland (Steno’s gland) of the rat. J. Ultrastruct. Res. 36,
127e148.
Moe, S.M., Chen, N.X., Newman, C.L., Gattone II, V.H., Organ, J.M.,
Chen, X., Allen, M.R., 2014. A comparison of calcium to zoledronic
acid for improvement of cortical bone in an animal model of CKD.
J. Bone Miner. Res. 29, 902e910.
Monteiro, A.R.L.S., 2014. Bronchial tree architecture in mammals of
diverse body mass. Int. J. Morphol. 32, 312e316.
Morgan, K.T., Jiang, X.Z., Patterson, D.L., Gross, E.A., 1984. The nasal
mucociliary apparatus correlation of structure and function in the
rat. Am. Rev. Respir. Dis. 130, 275e281.
Morsing, P., Persson, A.E., Boberg, U., 1988. A micropuncture assess-
ment of the effects of contrast media of different osmolality. Inves-
tig. Radiol. 23, 767e771.
BIOLOGY AND CARE
Mueller-Hoecker, J., Beitinger, F., Fernandez, B., Bahlmann, O.,
Assmann, G., Troidl, C., Dimomeletis, I., Kaab, S., Deindl, E.,
2008. Of rodents and humans: a light microscopic and ultrastruc-
tural study on cardiomyocytes in pulmonary veins. Int. J. Med.
Sci. 5, 152e158.
Muir, W.W., 2015. Cardiovascular physiology. In: Grimm, K.A.,
Lamont, L.A., Tranquilli, W.J., Greene, S.A., Robertson, S.A.
(Eds.), Veterinary Anesthesia and Analgesia, ” fifth ed. Wiley Black-
well, Ames, IA, pp. 417e510.
Mullins, L.J., Conway, B.R., Menzies, R.I., Denby, L., Mullins, J.J., 2016.
Renal disease pathophysiology and treatment: contributions from
the rat. Dis. Model. Mech. 9, 1419e1433.
Mulrow, P.J., 1986. The Adrenal Gland (Current Endocrinology). Elsev-
ier, New York.
Nagato, T., Ren, X.Z., Toh, H., Tandler, B., 1997. Ultrastructure of We-
ber’s salivary glands of the root of the tongue in the rat. Anat.
Rec. 249, 435e440.
Nakatsuji, S., Szabo, K.A., Elmore, S.A., 2018. Small and large intestine.
In: Suttie, A.W. (Ed.), Boorman’s Pathology of the Rat. Academic
Press, London, pp. 51e69.
Nam, M., Cooper, M.P., 2015. Role of energy metabolism in the brown
fat gene program. Front. Endocrinol. 30, 104.
National Research Council, 2011. Guide for the Care and Use of Labo-
ratory Animals, eighth ed. The National Academies Press, Wash-
ington, DC.
Nogueira, F.N., Carvalho, R.A., 2017. Metabolic remodeling triggered
by salivation and diabetes in major salivary glands. NMR Biomed.
30, e3683. https://doi.org/10.1002/nbm.3683.
Norrby, A., 1958. On the growth of the crystalline lens, the eyeball and
cornea in the rat. Acta Ophthalmol. 49, 5e5.
Norris, D.O., Carr, J.A., 2013. Organization of the mammalian
hypothalamusepituitary axes. In: Norris, D.O., Carr, J.A. (Eds.),
Vertebrate Endocrinology, fifth ed. Academic Press, San Diego,
CA, pp. 93e150.
Obineche,E.N., Mensah-Brown,E., Chandranath,S.I., Ahmed, I.,
Naseer, O., Adem,A., Morphological changes in the rat kidney
following long-term diabetes. Arch. Physiol. Biochem. 109, 245.
O’Flaherty, E.J., 1991. Physiologically based models for bone-seeking
elements. I. Rat skeletal and bone growth. Toxicol. Appl. Pharma-
col. 111, 299e312.
Oda, Y., Nakanishi, I., 1987. Ultrastructure of the caudal portion of the
fourth ventricular roof in the mouse. J. Comp. Neurol. 256,
299e307.
Ohkura, S., Tsukamura, H., Maeda, K., 2000. Endocrinology. In:
Krinke, G.J. (Ed.), The Laboratory Rat. Academic Press, London,
pp. 401e418.
Ojeda, S.R., Skinner, M.K., 2006. Puberty in the rat. In: Neill, J.D.,
Plant, T.M., Pfaff, D.W., Challis, J.R.G., de Kretser, D.M.,
Richards, J.S., Wassarman, P.M. (Eds.), Knobil and Neill’s Physiology
of Reproduction, third ed. Elsevier, St. Louis, MO, pp. 2061e2126.
Oller, A.R., Oberdörster, G., 2010. Incorporation of particle size differ-
ences between animal studies and human workplace aerosols for
deriving exposure limit values. Regul. Toxicol. Pharmacol. 57,
181e194.
Ortinau, L.C., Linden, M.A., Dirkes, R.K., Rector, R.S., Hinton, P.S.,
2017. Exercise initiated after the onset of insulin resistance im-
proves trabecular microarchitecture and cortical bone biome-
chanics of the tibia in hyperphagic Otsuka Long Evans
Tokushima Fatty rats. Bone 103, 188e199.
