Circumventricular organs and fever
YOSHIMI TAKAHASHI,1 PAULINE SMITH,2
ALISTAIR FERGUSON,2 AND QUENTIN J. PITTMAN1
1Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine,
The University of Calgary, Calgary, Alberta T2N 4N1; and 2Department of Physiology,
Queen’s University, Kingston, Ontario, Canada K7L 3N6
Takahashi, Yoshimi, Pauline Smith, Alistair Fergu-
son, and Quentin J. Pittman. Circumventricular organs
and fever. Am. J. Physiol. 273 (Regulatory Integrative Comp.
Physiol. 42): R1690–R1695, 1997.—We have examined the
roles of three circumventricular organs, the area postrema,
the subfornical organ, and the organum vasculosum of the
lamina terminalis (OVLT), as possible access points for
circulating pyrogens to cause fever. In conscious, unre-
strained rats prepared with telemetry devices, intracerebro-
ventricular cannulas, and intravenous catheters, body tem-
perature was monitored after intravenously administered
lipopolysaccharide and, on a different occasion, after intra-
cerebroventricular prostaglandin E1. Lipopolysaccharide-
induced fevers in sham control lesioned rats were indistin-
guishable from those observed in animals with lesions of the
area postrema, the OVLT, or the tissue immediately adjacent
to this structure (peri-OVLT). In contrast, rats with lesions of
the subfornical organ displayed reduced fevers. In none of the
groups of lesioned animals were prostaglandin E1 fevers
reduced. Thus lesions did not interfere with central thermo-
genic pathways responsive to prostaglandin. Our results
indicate that subfornical organ neurons respond to circulat-
ing pyrogens and through their efferent projections activate
central pathways involved in fever.
area postrema; subfornical organ; organum vasculosum of the
lamina terminalis; lipopolysaccharide; prostaglandin; cytokine
ALTHOUGH PYROGENS such as lipopolysaccharide (LPS)
and interleukins (ILs) can elicit fever when adminis-
tered either intravenously, intraperitoneally, or cen-
trally (intracerebroventricularly), it is now generally
accepted that the blood-brain barrier precludes general
access of pyrogens into the brain (23). Attention has
thus focused on how the pyrogenic signal reaches the
brain to cause activation of the appropriate neural
pathways. Recently, evidence has been provided that
the subdiaphragmatic vagus may be activated by the
pyrogenic cytokine IL-1 in the gut to cause fever (26,
30), sickness behavior (15), and activation of the hypo-
thalamic-pituitary-adrenal axis (7). Interestingly, c-fos
activation in the brain in response to intraperitoneal
LPS is completely blocked by subdiaphragmatic va-
gotomy, whereas that due to intravenous LPS is only
minimally affected (29). Thus it is possible that there
are several means by which peripheral immune signals
can activate the central nervous system (CNS), depend-
ing on the specific location of the immune challenge.
Over 10 years ago, the potential sensory role of the
circumventricular organs (CVOs), which lie outside of
the blood-brain barrier, in transducing the pyrogenic
signal to the brain was recognized (2). The organum
vasculosum of the lamina terminalis (OVLT) is one
structure that may be an access point for pyrogens to
R1690 0363-6119/97 $5.00 Copyright r 1997 the American Physiological Society
the brain (1, 32), as, in several species, fever can be
elicited after injection of pyrogens directly into the
structure. In response to intravenously administered
LPS, cytokine mRNA and protein levels increase in the
OVLT (18, 19). Similarly, the immediate early gene
c-fos, is activated in this structure after pyrogens are
given peripherally (9, 22, 24, 29). Several investigators
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have examined the consequences of lesions to the OVLT
on fever generation; in sheep (3) and guinea pigs (2),
lesions of the OVLT suppress fever, whereas similar
lesions in rats have been reported to enhance fever (27).
