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The Neuroscientist http://nro.sagepub.com 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 The online version of this article can be found at: http://nro.sagepub.com/cgi/content/abstract/14/2/182 Published by: http://www.sagepublications.com Additional services and information for The Neuroscientist can be found at: Email Alerts: http://nro.sagepub.com/cgi/alerts Subscriptions: http://nro.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations http://nro.sagepub.com/cgi/content/refs/14/2/182 Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 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), THE NEUROSCIENTIST Volume 14, Number 2, 2008 Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 Copyright © 2008 Sage Publications 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 Volume 14, Number 2, 2008 THE NEUROSCIENTIST Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 183 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 184 (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). THE NEUROSCIENTIST The AP and Autonomic Control Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 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 Volume 14, Number 2, 2008 THE NEUROSCIENTIST Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 185 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, 186 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 THE NEUROSCIENTIST The AP and Autonomic Control Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 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 Volume 14, Number 2, 2008 THE NEUROSCIENTIST Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 187 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). 188 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 THE NEUROSCIENTIST The AP and Autonomic Control Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 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 Volume 14, Number 2, 2008 THE NEUROSCIENTIST Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 189 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). 190 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 THE NEUROSCIENTIST The AP and Autonomic Control Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 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. Volume 14, Number 2, 2008 THE NEUROSCIENTIST Downloaded from http://nro.sagepub.com at QUEENS UNIV LIBRARIES on February 3, 2009 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. 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