Otto, G.M., Franklin, C.L., Clifford, C.B., 2015. Biology and diseases of
rats. In: Fox, J.G., Anderson, L.C., Otto, G., Pritchett-Corning, K.R.,
Whary, M.T. (Eds.), Laboratory Animal Medicine, third ed. Aca-
demic Press, Boston, MA, pp. 151e207.
Ozdemir, M.B., Akdogan, I., Adiguzel, E., Yonguc, N., 2005. Three
dimensional (3D) reconstruction of the rat ventricles. Neuro-
anatomy 4, 49e51.
 REFERENCES
Paccola, C.C., Resende, C.G., Stumpp, T., Miraglia, S.M., Cipriano, I.,
2013. The rat estrous cycle revisited: a quantitative and qualitative
analysis. Anim. Reprod. 10, 677e683.
Pacha, J., 2000. Development of intestinal transport function in
mammals. Physiol. Rev. 80, 1633e1667.
Palma, J.A., Benarroch, E.E., 2014. Neural control of the heart: recent
concepts and clinical correlations. Neurology 83, 261e271.
Pannabecker, T.L., 2012. Structure and function of the thin limbs of the
loop of Henle. Comp. Physiol. 2, 2063e2086.
Pannabecker, T.L., Abbott, D.E., Dantzler, W.H., 2004.
Three-dimensional functional reconstruction of inner medullary
thin limbs of Henle’s loop. Am. J. Physiol. Renal. Physiol. 286,
38e45.
Pasierbek, M., 2014. Functional anatomy of the mediastinal lymph
nodes in rats. Lymphatic Res. Biol. 12, 157e163.
Paxinos, G.E., 2015. The Rat Nervous System, fourth ed. Academic
Press, San Diego, CA.
Paxinos, G., Watson, C., 2013. The Rat Brain in Stereotaxic Coordinates,
seventh ed. Academic Press, San Diego, CA.
Pazirandeh, A., Jondal, M., Okret, S., 2004. Glucocorticoids delay age-
associated thymic involution through directly affecting the
thymocytes. Endocrinology 145, 2392e2401.
Pelleymounter, M.A., Cullen, M.J., Baker, M.B., Hecht, R.,
Winters, D., Boone, T., Collins, F., 1995. Effects of the obese gene
product on body weight regulation in ob/ob mice. Science 269,
540e543.
Penn, J.S., Baker, B.N., Howard, A.G., Williams, T.P., 1985. Retinal light-
damage in albino rats: lysosomal enzymes, rhodopsin, and age.
Exp. Eye Res. 41, 275e284.
Pennell, J.P., Lacy, F.B., Jamison, R.L., 1974. An in vivo study of the
concentrating process in the descending limb of Henle’s loop. Kid-
ney Int. 5, 337e374.
Permezel, N.C., Webling, D.D., 1971. The length and mucosal
surface area of the small and large gut in young rats. J. Anat. 108,
295e296.
Perrier, E.T., Buendia-Jimenez, I., Vecchio, M., Armstrong, L.E., Tack, I.,
Klein, A., 2015. Twenty-four-hour urine osmolality as a physiolog-
ical index of adequate water intake. Dis. Markers. Article ID 231063,
8 pages. https://doi.org/10.1155/2015/231063.
Perry, S.W., 1965. Proteinuria in the wistar rat. J. Pathol. Bacteriol. 89,
729e733.
Peti-Peterdi, J., Kidokoro, K., Riquier-Brison, A., 2015. Novel in vivo
techniques to visualize kidney anatomy and function. Kidney Int.
88, 44e51.
Pevsner, J., Hwang, P.M., Sklar, P.B., Venable, J.C., Snyder, S.H., 1988.
Odorant-binding protein and its mRNA are localized to lateral
nasal gland implying a carrier function. Proc. Natl. Acad. Sci.
U.S.A. 85, 2383e2387.
Pfaller, W., 1982. Structure function correlation on rat kidney. Quantita-
tive correlation of structure and function in the normal and injured
rat kidney. Adv. Anat. Embryol. Cell Biol. 70, 1e106.
Picut, C.A., Remick, A.K., 2016a. Male reproductive system. In:
Parker, G.A., Picut, C.A. (Eds.), Atlas of Histology of the Juvenile
Rat. Academic Press, London, pp. 227e256.
Picut, C.A., Remick, A.K., 2016b. Female reproductive system. In:
Parker, G.A., Picut, C.A. (Eds.), Atlas of Histology of the Juvenile
Rat. Academic Press, London, pp. 203e226.
Pinilla, M., Ramı́rez-Camacho, R., Jorge, E., Trinidad, A., Vergara, J.,
2001. Ventral approach to the rat middle ear for otologic research.
Otolaryngol. Head Neck Surg. 124, 515e517.
Pinkerton, K.E., Barry, B.E., O’Neil, J.J., Raub, J.A., Pratt, P.C.,
Crapo, J.D., 1982. Morphologic changes in the lung during the life-
span of Fischer 344 rats. Am. J. Anat. 164, 155e174.
Pinto, Y.M., Paul, M., Ganten, D., 1998. Lessons from rat models of hy-
pertension: from Goldblatt to genetic engineering. Cardiovasc. Res.
39, 77e88.
BIOLOGY AND CARE
129
Piskuric, N.A., Vollmer, C., Nurse, C.A., 2011. Confocal immunofluo-
rescence study of rat aortic body chemoreceptors and associated
neurons in situ and in vitro. J. Comp. Neurol. 519, 856e873.