As circulating pyrogens activate many different cen-
tral functions and pathways, evidence that the OVLT
responds with increased c-Fos or IL-1b synthesis in
response to peripheral pyrogens is not, in itself, evi-
dence for its involvement in fever. Few studies have
verified that central thermoregulatory pathways re-
main intact after OVLT lesions and it has been sug-
gested (26) that OVLT lesions may impinge on sites in
the ventromedial preoptic area (VMPO) that are re-
ported to be exquisitely sensitive to prostaglandin E
(PGE) (25); furthermore, the fact that, in rats, lesions of
the OVLT can be associated with elevated fevers (27)
raises the possibility that this structure actually re-
sponds to circulating antipyretics that may be gener-
ated after exposure to LPS (12). It is also possible that
lesions to the OVLT may have produced damage in
descending pathways from another CVO, the subforni-
cal organ (SFO); this structure is known to project to
the hypothalamus via axons passing very close to the
OVLT (10, 17). It is interesting that c-Fos immunoreac-
tivity, increased protein synthesis, and increased levels
of IL-1b are also found in the SFO after systemically
administered pyrogens (20, 24, 31). To the best of our
knowledge, the possible involvement of the SFO as a
structure important in febrile responses to peripheral
pyrogens has not been determined.
Despite the evidence alluded to above, it is often
overlooked that decerebrate animals, with connections
between forebrain and hindbrain structures severed,
are still capable of developing fevers (16). Furthermore,
disruption of descending projections from structures
anterior to the hypothalamus (i.e., OVLT or SFO) did
not affect c-Fos induction in the paraventricular nucleus
after intravenous IL-1b (5). Such observations would
suggest that there are midbrain or brain stem sites also
capable of transducing the peripheral pyrogenic signal
and eliciting a febrile response. Although vagal afferent
signals would presumably use such brain stem sites as
the nucleus of the solitary tract, it is possible that the
area postrema (AP), a CVO sensitive to many circulat-
ing substances (6), could mediate the peripheral pyro-
genic actions of circulating LPS. There is considerable
 CIRCUMVENTRICULAR ORGANS AND FEVER
evidence for c-fos activation and enhanced IL-1b mRNA
activity in this structure (9, 22, 24, 29, 31) after
peripheral injection of various pyrogens.
In light of this evidence for a possible involvement in
fever of other CVOs in addition to the OVLT, we have
carried out experiments designed to test the hypothesis
that the SFO and AP are structures important in
transducing circulating peripheral pyrogenic signals to
brain structures involved in fever generation. We have
also reexamined the role of the OVLT in this regard. To
ensure that any effects on fever were not due simply to
disruption of brain thermogenic pathways, we also
tested the responses of lesioned animals to the central
pyrogen mediator PGE1. Our data do not indicate an
obligatory role for any one CVO in fever generation in
the rat, but point to a possible involvement of the SFO
in responding to circulating pyrogens.
METHODS
Adult, male Sprague-Dawley rats (300–350 g body wt)
were purchased from Charles River, QC, Canada. All experi-
ments were carried out in accordance with guidelines set and
approved by Animal Care Committees of The University of
Calgary and Queen’s University.
AP lesions. Under pentobarbital sodium anesthesia (65
mg/kg ip), the rats were placed in a stereotaxic head holder,
the head was flexed, and the cisterna magna was opened to
permit access to the fourth ventricle. Under stereotaxic
control, rats were given electrolytic (Keithley Instruments
225 Current Source, 0.5 mA for 20 s) lesions of the AP using a
monopolar, parylene C-insulated tungsten electrode (Micro-
Probe) with a tip diameter of 100 µm. Other rats received
sham lesions in which the electrode was placed in the AP but
no current was passed. The midline incision was then sutured
and the animals were allowed to recover for a minimum of 1
wk. During this time, the animal’s health was carefully
monitored, and palatable foods were placed in the cages to
stimulate appetite and prevent undue weight loss. At the end
of this 1-wk recovery period, animals were shipped by air
from Kingston to Calgary and, following a further 7-day rest
period, a second surgery was performed. Under pentobarbital
sodium anesthesia (65 mg/kg), rats were stereotaxically
implanted with a stainless steel 23-gauge thin wall cannula
directed at the lateral ventricle, a jugular intravenous cath-
eter filled with sterile, heparinized saline, and an intraperito-
neal temperature telemetry device (model VMHF, Mini-
Mitter, Sunriver, OR) for remote body core temperature
measurements. The animals were then given a further 1-wk
recovery period before commencement of the experiments. All
rats were housed under a 12:12-h light-dark cycle and given
water and pelleted rat food ad libitum.
