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Annu Rev Neurosci. Author manuscript; available in PMC 2021 July 08.
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Published in final edited form as:

Annu Rev Neurosci. 2020 July 08; 43: 315–336. doi:10.1146/annurev-neuro-100419-100636.

Suckling, Feeding, and Swallowing: Behaviors, Circuits, and

Targets for Neurodevelopmental Pathology
Thomas M. Maynard1, Irene E. Zohn2,3, Sally A. Moody4, Anthony-S. LaMantia1,5
1Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia, 24016, USA
2Department of Pediatrics, George Washington University School of Medicine and Health
Sciences, Washington DC, 20037, USA
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3Centerfor Genetic Medicine Research, Children’s National Health System, Washington DC,
20037, USA
4Department of Anatomy and Cell Biology, George Washington University School of Medicine and
Health Sciences, Washington DC, 20037, USA
5Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, 24061, USA

Abstract
All mammals must suckle and swallow at birth, and subsequently chew and swallow solid foods,
for optimal growth and health. These initially innate behaviors depend critically upon coordinated
development of the mouth, tongue, pharynx, and larynx as well as the cranial nerves that control
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these structures. Disrupted suckling, feeding, and swallowing from birth onward—perinatal
dysphagia—is often associated with several neurodevelopmental disorders that subsequently alter
complex behaviors. Apparently, a broad range of neurodevelopmental pathologic mechanisms also
target oropharyngeal and cranial nerve differentiation. These aberrant mechanisms, including
altered patterning, progenitor specification, and neurite growth, prefigure dysphagia and may then
compromise circuits for additional behavioral capacities. Thus, perinatal dysphagia may be an
early indicator of disrupted genetic and developmental programs that compromise neural circuits
and yield a broad range of behavioral deficits in neurodevelopmental disorders.

Keywords
dysphagia; neurodevelopmental disorders; cranial nerves; oropharyngeal development; suckling
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Introduction
Newborn mammals must eat to survive. Thus, precise, genetically defined developmental
programs must be executed prenatally to ensure effective nursing at birth and subsequently
chewing and swallowing solid foods. Infants often encounter potentially life-threatening

anthonysl@vtc.vt.edu.
Disclosure statement
The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the
objectivity of this review.
 Maynard et al. Page 2

difficulties suckling, feeding, and swallowing (SFS)—referred to collectively as pediatric

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dysphagia. Nevertheless, relatively little is known about the integrated development of the
biomechanical apparatus and neural circuits that facilitate effective SFS. We consider how
fundamental mechanisms for oropharyngeal, hindbrain, and cranial nerve (CN) development
establish SFS and how disrupting these processes leads to pediatric dysphagia. Effective SFS
at birth requires the coordination of embryonic patterning; progenitor specification; and
cellular differentiation of cranial bones, muscles, and nerves (Alexander et al. 2009, Chai &
Maxson 2006, Cobourne et al. 2019, Cordes 2001, Ruder & Arber 2019, Yamane 2005). We
assess how these mechanisms are disrupted in dysphagia (Kleinert 2017, LaMantia et al.
2016, Robertson et al. 2017). Finally, we summarize studies of a mouse genetic model for
pediatric dysphagia and speculate on how SFS development informs our understanding of
behavioral deficits and neural circuit dysfunction in neurodevelopmental disorders.
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Defining an innate behavior: starting to suckle

The vocabulary that describes suckling parallels that for adult feeding and swallowing (Jean
2001, Matsuo & Palmer 2008, Sasegbon & Hamdy 2017). Three phases define the adult
behavior: oral, pharyngeal, and esophageal (Figure 1, left; Table 1). In the oral phase, food is
brought into the mouth and chewed and mixed with saliva—essential for solid food—by jaw
and tongue movements, yielding a bolus for swallowing. The pharyngeal phase begins as the
bolus is pushed back on the tongue. Pharyngeal muscles pull the larynx forward, elevate the
hyoid bone, and close the epiglottis, protecting the airway as the bolus traverses the pharynx.
In concert, soft palate muscles elevate to close the nasopharynx, preventing aspiration into
nasal sinuses. Finally, in the esophageal phase, the esophageal sphincter relaxes to allow the
bolus to enter the esophagus and then closes as a peristaltic wave pushes food toward the
stomach.
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In infants, a suck-swallow-breathe cycle is in place at birth and then advances toward a

chew-swallow-breathe cycle (Matsuo & Palmer 2015). To suck liquids, infants use the same
oropharyngeal structures used by adults for chewing and swallowing (Lau 2015, Medoff-
Cooper et al. 2010); however, their underdeveloped state facilitates sucking liquids (Figure
1b). There are two key distinctions: First, in the oral phase, lips, cheeks, and tongue produce
a vacuum for sucking movements. Second, the larynx and hyoid lay relatively higher in the
neck, closer to the tongue and soft palate, and the epiglottis is horseshoe shaped rather than
flat as in adults. Thus, during the pharyngeal phase, the immature epiglottis presses
anteriorly against the soft palate and tongue, diverting milk around the trachea into the
esophagus (Figure 1b, right). During the esophageal phase, the tongue pulses to draw milk
through the mouth, around the epiglottis, to swallow a continual stream. The trachea remains
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open, allowing breathing through the nose during uninterrupted feeding. Over the first year,
the neck grows, the hyoid and larynx lower, the epiglottis flattens, and the soft palate
matures, facilitating the transition to eating solid food between four and six months
(Laitman et al. 1977, Westhorpe 1987). Additional feeding difficulties often arise during this
transition, suggesting that in some infants, ongoing anatomical and circuit differentiation fail
to accommodate the dynamics of SFS.