Plecas-Solarovic, B., Lalic, L., Leposavic, G., 2004. Age-dependent mor-
phometrical changes in the thymus of male propranolol-treated
rats. Ann. Anat. 186, 141e147.
Poling, A., Mahoney, A., Beyene, N., Mgode, G., Weetjens, B., Cox, C.,
Durgin, A., 2015. Using giant African pouched rats to detect human
tuberculosis: a review. Pan Afr. Med. J. 21, 333.
Popesko, P., Rajitova, V., Horak, J., 2002. A Color Atlas of Anatomy of
Small Laboratory Animals: Vol. 2: Rat, Mouse, Hamster. Saunders,
London.
Portfors, C.V., 2007. Types and functions of ultrasonic vocalizations in
laboratory rats and mice. J. Am. Assoc. Lab. Anim. Sci. 46, 28e34.
Postle, A.D., Heeley, E.L., Wilton, D.C., 2001. A comparison of the mo-
lecular species compositions of mammalian lung surfactant
phospholipids. Comp. Biochem. Physiol. A. Mol. Integr. Physiol.
129, 65e73.
Prusky, G., West, P.W., Douglas, R.M., 2000. Behavioral assessment of
the visual acuity in mice and rats. Vis. Res. 40, 2201e2220.
Prusky, G., Harker, K., Douglas, R., Whishaw, I., 2002. Variation in vi-
sual acuity within pigmented, and between pigmented and albino
rat strains. Behav. Brain Res. 136, 339e348.
Puche, R.C., Alloatti, R., Ledesma, S., 1988. Growth and development
of the bone mass of two strains of inbred rats. Bone Miner. 4,
341e353.
Rakshit, P., 1949. Communicating blood vessels between bronchial and
pulmonary circulations in the guinea pig and rat. Q. J. Exp. Physiol.
Cogn. Med. Sci. 47e53.
Ramos, S.D., Lee, J.M., Peuler, J.D., 2001. An inexpensive meter to mea-
sure differences in electrical resistance in the rat vagina during the
ovarian cycle. J. Appl. Physiol. 91, 667e670.
Rao, G.N., 1991. Light intensity-associated eye lesions of Fischer 344
rats in long-term studies. Toxicol. Pathol. 19, 148e155.
Rao, M., Jaber, B.L., Balakrishnan, V.S., 2017. Chronic kidney disease
and acquired mitochondrial myopathy. Curr. Opin. Nephrol.
Hypertens. 27, 113e120.
Reddy, S.S., Shruthi, K., Prabhakar, Y.K., Sailaja, G., Reddy, G.B., 2018.
Implication of altered ubiquitin-proteasome system and ER stress
in the muscle atrophy of diabetic rats. Arch. Biochem. Biophys.
639, 16e25.
Reid, L., Meyrick, B., Antony, V.B., Chang, L.Y., Crapo, J.D.,
Reynolds, H.Y., 2005. The mysterious pulmonary brush cell: a cell
in search of a function. Am. J. Respir. Crit. Care Med. 172, 136e139.
Reiter, R.J., 1991. Neuroendocrine effects of light. Int. J. Biometeorol. 35,
169e175.
Remuzzi, A., Puntorieri, S., Mazzoleni, A., Remuzzi, G., 1988. Sex
related differences in glomerular ultrafiltration and proteinuria in
Munich-Wistar rats. Kidney Int 34, 481e486.
Reynolds, S.D., Pinkerton, K.E., Marissay, A.T., 2015. Epithelial cells of
the trachea and bronchi. In: Parent, R.A. (Ed.), Comparative Biology
of the Normal Lung. Elsevier, London, pp. 61e81.
Rogers, D.F., 1994. Airway goblet cells: responsive and adaptable front-
line defenders. Eur. Respir. J. 7, 1690e1706.
Rogers, A.B., Dintzis, S.M., 2018. Hepatobiliary system. In:
Treuting, P.M., Dintzis, S.M., Montine, K.S. (Eds.), Comparative
Anatomy and Histology: A Mouse, Rat, and Human Atlas, second
ed. Academic Press, London, pp. 229e239.
Rokicki, W., Rokicki, M., Wojtacha, J., Dzeljijli, A., 2016. The role and
importance of club cells (Clara cells) in the pathogenesis of
some respiratory diseases. Kardiochir Torakochirurgia Pol 13,
26e30.
Roper, S.D., 2013. Taste buds as peripheral chemosensory processors.
Semin. Cell Dev. Biol. 24, 71e79.
Ruttimann, G., Daicker, B., 1989. Retrolental cloudiness of the vitreous
humor in the rat eye. Zentralbl. Veterinarmed. A. 36, 340e347.
130 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
Rybalko, N., Chumak, T., Bures, Z., Popelar, J., Suta, D., Syka, J., 2015.
Development of the acoustic startle response in rats and its
change after early acoustic trauma. Behav. Brain Res. 286, 212e221.
Saely, C.H., Geiger, K., Drexel, H., 2012. Brown versus white adipose
tissue: a mini-review. Gerontology 58, 15e23.
Saleh, M.A., Sandoval, R.M., Rhodes, G.J., Campos-Bilderback, S.B.,
Molitoris, B.A., Pollock, D.M., 2012. Chronic endothelin-1 infusion
elevates glomerular sieving coefficient and proximal tubular albu-
min reuptake in the rat. Life Sci. 91, 634e637.
