Elevated hypothalamic neuropeptide Y levels in rats with dorsomedial hindbrain lesions

Lesions centered on the area postrema (AP) and adjacent nucleus of the solitary tract (AP/mNTS-lesions) are reported to result in increased consumption of highly palatable diets. Recent studies suggest that neuropeptide Y (NPY) may cause a preference for carbohydrate-rich diets. Thus, it is possible that NPY may play a role in the enhanced intake of highly palatable diets by AP/mNTS-lesioned rats. In the studies reported here, we found that lesions centered on the AP result in increased levels of NPY-immunoreactivity in the paraventricular nucleus of the hypothalamus. Additionally, steady-state NPY mRNA in the basomedial hypothalamus including the arcuate nucleus was elevated. Enhanced NPY was not found throughout the hypothalamus however, as NPY-immunoreactivity was not elevated in the lateral hypothalamus or the tissue bordering the anteroventral third ventricle. These data suggest the possibility that elevated hypothalamic NPY, particularly in the arcuate and paraventricular nuclei, may contribute to the altered food intake and energy balance observed in rats with lesions centered on the AP.     

Role of the paraventricular nucleus in the projection from the nucleus of the solitary tract to the olfactory bulb

Electrophysiological experiments were performed on anesthetized rats to determine the effects of lesions of the paraventricular nucleus on the amplitude of evoked potentials recorded in the periglomerular layer of the olfactory bulb after nucleus of the solitary tract electrical stimulation. Lesions of the paraventricular nucleus enhance the amplitude of both the positive and negative components of the evoked potential in the olfactory bulb. The pathway from the paraventricular nucleus to the olfactory bulb seems to exert a suppressive influence over the projection from the nucleus of the solitary tract to the olfactory bulb under these conditions.     

Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses

In response to stress, defined as a real or perceived threat to homeostasis or well-being, brain systems initiate divergent physiological and behavioral processes that mobilize energy and promote adaptation. The brainstem contains multiple nuclei that engage in autonomic control and reflexive responses to systemic stressors. However, brainstem nuclei also play an important role in neuroendocrine responses to psychogenic stressors mediated by the hypothalamic-pituitary-adrenocortical axis. Further, these nuclei integrate neuroendocrine responses with stress-related behaviors, significantly impacting mood and anxiety. The current review focuses on the prominent brainstem monosynaptic inputs to the endocrine paraventricular hypothalamic nucleus (PVN), including the periaqueductal gray, raphe nuclei, parabrachial nuclei, locus coeruleus, and nucleus of the solitary tract (NTS). The NTS is a particularly intriguing area, as the region contains multiple cell groups that provide neurochemically-distinct inputs to the PVN. Furthermore, the NTS, under regulatory control by glucocorticoid-mediated feedback, integrates affective processes with physiological status to regulate stress responding. Collectively, these brainstem circuits represent an important avenue for delineating interactions between stress and health.     

Effect of fasting and immobilization stress on estrogen receptor immunoreactivity in the brain in ovariectomized female rats

The present study examined the effect of 48-h fasting and 1-h immobilization on estrogen receptor immunoreactivity in selected hypothalamic areas and the nucleus of the solitary tract (NTS) in ovariectomized rats. Fasting induced an increase in ER-immunoreactive cells in the paraventricular nucleus (PVN), paraventricular nucleus (PeVN) and NTS compared with the unfasted control group. Similarly, immobilization caused an increase in ER-positive cells in the same areas, PVN, PeVN and NTS, versus the non-immobilized group. There was no significant increase in the number of ER-immunoreactive cells in the preoptic area (POA), arcuate nucleus (ARC) or ventromedial hypothalamic nucleus (VMH) following fasting and immobilization. Our previous work in ovariectomized rats with estrogen microimplants in the brain revealed that the PVN and A2 region of the NTS are the feedback sites of estrogen in activating the neural pathway to suppress pulsatile LH secretion during 48-h fasting. The result in the food-deprived rats suggests that estrogen modulation of the suppression of LH secretion during fasting is partly due to the increase in estrogen receptors in the PVN and A2 region. The physiological significance of the increase in neural ER following immobilization remains to be elucidated.     

Olfactory and visceral projections to the paraventricular nucleus

Electrophysiological studies were performed to determine if neurons of the paraventricular nucleus (PVN) which receive inputs from the stomach via vagal afferents also respond to nucleus of the solitary tract (NTS) and olfactory bulb (OB) stimulation. We found that the NTS, OB stimulation, and gastric distension depress the firing frequency of PVN neurons. The pathway from the NTS to the PVN contains larger fibers than the projection from the PVN to the NTS.     

