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The Area Postrema: A Brain Monitor and Integrator of Systemic Autonomic State
Christopher J. Price, Ted D. Hoyda and Alastair V. Ferguson
Neuroscientist 2008; 14; 182 originally published online Dec 13, 2007;
DOI: 10.1177/1073858407311100
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http://nro.sagepub.com/cgi/content/abstract/14/2/182
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The Area Postrema: A Brain Monitor and
Integrator of Systemic Autonomic State
CHRISTOPHER J. PRICE, TED D. HOYDA, and ALASTAIR V. FERGUSON
Department of Physiology, Queen’s University, Kingston, Ontario, Canada
The area postrema is a medullary structure lying at the base of the fourth ventricle. The area postrema’s privileged location outside of the blood-brain barrier make this sensory circumventricular organ a vital player in the
control of autonomic functions by the central nervous system. By virtue of its lack of tight junctions between
endothelial cells in this densely vascularized structure and the presence of fenestrated capillaries, peptide and
other physiological signals borne in the blood have direct access to neurons that project to brain areas with
important roles in the autonomic control of many physiological systems, including the cardiovascular system
and systems controlling feeding and metabolism. However, the area postrema is not simply a conduit through
which signals flow into the brain, but it is now being recognized as the initial site of integration for these
signals as they enter the circuitry of the central nervous system. NEUROSCIENTIST 14(2):182–194, 2008. DOI:
10.1177/1073858407311100
KEY WORDS
Circumventricular organ, Feeding, Blood pressure, Peptides, Blood-brain barrier
The CNS plays an essential role in maintaining constancy
of the “milieu interieur” as a consequence of the ability of
autonomic control centers in the hypothalamus and
medulla to continually monitor and regulate the constituents of this internal environment. To achieve this end
point these control centers must obtain information about
the “current state” of all important variables (e.g., glucose,
sodium, calcium, temperature, pH, osmolarity), in all
regions of the body (e.g., systemic, peripheral, CNS, visceral). Autonomic control centers derive this afferent information from a variety of specialized sensory structures;
they then integrate and compare such sensory input to regulatory “set points” and finally translate error signals into
appropriate physiological responses.
Traditionally, sensory information was believed to reach
the brain either by direct diffusion from the circulation into
the CNS (substances that cross the blood-brain barrier), or
as a result of neural input derived from peripherally located
sensory structures (e.g., osmoreceptors, baroreceptors,
chemoreceptors) transmitted to the CNS through autonomic afferents (e.g., vagus, glossopharyngeal nerves).
However, neither of these mechanisms provides adequate
explanations for the established roles of many blood-brain
barrier (BBB)-impermeable circulating signals in controlling the output of autonomic control centers in the brain.
Recent work has suggested mechanisms through which
such information may reach autonomic control centers
behind the BBB, including specific transporters (Kastin
and others 1999), transendothelial cell signaling (Paton
and others 2007), and the focus of this particular review,
actions at circumventricular organs (CVOs) of the brain,
structures that represent the only regions of the CNS that
are not protected by the normal BBB. This review will
focus on one of these specialized structures known as the
area postrema (AP) and examine its role in coordinating
and transmitting signals from the periphery to autonomic
nuclei in the hypothalamus and brainstem to control autonomic outputs that are critical to the stable control of the
milieu interieur.
The Blood-Brain Barrier
Neurons in the CNS are protected from harmful substances
and fluctuations of blood constituents through a specialized vascular structure in which endothelial cells lining the
cerebral microvasculature are connected by complex
intramembranous protein matrices called “tight junctions”
(Abbott and others 2006; Wolburg and others 2003). In
addition, cerebral endothelial cells are wrapped in astrocyte end-feet providing another filter to harmful substances
in the periphery (Abbott and others 2006). The BBB therefore forces molecular information from the periphery to
access the CNS through one of four ways: 1) diffusion
across the BBB (restricted to gases and certain hydrophobic molecules), 2) selective transport mechanisms present
at the BBB interface (leptin, Banks and Kastin 1996; and
insulin, Baura and others 1993), 3) endothelial information translation (a proposed mechanism for peripheral
adiponectin signaling (Spranger and others 2006; Paton
and others 2007), or 4) accessing the CNS through the sensory CVOs.