Salvatori, G., Lattanzi, L., Coletta, M., Aguanno, S., Vivarelli, E.,
Kelly, R., Ferrari, G., Harris, A.J., Mavilio, F., Molinaro, M., 1995.
Myogenic conversion of mammalian fibroblasts induced by differ-
entiating muscle cells. J. Cell Sci. 108, 2733e2739.
Sands, J.M., Layton, H.E., 2009. The physiology of urinary concentra-
tion: an update. Semin. Nephrol. 29, 178e195.
Sasaki, S., Kobayashi, N., Dambara, T., Kira, S., Sakai, T., 1995. Struc-
tural organization of pulmonary arteries in the rat lung. Anat.
Embryol. 191, 477e489.
Sato, A., Miyoshi, S., 1998. Cells in the duct system of the rat subman-
dibular gland. Eur. J. Morphol. 36 (Suppl. l), 61e66.
Sbarbati, A., Crescimanno, C., Osculati, F., 1999. The anatomy and
functional role of the circumvallate papilla/von Ebner gland
complex. Med. Hypotheses 53, 40e44.
Sbarbati, A., Merigo, F., Bernardi, P., Crescimanno, C., Benati, D.,
Osculati, F., 2002. Ganglion cells and topographically related nerves
in the vallate papilla/von Ebner gland complex. J. Histochem.
Cytochem. 50, 709e718.
Schittny, J.C., Djonov, V., Fine, A., Burri, P.H., 1998. Programmed cell
death contributes to postnatal lung development. Am. J. Respir.
Cell Mol. Biol. 18, 786e793.
Schlingmann, F., De Rijk, H., Pereboom, W., Remie, R., 1993a. Avoid-
ance as a behavioural parameter in the determination of distress
amongst albino and pigmented rats at various light intensities.
Anim. Technol. 44, 87e96.
Schlingmann, F., De Rijk, H., Pereboom, W., Remie, R., 1993b. Light in-
tensity in animal rooms and cages in relation to the care and man-
agement of albino rats. Anim. Technol. 44, 97e107.
Schmidt, R.E., Dorsey, D.A., Beaudet, L.N., Peterson, R.G., 2013. Anal-
ysis of the Zucker Diabetic Fatty (ZDF) type 2 diabetic rat model
suggests a neurotrophic role for insulin/IGF-I in diabetic auto-
nomic neuropathy. Am. J. Pathol. 163, 21e28.
Schmidt-Nielsen, B., Churchill, M., Reinking, L.N., 1980. Occurrence of
renal pelvic refluxes during rising urine flow rate in rats and
hamsters. Kidney Int. 18, 419e431.
Schraufnagel, D.E., Patel, K.R., 1990. Sphincters in pulmonary veins.
An anatomic study in rats. Am. Rev. Respir. Dis. 141, 721e726.
Schulz, H., Muble, H., 2000. Respiration. In: Krinke, G.J. (Ed.), The Lab-
oratory Rat. Academic Press, London, pp. 323e344.
Seely, J.C., Brix, A., 2014. Kidney, renal tubuledaccumulation, hyaline
droplet. In: Cesta, M.F., Herbert, R.A., Brix, A., Malarkey, D.E.,
Sills, R.C. (Eds.), National Toxicology Program Nonneoplastic
Lesion Atlas. https://ntp.niehs.nih.gov/nnl/urinary/kidney/
rtaccum/index.htm.
Seely, J.C., Hard, G.C., Blankenship, B., 2018. Kidney. In: Suttie, A.W.
(Ed.), Boorman’s Pathology of the Rat, second ed. Academic Press,
London, pp. 125e166.
Senoo, H., 2000. Digestion, metabolism. In: Krinke, G.J. (Ed.), The Lab-
oratory Rat. Academic Press, London, pp. 359e383.
Severson, K.S., O’Connor, D.H., 2017. Active sensing: the rat’s nose dan-
ces in step with whiskers, head, and breath. Curr. Biol. 27, 183e185.
Sha, O., Kwong, W.H., 2006.
Postnatal developmental changes of vitreous and lens volumes in
Sprague-Dawley rats. Neuroembryol. Aging 4, 183e188.
Sharma, D.K., Mehrotra, T.N., Pandher, K., 2008. Comparative histo-
logical study of the prostate in rat, rabbit, dog, and man. J. Anat.
Soc. India 57, 124e130.
BIOLOGY AND CARE
Shea, S.M., Raskova, J., 1985. Glomerular morphometry in the
Munich-Wistar rat. Microcirc. Endothelium Lymphatics 2, 499e515.
Sheikhbahaei, S., Gourine, A.V., Smith, J.C., 2017. Respiratory rhythm
irregularity after carotid body denervation in rats. Respir. Physiol.
Neurobiol. 246, 92e97.
Singletary, S.J., Kirsch, A.J., Watson, J., Karim, B.O., Huso, D.L.,
Hurn, P.D., Murphy, S.J., 2005. Lack of correlation of vaginal imped-
ance measurements with hormone levels in the rat. Contemp. Top.
Lab. Anim. Sci. 44, 37e42.
Sivak, J.G., Dovrat, A., 1984. Early postnatal development of the rat
lens. Exp. Biol. 43, 57e65.