SFO lesions. SFO-lesioned rats were treated identically to
those in the AP study except that electrolytic lesions were
made in the SFO using a current of 0.5 mA delivered for 30 s;
peri-SFO lesions were made by lesioning adjacent tissue in
the hippocampal commissure, and, in controls, the electrode
was lowered into the brain near the SFO, but no current was
passed. Stereotaxic coordinates for the SFO lesions were
midline, 0.8 mm anterior to bregma, 4.5 mm below dura.
OVLT lesions. Adult rats under pentobarbital sodium
anesthesia were given electrolytic (Grass, DC Constant Cur-
rent Lesion Maker, 1.5 mA for 30 s) lesions in the OVLT (10.8
mm anterior to bregma; on the midline and 8.3 mm below
dura) or just adjacent to this structure. Other control rats
received sham lesions in which the electrode was lowered in
R1691
the vicinity of the OVLT and no current was passed. As these
experiments were all carried out in Calgary, rats were
prepared with the Mini-Mitter telemetry device and the
indwelling intravenous catheter at the same time.
Experimental protocol.. During at least a 1-wk postopera-
tive period, animals were monitored daily, and palatable
solutions were available to encourage resumption of normal
eating and drinking. All rats lost weight as a result of the
surgeries and lesions, and animals with SFO or AP lesions
were polydipsic. Nonetheless, all animals displayed stable
eating and drinking patterns and appeared healthy before
experiments commenced. This was a minimum of 3 wk after
AP and SFO lesions and at least 1 wk after all other surgical
interventions. All experiments were carried out in a tempera-
ture-controlled room (22°C) in which the rats had been placed
for at least 12 h before they were subjected to experimenta-
tion. Baseline temperature recordings were taken for a
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minimum of 1 h, after which all rats were given injections of
30 µg/kg lipopolysaccharide iv (LPS; Escherichia coli, L-3755,
Sigma) in sterile saline between 1000 and 1200. Body core
temperature was recorded for a further 6 h. Approximately 1
wk later, each rat was subjected to a second experimental
protocol in which body temperature was again measured and
25 ng PGE1 in 5 µl sterile NaCl was given intracerebroven-
tricularly through a 27-gauge stainless steel needle. Tempera-
ture was recorded for a further 2 h.
On termination of the experiments, all rats were deeply
anesthetized with pentobarbital sodium (65 mg/kg ip), then
perfused through the heart with 0.9% saline followed by 4%
formal saline, and postfixed in 10% Formalin for 3 days.
Frozen coronal sections were taken and stained with a Nissl
stain. An individual blind to the experimental protocol and to
the temperature data evaluated the sections for placement of
lesions and assigned animals into lesioned, perilesioned, or
control (sham lesioned) groups on the basis of histological
examination.
All data are reported and plotted as means 6 SE. Tempera-
ture data were evaluated by one-way analysis of variance
corrected for repeated measures (ANOVA), followed by Stu-
dent-Newman-Keuls pairwise comparisons for statistical com-
parison of lesioned, perilesioned, and control groups. After
identification of significant differences between experimental
groups, further ANOVAs were carried out to reveal signifi-
cance at key time points. In addition, fever indexes (FI),
calculated as change in degrees Celsius per hour (D°C/h) after
injection of LPS or PGE, were obtained for each animal, and
differences between controls and experimental groups were
evaluated by an unpaired Student’s t-test for the AP groups
and by an ANOVA for the OVLT and SFO groups. Similar
tests were used to compare baseline temperatures. Statistical
significance was set at P # 0.05.