Sensory Circumventricular Organs
Address correspondence to: Alastair V. Ferguson, Botterell Hall, Queen’s
University, Kingston, Ontario, Canada K7L 3N6 ([email protected]).
182
Sensory CVOs include the subfornical organ (SFO), the
organum vasculosum of the lamina terminalis (OVLT),
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ISSN 1073-8584
The AP and Autonomic Control
Fig. 1. Salient features of the blood-brain interface seen at the sensory circumventricular organs (CVOs) compared
with that seen throughout the rest of the brain. The lack of tight junctions between endothelial cells creates holes
through which large sized molecules being carried in the blood can gain access to the cells within the CNS. Sinuses
called Virchow-Robin spaces slow the flow of blood through CVOs to facilitate the diffusion of molecules from the blood.
and the AP. The sensory CVOs are all highly vascularized midline structures strategically positioned in
(OVLT) and descending out of the walls (SFO and AP)
of the third and fourth ventricles. The capillaries of the
sensory CVOs share many of the same characteristics
(Fig. 1); specifically each exhibit fenestrations between
endothelial cells lining the vasculature due to the
absence of the tight-junction protein ZO-1 (Petrov and
others 1994). In addition, capillaries of the sensory
CVOs exhibit an abnormally high blood volume–to–
tissue weight ratio compared with other areas in the
CNS (McKinley and others 2003). This is accomplished
by a unique capillary architecture in which blood vessels
form large loops extending into the ependymal side and
are surrounded by large perivascular areas called
Virchow-Robin Spaces (Gross 1991). Finally, and perhaps most importantly, in the context of this review, each
of these structures contains high densities of receptors
for a large number of different circulating signals that
are known to play vital roles in signaling autonomic
state from the periphery to the CNS.
Considerable recent work has focused on the potential
roles of the sensory CVOs as autonomic control centers situated at the blood-brain interface. These structures appear
to play important roles in sensing and integrating information about the systemic milieu, and transmitting this information to regulatory control centers protected by the BBB
that in turn play essential roles in regulating fluid balance,
metabolism, cardiovascular and immune function. The
remainder of this review will describe our current knowledge of the mechanisms through which one of these CVOs,
the AP, exerts its extensive influence over autonomic control systems.
The Area Postrema
The AP is the most caudal of the sensory CVOs and was the
first to be recognized as such in the early part of last century (Wilson 1906). These early studies showed that the AP,
but not surrounding area, was stained by intravenously
injected dyes (Wislocki and King 1936; Wislocki and
Leduc 1952) suggesting the AP had unique access to the
circulation. These observations were later confirmed by
studies showing that systemic injections of horseradish peroxidase (HRP) resulted in extensive staining of the AP, as
well as anatomical studies that clearly demonstrated the
existence of the fenestrated capillaries within this CVO
(Dempsey 1973; Krisch and others 1978). Functionally, the
AP for many years gained notoriety as the “chemoreceptor
trigger zone” at which noxious chemical stimulation acts to
induce the emetic reflex (Borison and Brizzee 1951;
Carpenter and others 1983; Miller and Leslie 1994). Recent
studies, however, have suggested additional important roles
for the AP in the control of CSF balance, cardiovascular
regulation, metabolism, and immune function (for review,
see Borison 1974). It is now well recognized that the AP
expresses a number of receptors and sensors on neuronal
cell bodies the activation of which has been shown to influence the excitability of AP neurons (for reviews, see Fry
and others 2007; Ferguson and Bains 1996). Efferent projections of these AP neurons to important autonomic control centers behind the BBB in turn play important roles in
regulation of the autonomic nervous system.