Skorecki, K., Chertow, G.M., Marsden, P.A., Taal, M.W., Yu, A.S.L., 2016.
Brenner and Rector’s the Kidney, tenth ed. Elsevier, Philadelphia.
Slavin, B.G., Bernick, S., 1974. Morphological studies on denervated
brown adipose tissue. Anat. Rec. 179, 497e506.
Small, D.M., Sanchez, W.Y., Gobe, G.C., 2016. Intravital multiphoton
imaging of the kidney: tubular structure and metabolism. In:
Hewitson, T., Smith, E., Holt, S. (Eds.), Kidney Research. Methods
in Molecular Biology, vol. 1397. Humana Press, New York,
pp. 155e172.
Snipes, R.L., 1981. Anatomy of the cecum of the laboratory mouse and
rat. Anat. Embryol. 162, 455e474.
Snyder, J.M., Hagen, C.E., Bolon, B., Keene, C.D., 2018. Nervous
system. In: Treuting, P.M., Dintzis, S.M., Montine, K.S. (Eds.),
Comparative Anatomy and Histology: A Mouse, Rat, and Human
Atlas, second ed. Academic Press, London, pp. 403e444.
Sofikitis, N., Takahashi, C., Kadowaki, H., Okazaki, T., Shimamoto, T.,
Nakamura, I., Miyagawa, I., 1992. The role of the seminal vesicles
and coagulating glands in fertilization in the rat. Int. J. Androl.
15, 54e61.
Sofroniew, N.J., Svoboda, K., 2015. Whisking. Curr. Biol. 25, 137e140.
Sohn, W.J., Gwon, G.J., An, C.H., Moon, C., Bae, Y.C., Yamamoto, H.,
Lee, S., Kim, J.Y., 2011. Morphological evidences in circumvallate
papilla and von Ebners’ gland development in mice. Anat. Cell
Biol. 44, 274e283.
Sorrells, S.F., Caso, J.R., Munhoz, C.D., Sapolsky, R.M., 2009. The
stresses CNS: when glucocorticoids aggravate inflammation.
Neuron 64, 33e39.
Souma, T., 1987. The distribution and surface ultrastructure of airway
epithelial cells in the rat lung: a scanning electron microscopic
study. Arch. Histol. Jpn. 50, 419e436.
Srinivasan, K., Viswanad, B., Asrat, L., Kaul, C.L., Ramarao, P., 2005.
Combination of high-fat diet-fed and low-dose streptozotocin-
treated rat: a model for type 2 diabetes and pharmacological
screening. Pharmacol. Res. 52, 313e320.
Stone, K.C., Mercer, R.R., Freeman, B.A., Chang, L.Y., Crapo, J.D., 1992.
Distribution of lung cell numbers and volumes between alveolar
and nonalveolar tissue. Am. Rev. Respir. Dis. 146, 454e456.
Strohl, K.P., Thomas, A.J., S.t Jean, P., Schlenker, E.H., Koletsky, R.J.,
Schork, N.J., 1997. Ventilation and metabolism among rat strains.
J. Appl. Physiol. 82, 317e323.
Stumpel, F., Scholtka, B., Jungermann, K., 2000. Stimulation by portal
insulin of intestinal glucose absorption via hepatoenteral nerves
and prostaglandin E2 in the isolated, jointly perfused small intes-
tine and liver of the rat. Ann. N. Y. Acad. Sci. 915, 111e116.
Suami, H., Chang, D.W., Matsumoto, K., Kimata, Y., 2011. Demon-
strating the lymphatic system in rats with microinjection. Anat.
Rec. 294, 1566e1573.
Sugiyama, K., Gu, Z.B., Kawase, C., Yamamoto, T., Kitazawa, Y., 1999.
Optic nerve and peripapillary choroidal microvasculature of the rat
eye. Investig. Ophthalmol. Vis. Sci. 40, 3084e3090.
Sundberg, J.P., Booth, C.J., Nanney, L.B., Fleckman, P., King Jr., L.E.,
2018. Skin and adnexa. In: Treuting, P.M., Dintzis, S.M.,
Montine, K.S. (Eds.), Comparative Anatomy and Histology: A
Mouse, Rat, and Human Atlas, second ed. Academic Press, Lon-
don, pp. 511e542.
 REFERENCES
Sutherland, M., Beland, C., Lukaszewski, M., Cloutier, A.,
Bertagnolli, M., Nuyt, A., 2016. Age and sex-related changes in
rat renal function and pathology following neonatal hyperoxia
exposure. Physiol. Rep. https://doi.org/10.14814/phy2.12887.
Swaney, W.T., Keverne, E.B., 2009. The evolution of pheromonal
communication. Behav. Brain Res. 200, 239e247.
Szel, A., Rohlich, P., 1991. Two cone types of rat retina detected by anti-
visual pigment antibodies. Exp. Eye Res. 55, 47e52.
Tabrizchi, R., Pugsley, M.K., 2000. Methods of blood flow measurement
in the arterial circulatory system. J. Pharmacol. Toxicol. Methods 44,
375e384.
Tachibana, T., Fujiwara, N., Nawa, T., 1991. Mechanoreceptors of the
hard palate of the Mongolian gerbil include special junctions be-
tween epithelia and Meissner lamellar cells: a comparison with
other rodents. Anat. Rec. 231, 396e403.