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Babies, behavior, and biomechanics: muscular control of suckling and

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swallowing
A sequence of activation by muscles that attach to and/or move the skull, jaws, hyoid, and
laryngeal cartilages (Matsuo & Palmer 2015) (Figure 1; Table 1) is necessary to suckle. This
sequence begins with contracting tongue muscles to latch under the nipple, lip muscles to
form a tight seal, cheek muscles to constrict the oral cavity, and tongue and palate muscles to
produce a sustained vacuum (Tamura et al. 1998). Suprahyoid and lateral pterygoid muscles
open the jaws, and masseter, temporalis, and medial pterygoid muscles close them,
facilitating tongue movements. Swallowing requires oropharyngeal relaxation and
constriction: The soft palate elevates and the uvula expands to prevent milk entering the
nasopharynx, while suprahyoid muscles elevate the hyoid, enlarging the oropharyngeal
lumen and upper esophagus (Figure 1b; Table 1). This sequence is engaged for ingesting
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liquids; however, it can be elicited spontaneously or in response to objects like pacifiers—

nonnutritive sucking—which also results in homeostatic responses for digestion and appetite
regulation in the absence of food intake (Pinelli & Symington 2000). During infancy, biting
fingers, toes, or toys also activates these movements (Tamura et al. 1998), reinforcing SFS as
an innate and reflex-driven behavior that then transitions to a learned, discriminatory
behavior (Hadders-Algra 2018, Koffman et al. 1998) (Figure 1b). To begin chewing solid
food, the infant engages rhythmic constriction/relaxation of jaw muscles with less
involvement of facial muscles. The tongue pushes the food bolus into the pharynx, and jaw
opener/closer muscles used for reflexive biting generate force for chewing as the suckling
reflex is lost (Tamura et al. 1998). When infants swallow, jaws open and lips purse tightly;
when adults swallow, maxillary and mandibular teeth are held together, the tongue is placed
on the hard palate, and lips relax. The infant-to-adult transition relies upon gradual changes
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in oropharyngeal muscle recruitment over several years that are not associated with weaning
(Festila et al. 2014).

A distributed cranial nerve network controls suckling, feeding, and

swallowing
SFS musculoskeletal activation and modulation require an equally dynamic neural circuit.
The essential SFS neural circuit is defined by 5 of the 12 CNs: CNs V, VII, IX, X, and XII
(Figure 1; Table 1). CNs V and VII mediate the oral phase; CNs IX, X, and XII regulate the
pharyngeal and esophageal phases. Peripheral trigeminal ganglion sensory neurons (CNgVs)
detect and relay somatosensation from the lower face and anterior oropharynx to brainstem
trigeminal nuclei. The mesencephalic trigeminal nucleus relays mechanosensory information
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from jaw-closer muscles and teeth. CN V motor neurons innervate jaw closer and some
oropharyngeal muscles. The facial nerve, CN VII, has several roles: Motor neurons
innervate lip, cheek, hyoid elevator, and jaw-opening muscles; preganglionic
parasympathetic fibers innervate salivary glands; and geniculate ganglion sensory neurons
relay taste from the tongue to the solitary nucleus. The remaining three CNs are responsible
for motor control of the pharyngeal and esophageal phases (Figure 1; Table 1). CNs IX
(glossopharyngeal) and X (vagus) include nucleus ambiguus motor neuron axons that
innervate laryngeal muscles and the palatoglossus, an extrinsic tongue muscle. CN XII

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(hypoglossal) innervates the remaining tongue muscles. Together, peripheral sensory and
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brainstem motor neurons that contribute to these five CNs, relevant brainstem motor or
sensory relay nuclei, and their interconnections constitute the primary SFS neural circuit.
Subsequent SFS refinement occurs as chemosensory (Al Ain et al. 2013, Coureaud et al.
2006, Logan et al. 2012, Loos et al. 2019), hypothalamic (Zimmer et al. 2019), and cortical
inputs to CN networks mature (Muscatelli & Bouret 2018).

Ready at birth: evidence for a distinct developmental program for suckling,

feeding, and swallowing
Antecedents of SFS emerge before birth. Sucking and swallowing movements are detected
by ultrasound by the end of the first trimester (Delaney & Arvedson 2008, Festila et al.
2014, Hadders-Algra 2018, McCain 2003, Miller et al. 2003, Reissland et al. 2012). Muscle
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differentiation begins with the tongue—around 30 days. Hypoglossal (CN XII) nerve
rootlets emerge from the brainstem around 28 days and reach nascent tongue muscles by 37
days (O'Rahilly & Muller 1984). Axons from the nucleus ambiguus (CNs IX and X) arrive
as early as 30 days (Brown 1990). All CNs exit the brainstem by gestational week 6, as
palatine and pharyngeal muscles—subsequently innervated by CNs V, IX, and X—appear
(Domenech-Ratto 1977, Muller & O'Rahilly 2011). In most mammals, including those born
at relatively early (altricial) stages, SFS muscles and nerves are established at similar stages
(Chandrasekhar 2004, Schmidt et al. 2013). Nevertheless, additional development is
required. In preterm infants, suckling is not fully effective until 32–34 gestational weeks
(Delaney & Arvedson 2008), a clinical challenge for their care. The early emergence of the
integrated biomechanic/neural SFS system and behavior suggests a new significance for
cranial and hindbrain developmental mechanisms (Figure 2): They define a dedicated
developmental program based upon a distinct genetic architecture that ensures SFS
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functional integrity from birth onward.