Anatomy and Structure of the Area Postrema
The AP is a hindbrain structure situated in the fourth ventricle on the dorsal surface of the medulla immediately
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Fig. 2. Compartmentalization of the area postrema (AP). Schematic diagram of a coronal section through the brainstem
showing the AP and surrounding neuronal tissue. The AP can be subdivided into several zones, which differ in the predominant cell type found (neurons vs. glia) and where the neurons project. The funiculus separans represents a layer of
tanycytes that function much like the blood-brain barrier separating the AP from the underlying nucleus tractus solitary
(NTS). GR = gracilis nucleus; DMNX = dorsal motor nucleus of the vagus; HN = hypoglossal nucleus; CC = central canal.
adjacent to the nucleus tractus solitarius (NTS). In rodents,
the AP is a single structure that descends out in to the 4th
ventricle. In higher animals such as rabbits and primates,
the AP is a bilateral structure positioned on either side of
the medullary midline. The rodent AP is composed of
three distinct regions based on neuronal cell body location
and projection patterns (Fig. 2). Regions of the AP include
the mantle zone, the central zone, and the ventral zone
(containing a row of helically arranged tanycytes joined
together by tight junctions that define the boundary with
the NTS) (McKinley and others 2003). The central and
mantle zones are rich with neuronal cell bodies and axons
situated next to ependymal cells and the ventral zone contains mostly glia (McKinley and others 2003).
The AP, along with the other two sensory circumventricular organs (SFO and OVLT), is one of the most highly
vascularized regions in the entire mammalian brain
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(McKinley and others 2003). Calculations based on
plasma flow, neutral amino acid transfer, and capillary
permeability suggest that plasma flow in the AP is 50%
higher than through surrounding medullary regions, while
even more significantly the AP shows a 150-fold increase
in surface area/permeability ratio when compared with the
adjacent regions of the dorsomedial medulla (Gross 1991).
This is the result of an extensive network of highly fenestrated blood vessels complete with specialized “pockets,”
called Virchow-Robin spaces, which act to slow blood
flow for optimal diffusion into the perivascular space, prolonging exposure of the constituents of the circulation to
receptors and sensors on neurons and glia within the AP
(Gross 1991). Strategically neurons are present in the
perivascular sheaths of capillaries where they are positioned to optimally sense blood-borne agents (Dempsey
1973).
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Intrinsic Properties of Area Postrema Neurons
Ultrastructural analysis of AP neuronal dendritic trees suggests that apical dendrites extend out toward the basal lamina side of endothelial cells and receive limited synaptic
inputs and are therefore appropriately positioned to receive
blood-borne information from the vasculature (Morita and
Finger 1987). Basal dendrites, however, extend out in the
opposite direction and receive neuronal input from vagal
afferents of the lung, stomach, and cardiovascular system,
therefore making this structure uniquely situated to receive
both neuronal and humoral information that can then be
integrated by the cell body.
The combined dense vasculature and small size of AP
neurons has until recently created significant challenges
to detailed analysis of their intrinsic properties using
electrophysiological techniques. However, the recent
development of in vitro dissociated cell and slice preparations (Yang and Ferguson 2003; Funahashi and Adachi
1993; Hay and Lindsley 1995) have allowed a number
of groups to begin to examine the intrinsic electrical
properties of AP neurons. Both in vivo and in vitro
studies illustrate that AP neurons exhibit a relatively
low rate of spontaneous pacemaking activity (<1 Hz)
(Brooks and others 1983; Lowes and others 1995), which
has been suggested to be regulated by a cAMP-dependent
hyperpolarization-activated cation current (Ih) (Funahashi
and others 2003). AP neurons have relatively high input
resistances (~3 GΩ) indicative of a reduced number of
synaptic inputs (Yang and Ferguson 2003; Ferguson and
Bains 1996), although axosomatic and axodendritic connections clearly do exist (Dempsey 1973). AP neurons
express ion channels typical of many other populations of
CNS neurons (Funahashi and others 2002a, 2002b), which
can be modulated by a variety of signaling peptides, properties that will be described in more detail.