Fos expression in the brain induced by peripheral injection of CCK or leptin plus CCK in fasted lean mice

We previously reported a synergistic interaction between leptin and cholecystokinin (CCK) to reduce food intake through CCK-A receptors in lean mice fasted for 24 h. To identify the activated neuronal pathways, we investigated changes in Fos expression in brain nuclei 2 h after single or combined intraperitoneal (i.p.) injections of leptin (120 μg/kg) and sulfated CCK-8 (3.5 μg/kg) in male lean mice (C57BL/6) fasted for 24 h using immunohistochemistry for Fos, the protein product of the early gene, c-fos. Leptin did not increase Fos expression in the brain compared with vehicle-treated mice. CCK increased the numbers of Fos-positive neurons in the nucleus of the solitary tract (NTS)/area postrema (AP), central nucleus of the amygdala (CeA) and, to a smaller extent, in the paraventricular nucleus of the hypothalamus (PVN) (5.2-, 2.3- and 0.3-fold respectively). Injections of leptin–CCK further enhanced Fos expression by 40% in the PVN compared with that induced by CCK alone, but not in the other nuclei. Devazepide (a CCK-A receptor antagonist, 1 mg/kg, i.p.) prevented the increase in Fos expression induced by leptin–CCK in the PVN and by CCK alone in the PVN, CeA and NTS/AP. These results indicate that in fasted mice, i.p. injection of CCK increases Fos expression in specific brain nuclei through CCK-A receptors while leptin alone had no effect. Leptin in conjunction with CCK selectively enhanced Fos expression in the PVN. The PVN may be an important site mediating the synergistic effect of leptin–CCK to regulate food intake.     

Ultrastructural localization of inhibin β- and somatostatin-28-immunoreactivities in the paraventricular and supraoptic nuclei

Recent studies have supported the existence of projections to the paraventricular and supraoptic nuclei of the hypothalamus that arise from non-catecholaminergic neurons in the nucleus of the solitary tract, whose terminal distribution is suggestive of interactions with both parvocellular and magnocellular neurosecretory neurons. Pre-embedding immunolabeling methods were used to compare and characterize the termination patterns of axons immunoreactive for two putative markers for this projection system, inhibin β and somatostatin-28, at the ultrastructural level. Axon terminal profiles stained fro either peptide were found to form symmetric or asymmetric junctions predominantly with the shafts of unlabeled dendrites of varying caliber. A small percentage of peptidergic terminals was found in both hypothalamic nuclei to engage in so-called ‘shared synapses’, where a single terminal profile contacted two postsynaptic elements. Axo-somatic terminations were relatively rarely seen in the supraoptic nucleus, but were somewhat more abundant in the paraventricular nucleus. These comprised principally symmetric junctions onto the somatic membranes of an ostensibly mixed population of cells, some of which bore apparent neurosecretory specializations. Combined immunoperoxidase and immuno-autoradiographic staining methods were used to estimate the extent to which either terminal type interacts with oxytocin neurons. Oxytocin stained elements comprised a minority of the postsynaptic targets of both peptidergic terminal types in the paraventricular nucleus, and a scant majority of those in the supraoptic nucleus. These results support the view that peptidergic neurons in the caudal nucleus of the solitary tract interact synaptically with multiple cell types in the parvocellular division of the paraventricular nucleus, and preferentially with oxytocinergic elements in the magnocellular neurosecretory system.     

The organization of projections from the central nucleus of the amygdala to brainstem sites involved in central autonomic regulation: A combined retrograde transport-immunohistochemical study

The central nucleus of the amygdala (ACe) in the rat sends a considerable projection to, and receives projections from, the parabrachial nucleus (PB) and the dorsal vagal complex (DVC; the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve). In each part of this 'triangle', immunohistochemical staining for the following peptides has been observed in perikarya and fibers: neurotensin, somatostatin, substance-P, Leu-enkephalin and corticotropin-releasing factor. The aim of the present study was to investigate whether any of these peptides are involved in projections to the brainstem from the ACe, and to characterize the distribution of each cell type in the ACe. The results of double retrograde tracing studies indicate that most of the ACe neurons projecting to the PB and DVC are present in the medial part of ACe (ACem), and that many of them project to both the 1 B and the DVC. The combined use of immunohistochemistry with a retrograde fluorescent tracer, True Blue, indicated that the peptide-containing perikarya are found predominantly in the lateral part of ACe (ACe1), and that only a small proportion of neurotensin, somatostatin and corticotropin-releasing factor-stained neurons contained True Blue after injections into the PB or the DVC. The results suggest that most of the fibers in the descending projection from the ACe to the brainstem do not contain the peptides examined here.     