Building the biomechanics for suckling, feeding, and swallowing

The integrated SFS developmental program initially engages all three germ layers—
ectoderm, mesoderm, and endoderm—to generate bone, cartilage, skeletal and smooth
muscle, glandular tissue, epidermis, ciliated epithelia, neurons, and glia. The oral cavity,
trachea, and esophagus derive from the endodermal foregut tube, with some mesodermal/
ectodermal contributions (Billmyre et al. 2015, Jacobs et al. 2012, Lewis & Tam 2006,
Nowotschin et al. 2019, Ziermann et al. 2018). The SFS musculoskeletal scaffold develops
via coordination of pharyngeal and anterior neural tube/hindbrain/neural crest patterning
(Rinon et al. 2007) (Figure 2). The vertebrate cranial skeleton mostly derives from the
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hindbrain neural crest (Kuratani 2018). Oropharyngeal and esophageal skeletal muscles
derive from the mesoderm of the pharyngeal arches, with six evaginations (five in humans
and mice) on either side of the endoderm-derived pharynx (Kaplan et al. 2015, Ziermann et
al. 2018) (Figure 2). Each arch includes mesodermal mesenchyme covered by outer
ectodermal and inner endodermal epithelia. Hindbrain-derived neural crest cells in the
arches contribute to cranial cartilage and tendons. Cranial paraxial mesoderm generates the
myogenic precursors of key SFS muscles (Figure 2). The anterior-posterior (A-P)

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coordination of foregut, musculoskeletal, and hindbrain differentiation, based upon A-P

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position of the pharyngeal arches, is essential for the biomechanical and neural circuit
differentiation that ensure effective SFS at birth.

Building neural circuits for suckling, feeding, and swallowing

SFS stereotypy and the imperative for integrated behavior at birth raise a central
neurobiological question: What is the specific developmental program that ensures
functionally competent neural circuits for neonatal SFS? We suggest a developmental
program divided into two phases. The first phase starts before the neural tube closes and
depends critically on genetic constraints that impose an A-P pattern on the entire head,
including the hindbrain, in all vertebrates (Diogo et al. 2015, Parker et al. 2016, Schmidt et
al. 2013) (Figure 2). Hindbrain metameric organization (rhombomeres) emerges at this time,
embryonic day (E)8.0 in the mouse, and constrains the development of cranial bones and
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muscles as well as the sensory and motor neurons that constitute the SFS primary circuit.
The cranial sensory ganglia—CNgV, VII, IX, and X—coalesce as a mosaic of rhombomere-
specified neural crest and cranial placode cells (Breau & Schneider-Maunoury 2015, Fode et
al. 1998, Karpinski et al. 2016, Steventon et al. 2014) (Figure 2). They begin to extend axons
into the undifferentiated pharyngeal periphery and hindbrain between E9.0 and E9.5. Their
dual origin determines cranial sensory neuron functional identity—placode cells
differentiate, mostly, as mechanoreceptors and neural crest cells generate primarily
nociceptors (Klein et al. 1994, Smeyne et al. 1994).

In parallel, hindbrain motor neurons acquire excitable properties during this period. CN V
and VII motor neurons are physiologically active by E9.5, based upon optically recorded Ca
++ transients (Gust et al. 2003). By E10.5, CN V, VII, IX, and X motor neurons—key
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populations for SFS—fire autonomously (Abadie et al. 2000), and by E12.5, there is
rhythmic bilateral firing across the entire hindbrain ensemble. Apparently, the early
signaling and transcriptional regulation that underlie hindbrain axial organization and
rhombomere specification are critical for initial SFS-related motor circuit development. The
identities of rhombomeres r2, r3, r4, r6, and r7—the sources of CN V, VII, IX, and XII
sensory and motor neurons—must be established for optimal SFS circuit development
(Figure 2). CNs from r4 and r5 contribute to other aspects of SFS (e.g., taste, salivation; see
Table 1) but are not as crucial for the SFS behavioral sequence. Thus, patterning hindbrain
rhombomeric axes emerges as a crucial contributor to establishing the fundamental behavior.

This second phase, when neurons differentiate and synapses are made, ultimately facilitates
experience- and activity-dependent circuit maturation as feeding behaviors mature. At the
outset, axon growth and dendritic differentiation and synaptogenesis from, to, and within the
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brainstem accelerate, influenced by trophic interactions that depend upon the hindbrain or
oropharyngeal target differentiation (Buchman & Davies 1993, Huang et al. 1999, Lindsay
1996, Mikaels et al. 2000, Vogel & Davies 1991). These interactions also refine
mechanoreceptive versus nociceptive identities of cranial sensory neurons. Neurotrophic
ligands characterize distinct targets, and cognate receptors are expressed by subclasses of
mechanoreceptors or nociceptors (Ernsberger 2009, Snider & Silos-Santiago 1996, Wright
& Snider 1995). In addition, central pattern-generator circuits emerge in the trigeminal,

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facial, ambiguus, and hypoglossal motor nuclei to regulate SFS (Dellow & Lund 1971,
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Morquette et al. 2012, Nakamura et al. 2004). Presumably, this process reflects the
acquisition of burst-related intrinsic properties (Cifra et al. 2009), additional
interconnections between nuclei, and maturation of local interneuron networks (Bourque &
Kolta 2001, Kolta 1997) to generate the rhythmicity and force necessary to chew solid food.
Subsequently, forebrain inputs influence hindbrain CN circuits to refine modes of food
intake and preferences and to define homeostatic versus hedonic feeding (Muscatelli &
Bouret 2018, Rossi & Stuber 2018). These circuit changes may also contribute to adaptive
responses to varying food characteristics (e.g., hardness, viscosity, chemosensory aesthetics)
that operate over the remainder of life (Ashiga et al. 2019, Woda et al. 2006)