Teh, I., McClymont, D., Burton, R.A., Maguire, M.L., Whittington, H.J.,
Lygate, C.A., Kohl, P., Schneider, J.E., 2016. Resolving fine cardiac
structures in rats with high-resolution diffusion tensor imaging.
Sci. Rep. 6, 30573.
Tenney, S.M., Remmers, J.E., 1963. Comparative quantitative morphology
of the mammalian lung: diffusing area. Nature 197, 54e56.
Thomson, A.B.R., Keelan, M., Thiesen, A., Clandinin, M.T.,
Ropeleski, M., Wild, G.E., 2001. Small bowel reviewdnormal phys-
iology part 1. Dig. Dis. Sci. 46, 2567e2587.
Timm, K.I., 1979. Orbital venous anatomy of the rat. Lab. Anim. Sci. 29,
636e638.
Tisher, C.C., Madsen, K.M., 2000. Anatomy of the kidney. In:
Brenner, B.M. (Ed.), Brenner & Rector’s the Kidney. W. B. Saunders,
Philadelphia, PA, pp. 3e67.
Tobian, L., Nason, P., 1966. The augmentation of proteinuria after acute
sodium depletion in the rat. J. Lab. Clin. Med. 67, 224e228.
Tomonari, Y., Kurotaki, T., Sato, J., Doi, T., Kokoshima, H., Kanno, T.,
Tsuchitani, M., Seely, J.C., 2016. Spontaneous age-related lesions
of the kidney fornices in Sprague-Dawley rats. Toxicol. Pathol. 44,
226e232.
Townsley, M.I., 2012. Structure and composition of pulmonary arteries,
capillaries, and veins. Comp. Physiol. 2, 675e709.
Tran, H., Chen, H., Walz, A., Posthumus, J.C., Gong, Q., 2008.
Influence of olfactory epithelium on mitral/tufted cell dendritic
outgrowth. PLoS One 3, e3816. https://doi.org/10.1371/journal.
pone.0003816.
Travers, J.B., 2015. Oromotor nuclei. In: Paxinos, G. (Ed.), The Rat Ner-
vous System, fourth ed. Academic Press, San Diego, CA,
pp. 223e245.
Travers, S.P., Nicklas, K., 1990. Taste bud distribution in the rat pharynx
and larynx. Anat. Rec. 227, 373e379.
Trayhurn, P., 2017. Origins and early development of the concept that
brown adipose tissue thermogenesis is linked to energy balance
and obesity. Biochimie 134, 62e70.
Treuting, P.M., Arends, M.J., Dintzis, S.M., 2018a. Upper gastrointes-
tinal tract. In: Treuting, P.M., Dintzis, S.M., Montine, K.S. (Eds.),
Comparative Anatomy and Histology: A Mouse, Rat, and Human
Atlas, second ed. Academic Press, London, pp. 191e211.
Treuting, P.M., Arends, M.J., Dintzis, S.M., 2018b. Lower
gastrointestinal tract. In: Treuting, P.M., Dintzis, S.M.,
Montine, K.S. (Eds.), Comparative Anatomy and Histology: A
Mouse, Rat, and Human Atlas, second ed. Academic Press, Lon-
don, pp. 213e228.
Treuting, P.M., Dintzis, S.M., Sellers, R., 2018c. Special senses: ear. In:
Treuting, P.M., Dintzis, S.M., Montine, K.S. (Eds.), Comparative
Anatomy and Histology: A Mouse, Rat, and Human Atlas, second
ed. Academic Press, London, pp. 471e485.
Treuting, P.M., Morton Jr., T.H., Vogel, P., 2018d. Oral cavity and teeth.
In: Treuting, P.M., Dintzis, S.M., Montine, K.S. (Eds.), Comparative
Anatomy and Histology: A Mouse, Rat, and Human Atlas, second
ed. Academic Press, London, pp. 115e133.
BIOLOGY AND CARE
131
Trevisan, A., Cristofori, P., Fanelli, G., 1999. Glutamine synthetase ac-
tivity in rat urine as sensitive marker to detect S3 segment-
specific injury of proximal tubule induced by xenobiotics. Arch.
Toxicol. 73, 255e262.
Turner, C.H., Roeder, R.K., Wieczorek, A., Foroud, T., Liu, G.,
Peacock, M., 2001. Variability in skeletal mass, structure, and
biomechanical properties among inbred strains of rats. J. Bone
Miner. Res. 16, 1532e1539.
Turner, J.G., Parrish, J.L., Hughes, L.F., Toth, L.A., Caspary, D.M., 2005.
Hearing in laboratory animals: strain differences and nonauditory
effects of noise. Comp. Med. 55, 12e23.
Turner, J.G., Bauer, C.A., Rybak, L.P., 2007. Noise in animal facilities:
why it matters. J. Am. Assoc. Lab. Anim. Sci. 46, 10e13.
Uehara, T., Elmore, S.A., Szabo, K.A., 2018. Esophagus and stomach. In:
Suttie, A.W. (Ed.), Boorman’s Pathology of the Rat, second ed. Ac-
ademic Press, London, pp. 35e50.
Valerius, K.P., 1996. Size-dependent morphology of the conductive
bronchial tree in four species of myomorph rodents. J. Morphol.
230, 291e297.