Fos-like immunoreactivity and thirst following hyperosmotic loading in rats with subdiaphragmatic vagotomy

If receptors in the gut relay information about increases in local osmolality to the brain via the vagus nerve, then vagotomy should diminish this signaling and reduce both thirst and brain Fos-like immunoreactivity (Fos-ir). Water intake in response to hypertonic saline (i.p. or i.g., 1 M NaCl, 1% BW; i.g., 0.6 M NaCl, 0.5% BW) was reduced during 120 min in rats with subdiaphragmatic vagotomy (VGX) compared to sham-VGX rats. Brain Fos-ir was examined in response to both i.g. loads. After the smaller load, VGX greatly reduced Fos-ir in the supraoptic nucleus (SON) and the magnocellular and parvocellular areas of the paraventricular nucleus (PVN). Fos-ir in the subfornical organ (SFO) and nucleus of the solitary tract (NTS) was not affected. After the larger load, VGX significantly reduced Fos-ir in the parvocellular PVN and in the NTS, but not in the other regions. Thus, decreased water intake by VGX rats was accompanied by decreased Fos-ir in the parvocellular PVN after the same treatments, indicating a role for the abdominal vagus in thirst in response to signaling from gut osmoreceptors. The decreased water intake in the VGX group was not reflected as a decrease in Fos-ir in the SFO. Absorption of the larger i.g. load may have activated Fos-ir through more rapidly increasing systemic osmolality, thereby obscuring a role for the vagus at this dose in the SON and magnocellular PVN.     

Effect of lesions of forebrain circumventricular organs on c-fos expression in the central nervous system to plasma hypernatremia

Experiments were carried out on conscious adult male Wistar rats to investigate the effect of selective ablation of the subfornical organ (SFO), and/or the anteroventral third ventricular (AV3V) region on the induction of Fos in central structures in response to plasma hypernatremia. Fos induction, detected immunohistochemically, was used as a marker for neuronal activation. Intravenous infusions of hypertonic saline resulted in dense Fos-like immunoreactivity in several forebrain (paraventricular nucleus of the hypothalamus (PVH), supraoptic nucleus (SON), median preoptic nucleus (MnPO), medial preoptic nucleus, organum vasculosum of the laminae terminalis and SFO) and brainstem (nucleus of the solitary tract, ventrolateral medulla, and parabrachial nucleus) structures. Intravenous infusions of the hypertonic saline solution into animals with lesions of either the SFO, the AV3V or both resulted in a decreased number of Fos-like immunoreactive neurons in the MnPO, PVH and SON. In addition, the number of Fos-labeled neurons in the SON after lesions of both the SFO and the AV3V was significantly greater than that observed in isotonic saline infused controls. Finally, lesions of the forebrain circumventricular structures did not alter the Fos labeling in brainstem structures as a result of the infusion of the hypertonic solution. These data suggest that changes in plasma osmolality and/or concentration of sodium alter the activity of SON and brainstem neurons in the absence of afferent inputs from the SFO and AV3V.     

The anxiogenic drug yohimbine activates central viscerosensory circuits in rats

Systemic administration of the alpha(2)-adrenoceptor antagonist yohimbine (YO) activates the HPA stress axis and promotes anxiety in humans and experimental animals. We propose that visceral malaise contributes to the stressful and anxiogenic effects of systemic YO and that YO recruits brainstem noradrenergic (NA) and peptidergic neurons that relay viscerosensory signals to the hypothalamus and limbic forebrain. To begin testing these hypotheses, the present study explored dose-related effects of YO on food intake, conditioned flavor avoidance (CFA), and Fos immunolabeling in rats. Systemic YO (5.0 mg/kg BW, i.p.) inhibited food intake, supported CFA, and increased Fos immunolabeling in identified NA neurons in the ventrolateral medulla, nucleus of the solitary tract, and locus coeruleus. YO also increased Fos in the majority of corticotropin releasing hormone-positive neurons in the paraventricular nucleus of the hypothalamus. YO administered at 1.0 mg/kg BW did not inhibit food intake, did not support CFA, and did not increase Fos immunolabeling. Retrograde neural tracing demonstrated that neurons activated by YO at 5.0 mg/kg BW included medullary and pontine neurons that project to the central nucleus of the amygdala and to the lateral bed nucleus of the stria terminalis, the latter region receiving comparatively greater input by Fos-positive neurons. We conclude that YO produces anorexigenic and aversive effects that correlate with activation of brainstem viscerosensory inputs to the limbic forebrain. These findings invite continued investigation of how central viscerosensory signaling pathways interact with hypothalamic and limbic regions to influence interrelated physiological and behavioral components of anxiety, stress, and visceral malaise.     