Anatomical Connections of the Area Postrema
Anatomical studies completed in the mid-1980s described
the anatomical connections of the AP (van der Kooy and
Koda 1983; Shapiro and Miselis 1985) summarized in
Figure 3. Retrograde tracing studies using cholera-toxin
HRP and wheat germ agglutinin HRP showed that AP
sends major and minor efferents to a variety of different
nuclei in both the medulla and the hypothalamus. Major
projections include those to the adjacent NTS and the lateral parabrachial nucleus (LPBN), both of which are well
recognized as multifunctional integrative brainstem structures (Menani and others 1996; Miura and Takayama
1991; Vigier and Portalier 1979; van der Kooy and Koda
1983; Leslie and Osborne 1984; Shapiro and Miselis
1985). Less prominent efferent networks include projections to the nucleus ambiguus, dorsal motor nucleus of the
vagus, dorsal regions of the tegmental nucleus, cerebellar
vermis, paratrigeminal nucleus, ventrolateral catecholaminergic column in the medulla, and the spinal
trigeminal tract (Shapiro and Miselis 1985; van der Kooy
and Koda 1983). The AP also receives afferent input from
several different and functionally distinct regions of the
medulla and hypothalamus including reciprocal connections from the NTS and LPBN in addition to substantial
axonal projections arising from the parvocellular regions
of the paraventricular nucleus (PVN) and dorsomedial
nucleus of the hypothalamus (DMH) (van der Kooy and
Koda 1983; Shapiro and Miselis 1985; see Fig. 3).
Intriguingly information from the AP reaches the PVN
through both monosynaptic and polysynaptic connections
suggesting an integrative capacity with potentially bidirectional information processing. Other major sources of
neuronal information to the AP come from vagal and
carotid sinus nerve afferents originating from the lungs
and gastrointestinal and cardiovascular systems (Fig. 4).
Neurochemistry of AP Neurons
In addition to glutamate and GABA (Walberg and
Ottersen 1992) AP neurons have been shown to contain
a number of signaling neuropeptides which have therefore been suggested to play important roles as neurotransmitters at the identified primary termination sites of
AP neurons. Immunohistochemical studies have shown
the presence of enkephalin (Merchenthaler and others
1986), neurotensin (Newton and Maley 1985), and serotonin (Lanca and van der Kooy 1985; Newton and others 1985) containing neurons in the area postrema,
although neither the specific function nor projection site
of each chemical phenotype of neuron has been completely described. Cholecytokinin (CCK) and catecholamine (part of the A2 noradrenergic group from the
dorsolateral medulla) neurons are found in the central
zone and project to the NTS (Petrov and others 1992;
Hermann and others 2005) controlling the emetic reflex
and arousal states as the A2 neurons project to oxytocincontaining neurosecretory cells in the supraoptic area
and are activated during experimental fear conditioning
(Zhu and Onaka 2002).
In addition to peptidergic neurons described previously,
the AP also contains a tremendously rich complement
of peptide and hormone receptors (Fig. 5) including
adiponectin, adrenomedullin, amylin, angiotensin II, CCK,
endothelin, ghrelin, glucagon-like peptide 1 (GLP-1), interleukins, natriuretic peptides, orexins, prokineticin 2, peptide
YY (PYY), and vasopressin. The cellular consequences of
activation of these receptors and the functional roles they
play in modulating autonomic function will be the focus of
the remainder of this review.