Dysphagia: a first hit of neurodevelopmental behavioral pathology

The high frequency of perinatal dysphagia—up to 25% in otherwise typical infants, and as
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high as 85% in those with developmental disorders—suggests that the genetic network that
specifies the SFS developmental program is vulnerable to mutation and environmental
disruption. These disruptions may contribute to broader circuit pathology and indicate risk
for additional neurodevelopmental impairment (Berlin et al. 2011, Nicholls & Bryant-
Waugh 2009). Dysphagia is a frequent complication in cerebral palsy, in which motor
control is globally altered (Asgarshirazi et al. 2017). Perinatal dysphagia also coincides with
craniofacial anomalies in a broad range of neurodevelopmental disorders (Compton &
Walker 2009, Solzak et al. 2013, Tripi et al. 2019) (Table 2). Accordingly, dysphagia may
indicate a risk for deficits not diagnosed until an infant matures and complex behaviors
emerge (Berlin et al. 2011). Some infants with significant morphogenetic anomalies are
dysphagic at birth and subsequently diagnosed with intellectual disability (ID) or autism
spectrum disorder (ASD). In other children already diagnosed with ASD, SFS difficulties
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are recognized later due to diminished growth, aspiration-based infections, or altered food
preferences (Betalli et al. 2013, Field et al. 2003, Osugo et al. 2017, Twachtman-Reilly et al.
2008). In addition, children diagnosed with attention deficit hyperactivity disorder (ADHD)
(Beck et al. 2005, Celletti et al. 2015) and fetal alcohol syndrome (Amos-Kroohs et al. 2016,
Shen et al. 2013, Werts et al. 2014) have feeding and swallowing complications. Dysphagia
in congenital heart disease (CHD) may reflect altered neural as well as pharyngeal arch
differentiation (Table 2). In CHD, hindbrain motor and sensory relay neurons as well as the
neural crest can be compromised (Calmont et al. 2018, Plein et al. 2015). Moreover, CHD,
due to either hypoxia/ischemia or parallel disruption of cardiovascular and neural
development, results in a higher frequency of complex behavioral deficits (Cohen & Earing
2018, Snookes et al. 2010). Thus, dysphagia, pharyngeal and neural crest anomalies, and
complex behavioral deficits are shared by multiple neurodevelopmental disorders.
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Dysphagia is also a frequent complication in genetic neurodevelopmental syndromes,

including Down (Stanley et al. 2019), Rett (Mezzedimi et al. 2017), Christianson (Morrow
& Pescosolido 2018), Troyer (Baple & Crosby 2004), Kabuki (Adam et al. 2019), Noonan
(Shah et al. 1999), and CHARGE syndromes (Dobbelsteyn et al. 2008) (Table 2). Often, the
genes mutated in these syndromes are expressed widely or ubiquitously in the developing
brain. This suggests that broader gene networks associated with each syndrome may first
contribute to hindbrain development underlying early optimal SFS and then compromise

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additional circuit development. DiGeorge or 22q11.2 deletion syndrome (22q11DS) also

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disrupts both craniofacial and neural development as well as cardiac, limb, and digit
differentiation (McDonald-McGinn et al. 2015). The coincidence of pharyngeal and neural
phenotypes suggests that children with 22q11DS may have a higher frequency of feeding
and swallowing difficulties. This is indeed the case; at least 85% are diagnosed with
dysphagia early in life (Eicher et al. 2000). In addition, many 22q11-deleted genes are
expressed first in the neural crest or in the developing hindbrain early and then in multiple
brain regions, including the cerebral cortex, hippocampus, and basal ganglia (Maynard et al.
2003, 2008; Meechan et al. 2007; Motahari et al. 2019). Thus, dysphagia in 22q11DS may
reflect the diminished dosage of key genes in critical brain regions at essential times in their
development.

Dysphagia also arises after a lifetime of normal feeding and swallowing (Rommel & Hamdy
2016) due to stroke, brain injury, or neurodegenerative diseases, including amyotrophic
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lateral sclerosis, muscular dystrophy, multiple sclerosis, and Parkinson’s and Alzheimer’s
diseases (Aghaz et al. 2018, Audag et al. 2019, Chouinard 2000, Polychronis et al. 2019).
Adult dysphagia is primarily a disorder of the pharyngeal and esophageal phases of
swallowing due to diminished cortical control of CN function as well as cranial motor
neuron dysfunction or degeneration (Gonzalez-Fernandez et al. 2015). Apparently,
additional forebrain/midbrain control enables adult SFS, distinguishing it from the neonatal
behavior. The association of dysphagia with adult neurodegenerative disorders raises two
issues for individuals with neurodevelopmental disorders: First, perinatal dysphagia, even if
resolved, may establish greater risk for later neurodegenerative changes. Second, subclinical
disruptions in oropharyngeal or hindbrain/CN circuit development may enhance dysphagia
risk later in life.
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Interrupted programs: divergent oropharyngeal differentiation in dysphagia