Vallon, V., 2009. Micropuncturing the nephron. Pflügers Archiv. 458,
189e201.
Vallotton, M.B., Capponi, A.M., Johnson, E.I., Lang, U., 1990. Mode of
action of angiotensin II and vasopressin on their target cells. Horm.
Res. 34, 105e110.
Van Crutchen, S., Vrolyk, V., Perron Lepage, M.F., Baudon, M.,
Voute, H., Schoofs, S., Haruna, J., Benoit-Biancamano, M.O.,
Ruot, B., Allegaert, K., 2017. Pre- and postnatal development
of the eye: a species comparison. Birth Defects Res 109, 1540e1567.
Van Winkle, L.S., Kelty, J.S., Smiley-Jewell, S., Pinkerton, K.E., 2018.
Tracheobronchial airways. In: McQueen, C. (Ed.), Comprehensive
Toxicology, third ed. Elsevier, Oxford, pp. 30e46.
Vanderschueren, D., 1996. Androgens and their role in skeletal
homeostasis. Horm. Res. 46, 95e98.
Vanderschueren, D., Van Herck, E., De Coster, R., Bouillon, R., 1996.
Aromatization of androgens is important for skeletal maintenance
of aged male rats. Calcif. Tissue Int. 59, 179e183.
Verlander, J.W., 1998. Normal ultrastructure of the kidney and lower
urinary tract. Toxicol. Pathol. 26, 1e17.
Verloop, M., 1948. The arterial bronchioles and their anastomoses with
the arteria pulmonalis in the human lung. Acta Anat. 5, 171e205.
Vidal, P.P., Graf, W., Berthoz, A., 1986. The orientation of the cervical
vertebral column in unrestrained awake animals. I. Resting
position. Exp. Brain Res. 61, 549e559.
Vrolyk, V., Haruna, J., Benoit-Biancamano, M.O., 2017. Neonatal and
juvenile ocular development in Sprague-Dawley rats: a histomor-
phological and immunohistochemical study. Vet. Pathol. 55,
310e330.
Walker Jr., W.F., Homberger, D.G., 1997. Anatomy & Dissection of the
Rat. W.H. Freeman and Co., New York.
Walling, B., Marit, G., 2016. The eye and harderian gland. In:
Parker, G.A., Picut, C.A. (Eds.), Atlas of Histology of the Juvenile
Rat. Academic Press, London, pp. 373e394.
Wallis, R.H., Wang, K., Marandi, L., Hsieh, E., Ning, T., Chao, G.Y.,
Sarmiento, J., Paterson, A.D., Poussier, P., 2009. Type 1 diabetes in
the BB rat: a polygenic disease. Diabetes 58, 107e117.
Wang, S.J., Laulederkind, S.J., Hayman, G.T., Petri, V., Smith, J.R.,
Tutaj, M., Nigam, R., Dwinell, M.R., Shimoyama, M., 2016. Compre-
hensive coverage of cardiovascular disease data in the disease por-
tals at the rat genome database. Physiol. Genom. 48, 589e600.
Ward, J.M., Cherian, S., Linden, M.A., 2018. Hematopoietic and
lymphoid tissues. In: Treuting, P.M., Dintzis, S.M., Montine, K.S.
(Eds.), Comparative Anatomy and Histology: A Mouse, Rat, and
Human Atlas, second ed. Academic Press, London, pp. 365e401.
Watanabe, H., Tisdale, A.S., Gipson, I.K., 1993. Eyelid opening induces
expression of a glycocalyx glycoprotein of rat ocular surface
epithelium. Investig. Ophthalmol. Vis. Sci. 34, 327e338.
132 4. FUNCTIONAL ANATOMY AND PHYSIOLOGY
Watson, L.E., Sheth, M., Denyer, R.F., Dostal, D.E., 2004. Baseline echo-
cardiographic values for adult male rats. J. Am. Soc. Echocardiogr.
17, 161e167.
Weinstein, A.M., 1998. A mathematical model of the inner medullary
collecting duct of the rat: pathways for Na and K transport. Am.
J. Physiol. 274, 841e855.
Westwood, F.R., 2008. The female rat reproductive cycle: a practical his-
tological guide to staging. Toxicol. Pathol. 36, 375e384.
Whiddon, Z.D., Rynberg, S.T., Mast, T.G., Breza, J.M., 2017. Aging de-
creases chorda-tympani nerve responses to NaCl and alters
morphology of fungiform taste pores in rats. Chem. Senses 2,
117e128.
Whitney, K.M., 2018a. Male accessory sex glands. In: Suttie, A.W. (Ed.),
Boorman’s Pathology of the Rat, second ed. Academic Press, Lon-
don, pp. 579e587.
Whitney, K.M., 2018b. Male accessory sex glands. In: Parker, G.A.,
Picut, C.A. (Eds.), Atlas of Histology of the Juvenile Rat, second
ed. Academic Press, London, pp. 579e587.
Widdicombe, J.H., Chen, L.L., Sporer, H., Choi, H.K., Pecson, I.S.,
Bastacky, S.J., 2001. Distribution of tracheal and laryngeal mucous
glands in some rodents and the rabbit. J. Anat. 198, 207e221.
Williams, D., 2002. Ocular disease in rats: a review. Vet. Ophthalmol. 5,
183e191.