RESULTS
Examples of sham and effective lesions for each site
are presented in Fig. 1. With respect to AP lesions, all
animals that were placed in the ‘‘lesioned’’ group were
devoid of AP tissue, but in all cases the adjacent
nucleus of the solitary tract was intact. None of the
sham-lesioned animals from this group showed damage
to either the AP or the adjacent tissue aside from traces
of the electrode tract. Animals with lesions of the SFO
all showed a complete absence of SFO tissue with slight
damage to adjacent tissue in the hippocampal commis-
sure. Peri-SFO lesioned animals had lesions similar in
size, but some SFO tissue remained and the adjacent
R1692 CIRCUMVENTRICULAR ORGANS AND FEVER

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Fig. 1. Photomicrographs of coronal sections illustrating the area postrema (AP; A1), subfornical organ (SFO; B1),
and organum vasculosum of the lamina terminalis (OVLT; C1) and typical lesions of respective sites (A2, B2, C2).
Scale bar is 500 µM.

hippocampal commissure was more extensively dam-
aged. Sham-lesioned animals (controls) had evidence of
electrode tracks in the commissure, but in all cases the
SFO was intact and undamaged. With respect to the
OVLT, animals that were considered lesioned showed
destruction of tissue on the midline at locations similar
to those described previously as sites where lesions
interfered with fever generation (2). Lesions, however,
did not obliterate the VMPO, an area highly responsive
to PGE (25). In addition, in this area we identified a
number of ‘‘misses’’ in which tissue adjacent to the
OVLT, but sparing both OVLT and VMPO tissue, was
destroyed; these animals were considered to have le-
sions in the peri-OVLT area. The remaining sham-
lesioned animals exhibited no damage other than a
faint scar from the electrode tract.
AP lesions. At the time of experimentation, basal
body temperatures of rats with lesions of the AP (36.9 6
0.20°C; n 5 10) were identical (P . 0.05) to those of
control, sham-lesioned rats (37.1 6 0.12°C; n 5 7).
Fevers resulting from intravenous injection of 30 µg/kg
LPS are shown in lesioned and control animals in Fig.
 CIRCUMVENTRICULAR ORGANS AND FEVER
2A. In the sham-lesioned control rats, typical LPS-
induced fever was seen, with core temperature begin-
ning to rise ,1 h after injection and reaching a maxi-
mum of ,1.7°C, 2.5 h after injection. The lesioned
animals exhibited a similar profile of fever, although
the initial peak was marginally lower. ANOVA revealed
no significant difference between the groups (P . 0.05).
Fever indexes calculated for each group indicated that
there were no significant differences (P . 0.05) in the
magnitude of the fever as a function of the lesion. With
respect to prostaglandin fever magnitude, lesioned
animals showed delayed defervesence between 1 and
1.5 h after the PGE (P . 0.05, F 5 12.000, Fig. 2B).
Fever indexes were not significantly different in the
two groups.
SFO lesions. Basal core temperatures of the lesioned
(37.4 6 0.22°C; n 5 5), perilesioned (37.2 6 0.11°C, n 5
7), and control (37.3 6 0.12°C; n 5 13) groups were
identical. Figure 3 shows fever responses to LPS in
SFO-lesioned, perilesioned, and control animals. These
groups of animals showed fever profiles that were
slightly different from those of the rats in the AP group
in that they displayed a 0.5°C temperature rise associ-
ated with the injection procedure and handling. Fever
profiles of the SFO control and perilesioned rats were
markedly different from those of the lesioned rats (P ,
0.05; F 5 22.642). Whereas the control and perilesioned
R1693
Fig. 2. Change in body temperature plotted against
time for rats with either sham lesions (control; r; n 5 7)
or lesions (s; n 5 10) of AP in response to intravenous
lipopolysaccharide (LPS; A) and intracerebroventricu-
lar prostaglandin E1 (PGE1; B), each given at time 0.