Craniofacial and oropharyngeal developmental mechanisms are likely pathogenic targets for
perinatal dysphagia. Disrupted cranial neural crest patterning and differentiation, leading to
cleft lip/palate and micrognathia (Baudon et al. 2009, Breik et al. 2016, Miller 2011),
compromise the SFS oral phase. The pharyngeal phase relies on optimal tongue
development. Tongue morphogenesis engages a neural crest scaffold for cranial mesodermal
progenitors that generate muscles of the tongue, influenced by axial signals (i.e., Shh, Bmps,
Fgfs) and downstream transcription factors, including Dlx, Pax, and MyoD family members
(Parada & Chai 2015, Parada et al. 2012). Human aglossia, often in the context of
oromandibular-limb hypogenesis (Milam et al. 2014) or situs inversus (Amor & Craig 2001),
likely reflects disruption of similar signals and effectors. Failed trachea/esophagus
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separation, a fairly common occurrence (1/3,500 births) (Torfs et al. 1995), often
accompanies CHD or genetic syndromes (Billmyre et al. 2015), complicating the esophageal
phase. In animal models, tracheal/esophageal malformations reflect altered foregut/
notochord interactions via Bmp, Wnt, and Fgf signaling and altered transcription factor
expression, including Nkx2.1 and Sox2 (Que 2015, Que et al. 2006). Thus, craniofacial and
oropharyngeal anomalies associated with dysphagia often arise due to disrupted axial signals
and downstream patterning of related transcription factors.

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Most dysphagic infants and children, including those with neurodevelopmental syndromes,
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do not have these extreme defects. Infants and children with 22q11DS have an increased
incidence most likely due to subtler, but functionally significant, oropharyngeal
dysmorphology. In 22q11DS, the palatal velum, superior pharyngeal, and levator palatine
muscles are altered (Filip et al. 2018, Huang & Shapiro 2000, Kollara et al. 2019,
Vantrappen et al. 2001, Zim et al. 2003; but see Widdershoven et al. 2011). One of the most-
studied 22q11 candidate genes for pharyngeal and cardiovascular anomalies is the T-box
transcription factor Tbx1, a regulator of pharyngeal arch mesoderm/endoderm differentiation
(Dastjerdi et al. 2007, Grifone et al. 2008, Kelly et al. 2004, Scambler 2010). In Tbx1−/−
mouse embryos, which die by mid- to late gestation, first and second pharyngeal arch–
derived cranial muscles are hypoplastic or lost, the mandible is diminished, soft palate and
submucosal clefts are seen, and cranial bones are dysmorphic or absent. In both Tbx1−/− and
Tbx1+/− embryos, fourth pharyngeal arch–derived muscles that elevate the soft palate are
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compromised (Jerome & Papaioannou 2001, Kong et al. 2014, Lindsay et al. 2001, Merscher
et al. 2001), and CNs X and IX, which innervate these structures, are dysmorphic (Calmont
et al. 2018, Karpinski et al. 2014, Okubo & Takada 2015). Accordingly, disrupted
transcription factor activity in the pharyngeal mesoderm and endoderm compromises
oropharyngeal development in 22q11DS. Apparently, mutations associated with
neurodevelopmental syndromes target the earliest phases of the SFS developmental
program, prefiguring perinatal dysphagia.

Even mice have dysphagia: animal models of disrupted suckling, feeding,

and swallowing
This account of typical SFS and perinatal dysphagia raises key questions: What is the
genetic architecture that underlies the SFS developmental program, and how can disruption
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lead to perinatal dysphagia? Clinical history indicates that key events happen before the
mid–third trimester in humans: Premature infants cannot successfully suckle until 32–34
gestational weeks (McCain 2003). Insights from embryological and genetic analyses of
craniofacial and hindbrain development in fish, frogs, chicks, and mice indicate that critical
events likely occur very early in embryogenesis (see Figure 2); however, phenotypic
embryos rarely survive to birth and thus are not models for altered SFS behavior (Figure 2;
Supplemental Table 1). The mutant genes include transcription factors, adhesion molecules,
protein scaffolds, secreted and cell surface ligand receptors, and other signaling
intermediates. Existing dysphagia animal models—mostly focused on adults—rely upon
surgical or vascular lesions in animals without prior history of feeding or swallowing
difficulties. Parallel analyses in newborn animals of adequate size to perform selective
lesions, particularly of the superior laryngeal nerve, confirm the essential contributions of
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CNs to perinatal SFS (Ding et al. 2013, Gould et al. 2017). Nevertheless, this approach
creates pathology in newborns that would otherwise suckle normally rather than
characterizing pathogenesis that leads to disrupted SFS at birth. The challenge, therefore, is
to define an animal model for perinatal dysphagia that exhibits behavioral disruption without
experimental lesions and then analyze oropharyngeal, hindbrain, and CN development prior
to birth with sufficient resolution to determine when key mechanisms diverge, leading to
pathology.

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Novel mouse genetic models of some of the human neurodevelopmental syndromes

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described above may include dysphagia in their phenotypic spectrum, providing a new
approach to understanding the typical and pathogenic mechanisms for SFS. We approached
this problem in mouse models of 22q11DS (Meechan et al. 2015), based upon the
association of 22q11DS with craniofacial and brain anomalies (McDonald-McGinn et al.
2015) and, more essentially, a high frequency of perinatal dysphagia (Eicher et al. 2000,
LaMantia et al. 2016). A valid animal model of perinatal dysphagia should share key
characteristics with dysphagic infants, including those with 22q11DS: (a) failure to gain
weight compared to controls, (b) acute or chronic milk or food aspiration, (c) craniofacial
anomalies, and (d) altered CN function. The genomically accurate LgDel mouse model of
22q11DS (Meechan et al. 2015, Merscher et al. 2001, Motahari et al. 2019) meets these
criteria (Karpinski et al. 2014, Wang et al. 2017) (Figure 3a-d). Accordingly, the LgDel
mouse provides an opportunity to assess when and how genetic and developmental
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divergence in a neurodevelopmental disorder prefigure perinatal dysphagia.