Roles for the Area Postrema in Cardiovascular
Regulation
In simplistic terms, it is the role of the complex integrated
autonomic systems controlling the cardiovascular system
to ensure the heart beats hard enough and fast enough to
provide perfusion of tissues at a level appropriate to ensure
both the supply of oxygen and fuels, and the removal of
metabolic products. To achieve this, these autonomic systems must constantly monitor a variety of peripheral
controlled variables, using sensory structures (e.g.,
baroreceptors, chemoreceptors) connected to the brain by
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Fig. 3. Neural projections associated with the area postrema. (Top left) Schematic illustration showing a mid-sagittal
section of the rat brain. (Bottom) Major and minor afferent (blue) and efferent (red) projections to and from the area
postrema in the CNS. In addition, inputs from peripheral organ systems are also shown (green). LV = lateral ventricle;
PVN = paraventricular nucleus of the hypothalamus; DMH = dorsomedial hypothalamus; SON = supraoptic nucleus;
DTN = dorsal tegmental nucleus; PBN = parabrachial nucleus; 4V = 4th ventricle; NTS = nucleus tractus solitary; NA =
nucleus ambiguus; DMNV = dorsal motor nucleus of the vagus; AP = area postrema.
autonomic afferents, as well as CNS sensors that can constantly monitor the contents of the circulation such as the
CVOs. The AP plays a major role in this information gathering as a direct consequence of its unique medullary location within the CNS but outside the BBB.
Despite being intimately associated with the NTS, a
region of the medulla receiving substantial input from arterial baroreceptors, and providing a significant amount of
afferent input to NTS, there remains somewhat conflicting literature describing the effects of AP lesions on heart
rate and blood pressure, although the earliest studies
(Ylitalo and others 1974) report clear hypertensive effects
of AP destruction. However, in the absence of the AP, two
of the major peptide hormones regulating baroreflex function, angiotensin II and vasopressin, no longer exert their
opposing regulatory actions. During the baroreflex,
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baroreceptor activation, as blood pressure increases,
results in a reduction in heart rate. Angiotensin II weakens
this reflex, resetting its activation point to higher blood
pressures and establishing a potentially hypertensive situation. In contrast, vasopressin enhances the sensitivity of
this reflex as the activation point is adjusted to lower pressures (Bishop and Sanderford 2000; Cox and others 1990;
Xue and others 2003). In addition, the exercise pressor
reflex, which under normal conditions results in increases
in blood pressure and heart rate during exercise, is inhibited by the baroreflex preventing excessive increases in
cardiovascular output, an inhibition that is dependent on an
intact AP (Bonigut and others 1997). Vasopressin appears
to be central to this modulation of the exercise pressor
reflex because plasma vasopressin levels are seen to
increase during static muscle contraction, whereas V1
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Fig. 4. Peripheral neuronal inputs to the area postrema (AP). Blood-borne signals received by the AP are integrated
with signals from a variety of peripheral organs that are carried to the AP via vagal afferents. The information transmitted includes baroreceptor information from the carotid sinus and aorta, osmoreceptor information from the liver, and
mechanical information via stretch receptor in the stomach.
receptor antagonist treatment mimics the effect of lesioning the AP on inhibition of the exercise pressor reflex
(Stebbins and others 1998). Therefore, it would appear that
the ability of the AP to sense these blood-borne peptides
enables it to exert a modulatory influence on reflexes that
control important cardiovascular parameters.
In accordance with these observations, both angiotensin
AT1A and vasopressin V1 receptors have been shown to be
expressed in the AP (Gerstberger and Fahrenholz 1989;
Lenkei and others 1997; Huang and others 2003). Results
from both in vivo and in vitro electrophysiological experiments have shown that excitatory responses to angiotensin
II can be recorded in approximately half of rat AP neurons
(Ferguson and Bains 1996). Interestingly, circulating estrogen may be able to modulate some of angiotensin II’s
effects in the AP, because calcium imaging experiments
using dispersed AP neurons show calcium influx induced
by angiotensin II is reduced in the presence of 17ß-estradiol
(Pamidimukkala and Hay 2003). Vasopressin too can be
shown to have effects on AP neuron excitability; however,
the results were more variable with inhibition of firing rate
seen in 45% of rat AP neurons and increases seen in 38%
of neurons during in vivo recordings (Smith and others
1994). Further, vasopressin predominantly excited and
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Fig. 5. Blood-borne peptide signals that activate area postrema neurons. The AP (right) possesses receptors for a number of peptides that would arrive at this circumventricular organ via the blood. Evidence for these receptors comes from
several sources including immunostaining (protein), in situ hybridization (mRNA), and from pharmacological approaches.