Insets show fever indexes for each group for 6 h (A) and
2 h (B) after injections. All data are means 6 SE. * Time
points significantly different [P , 0.05; analysis of
variance (ANOVA)] from corresponding control time
point.
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animals displayed robust, 1.5°C fevers peaking at ,2.5
h postinjection, the lesioned rats at this time displayed
only a ,0.5°C fever. Fever indexes over 6 h did not
differ, but over 4 h that of the lesioned rats was
significantly less than for the control and perilesioned
rats (P , 0.05; F 5 20.116). In contrast to these
differences in LPS fevers, prostaglandin fevers in these
three groups of animals were virtually superimposable
with no statistical differences (P . 0.05 for both fever
curves and fever indexes) between them (Fig. 3B).
OVLT lesions. Three groups of animals were exam-
ined for their febrile response; these were divided into
OVLT-lesioned, sham-lesioned, and peri-OVLT-lesioned
animals. Fevers due to LPS were virtually superimpos-
able in all three groups, and the fever indexes were
identical (P . 0.05; Fig. 4A). Prostaglandin fevers in
the three groups were somewhat variable, although
there was no significant difference between the fever
indexes in the three groups (Fig. 4B). The peri-OVLT
groups displayed a slightly higher fever (P , 0.05; F 5
13.550) than did the other two groups.
DISCUSSION
These data indicate that discrete electrolytic lesions
of the AP and the OVLT do not interfere with fever
induced by intravenously injected LPS. In contrast,
Fig. 3. Change in body temperature plotted against
time for rats with either sham lesions (control; r; n 5
13), lesions of the SFO (s; n 5 5), or lesions in tissue
adjacent to the SFO (l; peri-SFO, n 5 7) in response to
intravenous LPS (A) and intracerebroventricular PGE1
(B), each given at time 0. Insets show fever indexes for
each group for 6 h (A) and 2 h (B) after injection. All
data are means 6 SE. * Time points significantly differ-
ent (P , 0.05; ANOVA) from both control and perile-
sioned groups.
R1694 CIRCUMVENTRICULAR ORGANS AND FEVER
Fig. 4. Change in body temperature plotted against
time for rats with either sham lesions (control; r; n 5
6), peri-OVLT lesions (l; n 5 8), or lesions of the OVLT
(s; n 5 7) in response to intravenous LPS (A) and
intracerebroventricular PGE1 (B), each given at time 0.
Insets show fever indexes for each group for 6 h (A) and
2 h (B) after injection. All data are means 6 SE. * Time
points significantly different (P , 0.05 ANOVA) com-
pared with control.
lesions of the SFO resulted in attenuated fevers. The
latter occurred in the absence of interference with
brain thermogenic pathways responsive to PGE, the
presumed end mediator of fever, as PGE-induced ther-
mogenesis was unaltered in these same animals. Thus
our data suggest that the SFO, a structure responsive
to many circulating substances (6), may participate in
the host defense reaction.
Many of the effects of LPS on body temperature are
thought to be mediated by PGE within the brain (4).
Therefore, in all lesioned animals, we evaluated their
responses to intracerebroventricular PGE1 to differenti-
ate between effects of the lesion in interfering with
transduction of the LPS-induced pyrogenic signal to
the brain and possible effects on the animal’s ability to
activate a thermogenic response involving increased
metabolism and decreased heat loss. With respect to all
groups of animals, PGE1 fevers were not reduced by the
lesions, indicating that central thermogenic pathways
responsive to this substance (and presumably to LPS-
activated prostaglandin) were intact. It was of interest
that AP-lesioned rats showed a slightly delayed defer-
vesence after PGE and peri-OVLT lesioned animals
showed a slightly elevated fever peak; we do not have
an explanation for these small differences.