Our work on LgDel mice offers two key insights into the SFS developmental program as a
target for dysphagia pathology (Figure 3). First, a highly specified sequence of
differentiation ensures that SFS is online at birth. Second, disrupting early steps in this
sequence prefigures dysphagia. In typically developing mouse embryos, hindbrain and
craniofacial gene–expression patterns and levels are distinct and quantitatively precise
(Karpinski et al. 2014, Meechan et al. 2007) (Figure 3), as are early coalescence, lineage,
proliferation, identities, and differentiation of cranial sensory ganglia precursors and neurons
(Karpinski et al. 2016) (Figure 3). Initial CN projections are stereotyped, with limited
variation (Karpinski et al. 2014, 2016), and matched by fasciculated projections of small
subsets of sensory and motor axons into as yet undifferentiated targets. By the end of the
first postnatal week, motor neurons in the hypoglossal nucleus that innervate a majority of
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the muscles of the tongue (CN XII) have mature firing patterns as well as excitatory and
inhibitory synaptic responses (Wang et al. 2017). The precision of these molecular and
cellular features declines in the LgDel, resulting in early and consistent, but survivable,
divergence in SFS circuit differentiation, growth of individual CN axons, and physiological
properties of hypoglossal motor neurons. A singular change precedes many of these
differences: A-P hindbrain patterning via retinoic acid (RA) signaling that normally defines
the posterior axis (r6, r7) shifts anterior rhombomeres toward a more posterior identity
(Figure 3). When rescued genetically by diminishing RA levels (Karpinski et al. 2014,
Maynard et al. 2013), CN differentiation in LgDel embryos returns to the wild-type state
(Figure 3). Thus, in LgDel, disrupting the earliest stages of the developmental program for
optimal neonatal SFS, particularly the initial step of A-P hindbrain patterning, prefigures
perinatal dysphagia.
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Suckling, feeding, and swallowing: a key to neurodevelopmental pathology

Simple innate behaviors like SFS are often considered separately from complex cognitive
behaviors. We suggest that disruptions of developmental programs for neural circuits that
enable simple behaviors, especially those essential at birth like SFS, provide insight into
complex circuits and behavioral dysfunction. Loss, gain, or polymorphic function of genes
that regulate circuit development for simple behaviors may fulfill similar roles for circuits

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that mediate complex behaviors. In addition, common circuit anomalies may be shared by
Author Manuscript

simple and complex behaviors—disrupted synaptic transmission, excitatory/inhibitory

balance, or neuromodulation—even if these anomalies occur via distinct pathological
processes. Indeed, mutations and polymorphisms associated with clinically defined
neurodevelopmental disorders like ID, ASD, and ADHD overlap with genes implicated in
hindbrain and CN development (Demontis et al. 2019, Krishnan et al. 2016, Willsey et al.
2018). Anomalies in another innate behavior that relies critically upon a different set of
hindbrain CNs (eye movements) are also correlated with neurodevelopmental disorders
(Oystreck et al. 2011, Whitman & Engle 2017). Mutated genes associated with these
disorders are essential for hindbrain patterning (Tischfield et al. 2005) or neuronal
differentiation (Tischfield et al. 2010, Yamada et al. 2003). The genetic architecture of
craniofacial, oropharyngeal, CN, and hindbrain patterning may provide a blueprint for
circuit differentiation underlying several innate, but nevertheless sophisticated, behaviors.
Author Manuscript

These behaviors emerge early, depend less on learning, and are critical for survival—like
SFS for nutrition or eye movements for vigilance. A similar fundamental plan, relying on
patterning, downstream transcriptional regulation, and subsequent cell-cell signaling, may
also establish dedicated circuits for cognitive behaviors and be targeted by the same
pathologies that alter SFS.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
Work in the coauthors’ laboratories on suckling, feeding, and swallowing is supported by the National Institute of
Child Health and Human Development, grant P01 HD083157. The authors thank David Mendelowitz, Xin Wang,
Author Manuscript

Norman Lee, Anelia Horvath, Anastas Popratiloff, Cheryl Clarkson-Pardes, Beverly Karpinski-Oakley, Zahra
Motahari, Elizabeth Paronett, Bethany Stokes, Corey Bryan, and Gelila Yitsege for their contributions to the
ongoing research effort in the developmental biology and neuroscience of suckling, feeding, and swallowing as part
of this integrated research program.

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Figure 1.
Mechanics, musculature, and cranial nerve innervation are distinct for (a) feeding and
swallowing in adults versus (b) suckling, feeding, and swallowing (SFS) in infants and
toddlers. (a, top row) The functional anatomy and mechanics of adult feeding and
swallowing include oral, pharyngeal, and esophageal phases. (Middle and bottom rows)
Each phase relies on key sets of muscles (middle) innervated by a subset of cranial nerves
(bottom). The essential muscles for each phase, and cranial nerves that innervate them, are
color coded as indicated in the bottom right panel. (b) In infants, SFS is performed as a
continuous behavior, without a need to pause for breathing as in the adult. (Top) The high
position of the larynx in the infant (compare location indicated in the top row of panel a with
that in the top row of panel b) allows for the epiglottis to latch against the back of the soft
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palate, creating separate channels for simultaneous nasal breathing and swallowing liquid.
(Top right) Position of the epiglottis during suckling/breathing; dotted arrows indicate flow
of milk. (Middle and bottom rows) Different positions and configurations of key muscles
and cranial nerves for suckling/swallowing are shown (compare to adult feeding/swallowing
in panel a).