Activation of these receptors can be assessed using anatomical (c-fos) and electrophysiological approaches. Abbreviation:
AP = area postrema; NTS = nucleus tractus solitarius; DMNX = dorsal motor nucleus; XII = hypoglossal nucleus.
angiotensin II predominantly inhibited the activity of neurons in the NTS when these peptides were applied at the AP
of rabbits (Cai and others 1994). Significantly, a large proportion of neurons in the AP also receive direct excitatory
input from baroreceptors via the aortic depressor nerve,
suggesting some interplay between neuronal and humoral
inputs during the angiotensin II and vasopressin modulation of the baroreflex (Papas and Ferguson 1991).
In addition to these two important peptides, the AP has
receptors for and responds to other peptides with cardiovascular actions. Endothelin is a potent vasoconstrictor
that is released from vascular endothelial cells and has a
high concentration of binding sites in the AP (Banasik
and others 1991). Moreover, receptors for endothelin
have been shown to occur in the AP (Kurokawa and others 1997). This peptide has excitatory actions on most
AP neurons, although direct administration into the AP
results in biphasic changes in blood pressure, the direction of the change depending on the absolute concentration administered (Ferguson and Smith 1990, 1991).
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Adrenomedullin is also produced by vascular endothelial cells and vascular smooth muscle where it acts as a
potent vasodilator. Surprisingly, it also increases blood
pressure when applied centrally to the AP and has predominantly excitatory effects on AP neurons in vivo
(Allen and Ferguson 1996; Allen and others 1997).
Adrenomedullin induces c-fos in the AP and its receptor
is expressed on AP neurons (Shan and others 2003;
Ueda T. and others 2001; Ueta Y. and others 2001).
Fluid Balance
The regulation of fluid balance is tightly linked with cardiovascular regulation, in that many of the same cardioactive
peptides sensed by the AP are involved in both regulatory
processes. In rats in which the AP has been removed,
there is a marked tendency to drink large amounts of saline
(Curtis and others 1999). Further, there is a reduced
increase in the secretion of oxytocin and vasopressin, to
enhance natriuresis and inhibit diuresis, following infusion
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of NaCl, which does not occur if the animal is infused with
an equiosmolar mannitol solution (Huang and others 2000).
This suggests that the AP receives information about, and
responds to, plasma sodium concentrations, likely through
inputs from hepatoportal osmoreceptors in the liver, stimulation of which increase c-fos expression in the AP (Osborn
and others 2000). This information is then relayed to the
hypothalamus to influence oxytocin and vasopressin release
from the posterior pituitary.
Feeding and Metabolism
The AP was originally recognized as an important CNS
regulatory control center in view of its identification as
the primary chemosensory site where toxins and other
molecules in the blood acted to cause nausea and/or emesis (Borison and Brizzee 1951; Borison and Wang 1951;
Hornby 2001). Studies over the past 20 years have suggested, however, that the sensory role of AP in monitoring
blood-borne signals is perhaps at its most dynamic in
terms of its roles in monitoring circulating concentrations
of a variety of signals that play important roles in the autonomic regulation of feeding and metabolism (Fig. 6).
Here peptide and nonpeptide signals are monitored by the
neurons of the AP and the signals transduced and
processed for subsequent transmission into the CNS.
Interestingly, it is during the course of feeding when AP
activation is the greatest, as judged by c-Fos induction
(Johnstone and others 2006), and many of the signals that
the AP is sensitive to, reviewed herein, are associated with
sensing the degree of satiation of the animal.