In light of a substantial body of literature implicating
the OVLT as an entry site for LPS, we were surprised
that discrete lesions of this structure did not alter
febrile responses. Thus our data add to the confusion in
the literature in which OVLT lesions have reduced in
some species (1) and augmented in others (27) the
febrile response to peripheral LPS. As pointed out by
Sehic and Blatteis (26), it is possible that, in pre-
vious studies, the lesions impinged on the nearby
VMPO, an area proposed to be a critical locus for
PGE-induced fever generation (11). Such a lesion could
therefore have disrupted central thermogenesis involv-
ing the prostaglandin end mediators. In our studies,
the lesions appeared to spare this area (albeit this area
is not defined by well-demarcated landmarks in our
Nissl-stained sections). It should be pointed out that
these data do not eliminate the OVLT as a potential
access point for circulating pyrogens to influence body
temperature; in the lesioned animal other routes of
access (e.g., the subdiaphragmatic vagus, other pri-
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mary afferent fibers, other CVOs) may provide ad-
equate access to sustain the febrile response, although
an intact OVLT may normally contribute to the overall
response.
A similar argument cautions against eliminating the
AP as a potential responsive site for circulating pyro-
gens. Despite our findings of fevers identical in control
and lesioned rats, some aspects of the CNS response to
circulating pyrogens may reside in this structure; for
example, the AP has recently been identified as a site
involved in central cardiovascular control (6, 8), and the
cardiovascular perturbations associated with LPS expo-
sure, particularly at higher doses (14, 28), may be a result
of actions of circulating pyrogens acting at the AP.
The SFO has not been previously implicated in
central thermoregulatory control, yet SFO-lesioned rats
developed significantly lower fevers than did their
peri-SFO-lesioned or control counterparts. As the hyper-
thermic response to intracerebroventricular PGE1 was
not affected, we conclude that this represents a reduced
response to the circulating pyrogenic signal. One possi-
bility is that the SFO is a structure where circulating
pyrogens can activate cells, which, in turn, project to
sites such as the VMPO and the PVN to activate PGE
synthesis and cause fever. The central connections of
the SFO would certainly support such a possibility (21).
It is also possible that the SFO lesions unmask a strong
antipyretic response to LPS. Finally, we cannot ignore
the possibility that animals with lesioned SFO some-
how respond differently to the intravenously injected
LPS, such that the distribution of the pyrogen is altered
so that access to other responsive tissues (CVOs, vagus)
is impaired.
Perspectives
It is apparent that the means by which the signal
elaborated by a circulating pyrogen can gain access to
the brain may be more complex than originally envi-
sioned. Under different circumstances the organism
may use markedly different means to transduce such a
signal. A local, peripheral inflammation may activate a
peripheral nerve, thereby obviating the need for pyro-
gens to escape from the inflammatory site to reach the
CNS. In contrast, systemic infections wherein pyrogens
 CIRCUMVENTRICULAR ORGANS AND FEVER
may be present in the cerebral circulation, may make
use of the responsive cells in the circumventricular
organs to transduce the signal to a neural one. In light
of the presumed survival value of fever (13), it is not
surprising that evolution has provided more than one
route of access for signaling the brain concerning
peripheral immune state. In this respect, the auto-
nomic response involved in fever is markedly similar to
that of many other homeostatic processes (i.e., energy
balance, water balance, etc.) that employ multiple
mechanisms and many different structures to provide
information concerning the body environment to the
brain.
This work was supported by Medical Research Council grants to A.
Ferguson and to Q. J. Pittman.
Address for reprint requests: Q. J. Pittman, Neuroscience Re-
search Group, Univ. of Calgary, Calgary, Alberta, Canada T2N 4N1.
Received 26 February 1997; accepted in final form 14 July 1997.
REFERENCES
1. Blatteis, C. M. Role of the OVLT in the febrile response to
circulating pyrogens. Prog. Brain Res. 91: 409–412, 1992.