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Figure 2.
The integrated developmental program for suckling, feeding, and swallowing (SFS) reflects
the regulation of pharyngeal arch and hindbrain patterning, progenitor specification, and
initial cellular differentiation, controlled by an extensive gene network. (a) Anterior-
posterior (A-P) organization of key muscles and essential cranial motor nerves used in SFS
arises based upon hindbrain/pharyngeal arch patterning. The left column illustrates muscles
derived from each pharyngeal arch or from the posterior (somitic) mesoderm. The muscles
and cranial nerves providing motor innervation are color coded as in Figure 1. (b) The A-P
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axes of the pharyngeal arches and hindbrain reflect metameric divisions (rhombomeres, r1–
r7). Secreted signals [e.g., Fgf, retinoic acid (RA)] define this organization as well as a
nested mosaic of gene expression, including homeobox (Hox) transcription factors. The
dorsal-ventral (D-V) axis, which establishes sensory/motor domains, is defined primarily by
the secreted signals Bmp (dorsal) and Shh (ventral). (c) A-P organization of the sensory
cranial nerves for SFS. The correspondence between the sensory component of each cranial
nerve and its craniofacial field is indicated by the same color code used in Figure 1. (d) A
mixture of neural crest (Wnt1:Cre-recombined, green)- and placode (Six1 protein, red)-
derived progenitors generate sensory neurons in the cranial ganglia (left). These progenitors,
as well as those for cranial motor neurons, generate the rudimentary embryonic cranial
nerves, labeled by beta-3 Tubulin (Tubb3, blue, right). (e) A-P- and D-V-hindbrain
patterning is reflected in localized expression of specific markers, including the dorsal
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marker Pax3 (red, left) and the r4-specific protein Hoxb1 (red, right). (f) Mutations in
multiple genes, including many homeobox transcription factors, disrupt the formation of
specific cranial nerves (for a more complete description of the relationship between genes
and each cranial nerve, see Supplemental Table 1).

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Figure 3.
Disrupted suckling, feeding, and swallowing (SFS) parallels pediatric dysphagia in human
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infants in the LgDel mouse model of 22q11.2 deletion syndrome and reflects early
divergence of the SFS developmental program. (a) Similar to human infants, LgDel mice
show a failure to gain weight and aspirate milk into the nasopharynx, as illustrated by a
swallowing test using fluorescently labeled milk. Evidence of aspiration can be seen in the
nasal sinuses and lungs (bottom right), where residual milk can be immunohistochemically
detected, as can neutrophils, suggesting a resulting infection. (b) LgDel mice have
craniofacial anomalies, including delayed palate closure. This can be seen grossly as a gap in
the developing palate at embryonic day (E)14.5 (top panels, compare black arrows) and
histologically as a failure of the LgDel palatal shelves (black arrows) to elevate to a
horizontal position as in the wild type (WT). (c) The excitable properties of cranial motor
neurons are altered. Motor neurons in the hypoglossal nucleus [cranial nerve (CN) XII] have
been labeled using a choline acetyl transferase (ChAT):Cre driver and an eGFP reporter.
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Patch-clamp electrophysiological recordings of WT and LgDel hypoglossal motor neurons

demonstrate that the amplitude and duration of action potential after-hyperpolarization (AP/
AHP) is diminished in the LgDel. The amplitude, but not frequency, of spontaneous
excitatory postsynaptic currents (EPSCs) is diminished in the LgDel. The frequency of
inhibitory postsynaptic currents (IPSCs) and GABAergic miniature inhibitory postsynaptic
currents (mIPSCs) is diminished in the LgDel. (d) CNs in a whole-mount E10.5 mouse
embryo, labeled immunofluorescently for beta-III tubulin (Tubb3). The image is a composite

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 Maynard et al. Page 22

of a three-dimensional confocal z stack through the entire embryo, taken at a final

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magnification of 200x. The colors reflect a depth code, illustrating more superficial CNs in
red and those deeper in yellow, green, and blue. The inset shows tight fascicles of axons in
the maxillary (Mx, top inset) and mandibular (Md, bottom inset) of CN V extending into the
as yet undifferentiated pharyngeal arches. (e) WT CNs are patterned normally. In parallel,
anterior-posterior (A-P) rhombomere patterning, demonstrated by posterior expression of
Cyp26b1, is distinct. (f) In the LgDel embryo, A-P patterning is disrupted due to an apparent
increase in the retinoic acid (RA) signaling gradient. Cyp26b1, whose expression is
regulated by RA, expands into anterior rhombomeres (r2, r3, r4). CN V growth and
fasciculation is impaired; the ophthalmic (Op), maxillary (Mx), and mandibular (Md)
branches are hypomorphic; CN VII fails to bifurcate; and CNs IX and X are frequently
fused. (g) Reduction of RA signaling levels by heterozygous deletion of Raldh2 restores
Cyp26b1 expression to the WT pattern and rescues the CN V/VII (black arrow) but not the
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CN IX/X (black arrowhead) phenotypes. Whole-embryo image in panel d provided by Zahra