Amylin. This peptide is secreted with insulin from the
pancreas during and immediately after feeding, and has
powerful anorectic effects (Chance and others 1991; Lutz
and others 1994; Rushing and others 2000). In vivo, amylin
receptor antagonists inhibit feeding-induced c-Fos induction in the AP, reduce amylin-induced inhibition of feeding,
and increase feeding when applied alone, observations that
support the conclusion that the AP senses endogenous
amylin (Barth and others 2004; Mollet and others 2004;
Riediger and others 2004). Electrophysiological experiments have also shown that amylin has excitatory actions
on nearly half of AP neurons tested, and that half of these
amylin-sensitive AP neurons are also activated by increased
glucose concentrations (Riediger and others 2002). These
observations would indicate that during and immediately
following feeding when both glucose and amylin are maximal, the activity of these neurons would likewise be
strongly elevated (Riediger and others 2001, 2002).
Cholecystokinin. CCK is a peptide released into the
circulation by intestinal enteroendocrine cells in the
presence of fatty acids (McLaughlin and others 1998).
CCK inhibits feeding and this inhibition is reduced in
AP-lesioned animals (van der Kooy 1984). CCK has primarily excitatory actions on AP neurons recorded in
vitro in brain slices and, as with amylin, some glucose
sensitive neurons in the AP were also CCK sensitive
(Sun and Ferguson 1997; Funahashi and Adachi 1993).
Consistent with this, c-Fos expression is increased, following systemic CCK administration, in both the AP and
the NTS, and this expression is missing in rats that do
not express the CCK-1 receptor, which is expressed in
the AP (Hill and others 1987; Mercer and Beart 2004;
Covasa and Ritter 2005). C-fos expression in the AP,
however, was enhanced if combined with gastric distension, which is transmitted to the AP via serotonincontaining afferents and involves 5-HT3 receptor activation (Hayes and Covasa 2006). Here, we are beginning
to see that the AP is not a simple conduit through which
blood-borne signals are transferred into the CNS, but has
the potential to play an important integrative role in
assessing the total contribution of multiple signals.
Glucagon-like peptide 1 (GLP-1). GLP-1 is, like CCK,
produced by enteroendocrine cells in the gut and like
CCK this peptide inhibits feeding. Receptors for GLP-1
are found in catecholamine neurons of the AP, which
express c-fos when GLP-1 receptor agonist is injected
systemically but not in response to central administration
(Yamamoto and others 2003). Consistent with this, oxyntomodulin, a product of the proglucagon peptide, also
binds to the GLP-1 receptor and increases c-fos expression in the AP when injected intraperitoneally, and
decreases food intake (Baggio and others 2004).
Peptide YY (PYY). PYY is an inhibitor of feeding activity,
although this action of PYY is preserved in AP-lesioned animals (Cox and Randich 2004). PYY, however, does induce
c-fos expression in the AP and the Y1, Y2, and Y4 receptors
have all been found to be expressed in the AP (Bonaz and
others 1993; Kishi and others 2005; Lee and Miller 1998;
Parker and Herzog 1999; Stanic and others 2006). In addition, our laboratory has, using AP neurons in cell culture,
found direct electrophysiological actions of PYY on membrane excitability (Fig. 7A). Interestingly there appear to be
differential effects of PYY1-36 (depolarizing and excitatory)
and PYY3-36 (hyperpolarizing and inhibitory), which could
explain the lack of effects of AP lesions. PYY’s actions in
the AP have also been suggested to play a role in controlling
pancreatic secretion because lesioning the AP eliminates
PYY’s ability to inhibit CCK-induced stimulation of pancreatic activity (Deng and others 2001).