2. Blatteis, C. M., S. L. Bealer, W. S. Hunter, J. Llanos-Q, R. A.
Ahokas, and T. A. J. Mashburn. Suppression of fever after
lesions of the anteroventral third ventricle in guinea pigs. Brain
Res. Bull. 11: 519–526, 1983.
3. Blatteis, C. M., J. R. S. Hales, M. J. McKinley, and A. A.
Fawcett. Role of the anteroventral third ventricle region in fever
in sheep. Can. J. Physiol. Pharmacol. 65: 1255–1260, 1987.
4. Coceani, F., J. Lees, and I. Bishai. Further evidence implicat-
ing prostaglandin E2 in the genesis of pyrogen fever. Am. J.
Physiol. 254 (Regulatory Integrative Comp. Physiol. 23): R463–
R469, 1988.
5. Ericsson, A., K. J. Kovacs, and P. E. Sawchenko. A functional
anatomical analysis of central pathways subserving the effects of
interleukin-1 on stress-related neuroendocrine neurons. J. Neu-
rosci. 14: 897–913, 1994.
6. Ferguson, A. V. Neurophysiological analysis of mechanisms for
subfornical organ and area postrema involvement in autonomic
control. Prog. Brain Res. 91: 413–421, 1992.
7. Gaykema, R. P. A., I. Dijkstra, and F. J. H. Tilders. Subdia-
phragmatic vagotomy suppresses endotoxin-induced activation
of hypothalamic corticotropin-releasing hormone neurons and
ACTH secretion. Endocrinology 136: 4717–4720, 1995.
8. Graham, J. C., G. E. Hoffman, and A. F. Sved. c-Fos expres-
sion in brain in response to hypotension and hypertension in
conscious rats. J. Auton. Nerv. Syst. 55: 92–104, 1995.
9. Hare, A. S., G. Clarke, and S. Tolchard. Bacterial lipopolysac-
charide-induced changes in FOS protein expression in the rat
brain: correlation with thermoregulatory changes and plasma
corticosterone. J. Neuroendocrinol. 7: 791–799, 1995.
10. Johnson, A. K. The periventricular anteroventral third ven-
tricle (AV3V): its relationship with the subfornical organ and
neural systems involved in maintaining body fluid homeostasis.
Brain Res. Bull. 15: 595–601, 1985.
11. Johnson, R. W., M. J. Propes, and Y. Shavit. Corticosterone
modulates behavioral and metabolic effects of lipopolysaccha-
ride. Am. J. Physiol. 270 (Regulatory Integrative Comp. Physiol.
39): R192–R198, 1996.
12. Klir, J. J., J. L. McClellan, W. Kozak, Z. Szelényi, G. H. W.
Wong, and M. J. Kluger. Systemic but not central administra-
tion of tumor necrosis factor-a attenuates LPS-induced fever in
rats. Am. J. Physiol. 268 (Regulatory Integrative Comp. Physiol.
37): R480–R486, 1995.
13. Kluger, M. J. Fever: role of pyrogens and cryogens. Physiol. Rev.
71: 93–127, 1991.
R1695
14. Lang, C. H. Neural regulation of the enhanced uptake of glucose
in skeletal muscle after endotoxin. Am. J. Physiol. 269 (Regula-
tory Integrative Comp. Physiol. 38): R437–R444, 1995.
15. Layé, S., R.-M. Bluthé, S. Kent, C. Combe, C. Médina, P.
Parnet, K. Kelley, and R. Dantzer. Subdiaphragmatic va-
gotomy blocks induction of IL-1b mRNA in mice brain in re-
sponse to peripheral LPS. Am. J. Physiol. 268 (Regulatory
Integrative Comp. Physiol. 37): R1327–R1331, 1995.
16. Liu, J. C., and T. T. Shyy. Pyrogenic responses in the decer-
ebrate monkey (Macaca cyclopis). Exp. Neurol. 67: 481–491,
1980.