Motahari and Anastas Popratiloff; elements of panels a, b, and e–g adapted from Karpinski
et al. (2014) under a Creative Commons Attribution (CC-BY) 4.0 License; and elements of
panel c adapted with permission from Wang et al. (2017).
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Table 1

The contribution of each of five cranial nerves to the motor and sensory control of suckling, feeding, and swallowing

Muscle Motor function Sensory function

Oral Chew food (jaw) V Temporalis Jaw closure Sense food in V Touch, pain, and temperature for face, oral cavity,
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mouth teeth, anterior tongue

Close Mouth
Move food with tongue
V Medial pterygoid Jaw closure
V Lateral pterygoid Jaw opening, protrusion Proprioreception for jaw, teeth
V Masseter Jaw closure, protrusion
VII Orbicularis oris Purses lips VII Taste for anterior tongue
VII Buccinator Flattens cheeks
XII Intrinsic (longitudinal, Alter the shape of the tongue IX Taste, sensation for posterior tongue
vertical, transverse)

Pharyngeal Push food into pharynx XII Extrinsic (genioglossus, Alter the position of the tongue Sensation in IX Touch, pain and temperature for upper pharynx
(tongue) hyoglossus, styloglossus) in the mouth pharynx

X Palatoglossus Elevates post. tongue during

adult swallowing
Close nasopharynx V Tensor veli palatine Stiffens soft palate
(palate)
X Levator veli palatine
Elevates soft palate
X Palatopharyngeus
X Musculus uvulae Closes nasopharynx
Open pharynx IX Stylopharyngeus Elevates larynx and pharynx
during swallowing
X Salpingopharyngeus Shortens and widens pharynx
X Palatopharyngeus Shortens and widens pharynx
Elevate hyoid V Ant. belly of digastric Elevates hyoid bone
V Mylohyoid Elevates hyoid, tongue

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Cer1 Geniohyoid Elevates hyoid bone forward,
helps depress mandible
VII Post. belly of digastric Elevates hyoid, depresses
mandible
VII Stylohyoid Elevates hyoid and tongue

Esophageal Peristalsis; open X Pharyngeal constrictors Sphincters, push food into X Touch, pain and temperature for lower pharynx,
esophagus (superior, middle, inferior) esophagus larynx, and esophagus (including gag reflex)

Each key cranial nerve is color coded, parallel to the color code used in the figures. For each phase of suckling, feeding, and swallowing behavior, component tasks, in appropriate sequence, are listed; the
requisite cranial nerve(s) for motor and sensory control are identified, and the innervated muscles (motor), cranial/oropharyngeal cutaneous domain, or muscle domain (sensory) is identified.
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Table 2

Clinically and genetically defined developmental disorders with increased incidence of pediatric dysphagia
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Diagnosis of
Craniofacial Cardiovascular Dysphagia
Disorder associated Reference(s)
anomalies anomalies onset
genetic defect

Developmental/neurodevelopmental disorders
Premature birth ND ND Variable Early NA

Cerebral palsy Rare CNVs and Moderately Moderately Early Asgarshirazi et al. 2017,
monogenic mutations frequent frequent Fahey et al. 2017, Pharoah
2007, Self et al. 2012

Attention deficit/ Rare CNVs and ND ND Variable, later Beck et al. 2005, Celletti et
hyperactivity monogenic mutations al. 2015
disorder

Autistic spectrum Rare CNVs and Moderately Rare Variable, later Timonen-Soivio et al. 2015,
disorder monogenic mutations frequent Twachtman-Reilly et al.
2008
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Intellectual Multiple CNVs and rare Frequent NA Variable, early Berlin et al. 2011
disability monogenic mutations

Fetal alcohol NA Frequent Moderately Variable Keyte & Hutson 2012,

syndrome frequent Sant'Anna & Tosello 2006

Congenital heart Multiple CNVs and rare Variable 100% Early onset/ Indramohan et al. 2017,
disease monogenic mutations correlated with Pereira et al. 2015
heart repair
surgery

Genetic syndromes
22q11.2 deletion Heterozygous deletion Frequent, Frequent Early NA
syndrome 1.5 to 3 MB hChr including some
22q11.2 cleft lip/palate

Down syndrome Duplication, hChr21, Frequent Moderately Variable, early Stanley et al. 2019, Versacci
variable size frequent et al. 2018

Rett syndrome Monogenic MECP2, X- Variable Rare Variable, later Isaacs et al. 2003,
linked, male lethality, Mezzedimi et al. 2017
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females affected

Noonan syndrome Monogenic autosomal Frequent Frequent Frequent, early Roberts et al. 2013, Shah et
dominant; PTPN11, al. 1999
SOS1, RAF1, RIT1
CHARGE CHD7 Frequent Frequent Early Bergman et al. 2011,
syndrome Dobbelsteyn et al 2008
Kabuki syndrome KMT2D, KMD6A Frequent Frequent Early Adam et al. 2019

Troyer syndrome SPG20 Variable Not reported Variable Baple & Crosby 2004

Christianson NHE6/SLC9A6 Variable Not reported Variable Morrow & Pescosolido

syndrome 2018

Developmental/neurodevelopmental disorders for which diagnosis is primarily clinical and etiologies are diverse appear first. Genetic syndromes
associated with specific copy number, variants, or mutations in a limited number of single genes appear second. For both groups, pediatric
dysphagia is frequently associated with a much broader phenotypic spectrum, including craniofacial anomalies and cardiovascular malformations.
Abbreviations: CNV,copy number variant ; NA, not applicable; ND, no data.
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