Ghrelin. Ghrelin, on the other hand, is an orexigenic
peptide released from cells in the stomach, and in young
rats the stimulation of feeding induced by ghrelin
requires an intact AP (Gilg and Lutz 2006). An intact AP
is also required for ghrelin’s stimulation of pancreatic
secretion via activation of the vago-vagal circuitry (Li
and others 2006). The receptor for ghrelin, the growth
hormone secretagogue receptor, is found in the AP and
ghrelin was found to induce c-fos expression in the AP,
as well as in the NTS and motor nucleus of the vagus (Li
and others 2006; Zigman and others 2006). Further,
ghrelin was found to have direct electrophysiological
effects on the excitability of cultured AP neurons with
separate subpopulations being depolarized or hyperpolarized (Fig. 7B). Expression in the latter two structures
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Fig. 6. Blood-borne peptides that influence feeding and metabolism originate from a variety of sites. These include
traditional endocrine sources such as the pancreas and the more novel sources such as adipocytes or the stomach.
was inhibited in AP-lesioned animals demonstrating the
pathway of neuronal activation recruited following AP
stimulation (Li and others 2006).
Adiponectin. Receptors (AdipoR1 and AdipoR2) for
the adipokine adiponectin, an insulin sensitizing peptide,
have also been identified in the AP and when applied to
dissociated AP neurons this peptide also influences neuronal excitability in a large fraction of these cells (Fig. 8)
with separate subpopulations again showing hyperpolarizing and depolarizing response (Fry and others 2006).
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Although best known for its relationship with glucose
regulation, these authors also demonstrated that
adiponectin has cardiovascular effects, because direct
microinjection of adiponectin into the AP increased arterial blood pressure.
Immune Relationships
The interrelationship between the immune system and
nervous system is important during the induction of fever
and behaviors associated with immune responses to
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Fig. 7. Electrophysiological actions of peptides involved in the regulation of feeding recorded from AP neurons in vitro.
(A) Whole cell current clamp recordings from dissociated AP neurons revealed that PYY1-36 at low concentrations depolarized neurons (1), whereas PYY3-36 at higher concentrations neurons hyperpolarized AP cells (2). (B) However, with the
orexigenic peptide ghrelin, identical concentrations could result in either depolarization (1) or hyperpolarization (2) in a
cell-specific manner.
Fig. 8. Adiponectin directly affects the excitability of AP neurons in cells expressing both forms of the adiponectin
receptor. (A) Current clamp recording showing adiponectin-dependent depolarization of an AP neuron in cell culture.
Single cell reverse transcription–PCR revealed this neuron expressed mRNA for both subtypes of the adiponectin receptor. Interestingly, a sizable proportion of neurons were also seen to hyperpolarize following adiponectin exposure, and
these also expressed both receptor subtypes. (B) The lack of response to adiponectin by AP neurons was associated
with neither receptor subtype being expressed.
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191
infection, such as social withdrawal and loss of appetite.
Recent anatomical description of membrane apposition
between cytokine-expressing immune cells and the dendrites and somas of AP neurons establishes a framework
through which these immunological signals can enter the
nervous system via the AP (Goehler and others 2006).
Consistent with this, the interleukin (IL)-1R1 receptor is
found in the AP and c-fos is induced in the AP following its activation (Ericsson and others 1995; Brady and
others 1994). Furthermore, IL-1ß activation of the hypothalamo-pituitary-adrenal axis is dependent on there being
an intact AP, since both ACTH and corticosterone levels
were reduced following intravenous IL-1ß administration,
and c-fos induction in the NTS and PVN were also reduced
in AP-lesioned animals, identifying a pathway through
which immune stimulation of the AP leads to autonomic
responses to immune challenge (Lee and others 1998).
Conclusions
The privileged location of the AP, and the other sensory
circumventricular organs, within the CNS but outside the
BBB, coupled with its connectivity to brain structures
involved in autonomic control, provides what appear to be
very specialized sensory windows through which circulating signals can influence the output of these autonomic
centers and the physiological systems they regulate. In
addition, autonomic afferents provide important sensory
information from the periphery to AP neurons. Therefore,
does the AP serve as more than just an internal sensory
organ and does it have an integrative role in shaping the
signals that are passed on to other sites such as the NTS?
Surprisingly, few studies have been directed at understanding the integrative function of the AP, its network
structure, and how these neurons are influenced by the various blood-borne signals they clearly have the ability to
monitor.
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