Williams, D., 2012. The rat and mouse eye. In: Williams, D. (Ed.),
Ophthalmology of Exotic Pets, first ed. Wiley Blackwell, West Sus-
sex, UK, pp. 86e108.
Wilson, D.A., Sullivan, R.M., 1999. Respiratory airflow pattern at the
rat’s snout and an hypothesis regarding its role in olfaction. Phys-
iol. Behav. 66, 41e44.
Wong, D.L., Tai, T.C., Wong-Faull, D.C., Claycomb, R., Kvetnansky, R.,
2004. Genetic mechanisms for adrenergic control during stress.
Ann. N. Y. Acad. Sci. 1018, 387e397.
World Association of Veterinary Anatomists, 2017. Nomina Anatomica
Veterinaria, sixth ed. International Committee on Veterinary Gross
Anatomical Nomenclature, Hanover, Germany http://www.wava-
amav.org/index.html.
Wren, M., Dauchy, R., Hanifin, J., Jablonski, M., Warfield, B.,
Brainard, G., Blask, D., Hill, S., Ooms, T., Bohm, R., 2014. Effect of
different spectral transmittances through tinted animal cages on
circadian metabolism and physiology in Sprague-Dawley rats.
J. Am. Assoc. Lab. Anim. Sci. 53, 44e51.
Wren-Dail, M., Dauchy, R., Ooms, T., Baker, K., Blask, D., Hill, S.,
Dupepe, L., Bohm, R., 2016. Effects of colored enrichment devices
on circadian metabolism and physiology in male Sprague-Dawley
rats. Comp. Med. 66, 384e391.
Wüthrich, R.P., 2000. The urinary system. In: Krinke, G.J. (Ed.), The
Laboratory Rat. Academic Press, London, pp. 385e400.
BIOLOGY AND CARE
Xu, J.H., Yao, M., Ye, J., Wang, G.D., Wang, J., Cui, X.J., Mo, W., 2016.
Bone mass improved effect of icariin for postmenopausal osteopo-
rosis in ovariectomy-induced rats: a meta-analysis and systematic
review. Menopause 23, 1152e1157.
Yamamoto, M., Seedor, J.G., Rodan, G.A., Balena, R., 1995. Endogenous
calcitonin attenuates parathyroid hormone-induced cancellous
bone loss in the rat. Endocrinology 136, 788e795.
Yamamoto, Y., Tanaka, A., Kanamaru, A., Tanaka, S., Tsubone, H.,
Atoji, Y., Suzuki, Y., 2003. Morphology of aging lung in F344/N
rat: alveolar size, connective tissue, and smooth muscle
cell markers. Anat. Rec. A. Discov. Mol. Cell. Evol. Biol. 272,
538e547.
Yamamoto, Y., Ozawa, Y., Yokoyama, T., Nakamuta, N., 2018. Immuno-
histochemical characterization of brush cells in the rat larynx.
J. Mol. Histol. 49, 63e73.
Yanase, M., Kanosue, K., Yasuda, H., Tanaka, H., 1991. Salivary secre-
tion and grooming behaviour during heat exposure in freely mov-
ing rats. J. Physiol. 432, 585e592.
Yang, B., Bankir, L., 2005. Urea and urine concentrating ability: new in-
sights from studies in mice. Am. J. Physiol. Renal. Physiol. 288,
881e896.
Yang, D., Ye, Q., Williams, D.S., Hitchens, T.K., Ho, C., 2004. Normal
and transplanted rat kidneys: diffusion MR imaging at 7 T. Radi-
ology 231, 702e709.
Yorke, A., Kane, A.E., Hancock Friesen, C.L., Howlett, S.E.,
O’Blenes, S., 2017. Development of a rat clinical frailty index.
J. Gerontol. A. Biol. Sci. Med. Sci. 72, 897e903.
Young, B., Heath, J.W., 2000. Gastrointestinal tract. In: Young, B.,
Heath, J.W. (Eds.), Wheater’s Functional Histology: A Test and
Colour Atlas, fourth ed. Churchill Livingstone, New York,
pp. 249e273.
Zabel, M., Schiebler, T.H., 1980. Histochemical, autoradiographic and
electron microscopic investigations of the renal proximal tubule
of male and female rats after castration. Histochemistry 69, 276.
Zeiss, C.J., Tu, D.C., Phan, I., Wong, R., Treuting, P.M., 2018. Special
senses: eye. In: Treuting, P.M., Dintzis, S.M., Montine, K.S. (Eds.),
Comparative Anatomy and Histology: A Mouse, Rat, and Human
Atlas, second ed. Academic Press, London, pp. 445e470.
Zhang, Y., Kolli, T., Hivley, R., Jaber, L., Zhao, F.I., Yan, J., Herness, S.,
2010. Characterization of the expression pattern of adrenergic re-
ceptors in rat taste buds. Neuroscience 169, 1421e1437.
Zheng, D., Soh, B.S., Yin, L., Hu, G., Chen, Q., Choi, H., Han, J.,
Chow, V.T., Chen, J., 2017. Differentiation of club cells to alveolar
epithelial cells in vitro. Sci. Rep. 7, 41661. https://dx.doi.org/10.
1038/srep41661.
Ziv, E., Bendayan, M., 2000. Intestinal absorption of peptides through
the enterocytes. Microsc. Res. Tech. 49, 346e352.