17. Miselis, R. R. The efferent projections of the subfornical organ of
the rat: a circumventricular organ within a neural network
subserving water balance. Brain Res. 230: 1–23, 1981.
18. Nakamori, T., A. Morimoto, K. Yamaguchi, T. Watanabe,
N. C. Long, and N. Murakami. Organum vasculosum laminae
terminalis (OVLT) is a brain site to produce interleukin-1 beta
during fever. Brain Res. 618: 155–159, 1993.
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.4 on March 31, 2017
19. Nakamori, T., A. Morimoto, K. Yamaguchi, T. Watanabe,
and N. Murakami. Interleukin-1 beta production in the rabbit
brain during endotoxin-induced fever. J. Physiol. (Lond.) 476:
177–186, 1994.
20. Nakamori, T., Y. Sakata, T. Watanabe, A. Morimoto, S.
Nakamura, and N. Murakami. Suppression of interleukin-1b
production in the circumventricular organs in endotoxin-tolerant
rabbits. Brain Res. 675: 103–109, 1995.
21. Renaud, L. P., A. V. Ferguson, T. A. Day, C. W. Bourque, and
S. Sgro. Electrophysiology of the subfornical organ and its
hypothalamic connections—an in vivo study in the rat. Brain
Res. Bull. 15: 83–86, 1985.
22. Rivest, S., and N. Laflamme. Neuronal activity and neuropep-
tide gene transcription in the brains of immune-challenged rats.
J. Neuroendocrinol. 7: 501–525, 1995.
23. Rothwell, N. J., G. Luheshi, and S. Toulmond. Cytokines and
their receptors in the central nervous system: physiology, pharma-
cology, and pathology. Pharmacol. Ther. 69: 85–95, 1996.
24. Sagar, S. M., K. J. Price, N. W. Kasting, and F. R. Sharp.
Anatomic patterns of FOS immunostaining in rat brain following
systemic endotoxin administration. Brain Res. Bull. 36: 381–
392, 1995.
25. Scammell, T. E., J. K. Elmquist, J. D. Griffin, and C. B.
Saper. Ventromedial preoptic prostaglandin E2 activates fever-
producing autonomic pathways. J. Neurosci. 16: 6246–6254,
1996.
26. Sehic, E., and C. M. Blatteis. Blockade of lipopolysaccharide-
induced fever by subdiaphragmatic vagotomy in guinea pigs.
Brain Res. 726: 160–166, 1996.
27. Stitt, J. T. Evidence for the involvement of the organum
vasculosum laminae terminalis in the febrile response of rabbits
and rats. J. Physiol. (Lond.) 368: 501–511, 1985.
28. Tkacs, N. C., and A. M. Strack. Systemic endotoxin induces
Fos-like immunoreactivity in rat spinal sympathetic regions. J.
Auton. Nerv. Syst. 51: 1–7, 1995.
29. Wan, W., L. Wetmore, C. M. Sorensen, A. H. Greenberg, and
D. M. Nance. Neural and biochemical mediators of endotoxin
and stress-induced c-fos expression in the rat brain. Brain Res.
Bull. 34: 7–14, 1994.
30. Watkins, L. R., L. E. Goehler, J. K. Relton, N. Tartaglia, L.
Silbert, D. Martin, and S. F. Maier. Blockade of interleukin-1
induced hyperthermia by subdiaphragmatic vagotomy: evidence
for vagal mediation of immune-brain communication. Neurosci.
Lett. 183: 27–31, 1995.
31. Williams, L. M., P. E. Ballmer, L. T. Hannah, I. Grant, and
P. J. Garlick. Changes in regional protein synthesis in rat brain
and pituitary after systemic interleukin-1 beta administration.
Am. J. Physiol. 267 (Endocrinol. Metab. 30): E915–E920, 1994.
32. Zeisberger, E., and G. Merker. The role of OVLT in fever and
antipyresis. Prog. Brain Res. 91: 403–408, 1992.