Psychological stress increased corticotropin-releasing hormone mRNA and content in the central nucleus of the amygdala but not in the hypothalamic paraventricular nucleus in the rat

The central administration of corticotropin-releasing hormone (CRH) to experimental animals sets into motion a coordinated series of physiological and behavioral events that promote survival during threatening situation. A large body of evidence suggest that CRH in the central nucleus of the amygdala (CEA) induces fear-related behaviors and is essential to fear conditioning; however, evidence of CRH-mediated activation of the amygdala under physiological situation is still limited. We report here a study of the impact of a psychological stressor on hypothalamic and amygdala CRH systems in the rat. Non-footshocked rats placed in a floored compartment surrounded by footshocked rats were defined as the psychological stress group. Rats were exposed to psychological stress for 15 min, and then sacrificed 1.5 and 3 h after cessation of stress. We found that our psychological stressor induced an increase in both CRH mRNA levels, as assessed by in situ hybridization histochemistry, and CRH content, as assessed by micropunch RIA, in the CEA. Exposure to the psychological stressor also caused a significant increase in CRH mRNA levels with a trend for an increase in CRH content in the dorsolateral subdivision of the bed nucleus of the stria terminalis (BNST) which is anatomically associated with the CEA. In contrast, psychological stress induced a small, but significant increase in type-1 CRH receptor (CRHR-1) mRNA in the hypothalamic paraventricular nucleus (PVN), while it failed to elevate either PVN CRH mRNA levels or content, CRH content in the median eminence (ME), or levels of plasma ACTH or corticosterone (CORT). Thus, in the context of a psychological stressor, the activation of the amygdala CRH system can occur without robust activation of the hypothalamic CRH system. In the light of previous data that the psychological stress-induced loss of sleep was reversed by the central administration of a CRH antagonist, these data suggest that CRH in the CEA may contribute to the psychological stress-evoked fear-related behavior such as hyperarousal. These data also indicate that in response to a psychological stressor, the amygdala CRH system is much more sensitive than is the CRH system emanating from the PVN.     

Perinatal undernutrition increases meal size and neuronal activation of the nucleus of the solitary tract in response to feeding stimulation in adult rats

During the early periods of development, i.e., gestation and lactation, the influences of stimulus such as undernutrition can lead to several behavioural and morphofunctional damages to organs and systems in general, including pathways and structures that control energy balance and feeding behaviour. Although a large body of evidences have shown the effects of this stimulus on structures such as hypothalamus, only few studies have directed their attention to the long-term effects of undernutrition on the nucleus of the solitary tract (NTS). The aim of this study was to investigate the effects of early undernutrition on the NTS and control of food intake in adulthood. Male Wistar rats were divided into two groups according to the diet offered to the dams during gestation and lactation: control group (C, diet containing 17% casein) or isocaloric low-protein group (LP, diet containing 8% casein). On 35 or 180 days, we evaluated the rats’ body weight, food intake, behavioural satiety sequence and c-Fos protein expression in the NTS in response to food stimulus. Based on these assessments, it was found that perinatal undernutrition promoted an increase in food intake and the number of activated cells in rostral and, mainly, medial NTS in response to food stimulation in adulthood. These results indicated that the NTS is a structure particularly vulnerable to the influences of nutritional manipulation in the early stages of development with effects on food control in adulthood.     

Fos induction in selective hypothalamic neuroendocrine and medullary nuclei by intravenous injection of urocortin and corticotropin-releasing factor in rats

CRF and urocortin, administrated systemically, exert peripheral biological actions which may be mediated by brain pathways. We identified brain neuronal activation induced by intravenous (i.v.) injection of CRF and urocortin in conscious rats by monitoring Fos expression 60 min later. Both peptides (850 pmol/kg, i.v.) increased the number of Fos immunoreactive cells in the paraventricular nucleus of the hypothalamus, supraoptic nucleus, central amygdala, nucleus tractus solitarius and area postrema compared with vehicle injection. Urocortin induced a 4-fold increase in the number of Fos-positive cells in the supraoptic nucleus and a 3.4-fold increase in the lateral magnocellular part of the paraventricular nucleus compared with CRF. Urocortin also elicited Fos expression in the accessory hypothalamic neurosecretory nuclei, ependyma lining the ventricles and choroid plexus which was not observed after CRF. The intensity and pattern of the Fos response were dose-related (85, 255 and 850 pmol/kg, i.v.) and urocortin was more potent than CRF. Neither CRF nor urocortin induced Fos expression in the lateral septal nucleus, Edinger-Westphal nucleus, dorsal raphe nucleus, locus coeruleus, or hypoglossal nucleus. These results show that urocortin, and less potently CRF, injected into the circulation at picomolar doses activate selective brain nuclei involved in the modulation of autonomic/endocrine function; in addition, urocortin induces a distinct activation of hypothalamic neuroendocrine neurons.     

Angiotensin II-induced hypertension differentially affects estrogen and progestin receptors in central autonomic regulatory areas of female rats

Estrogen receptor (ER) activation in central autonomic nuclei modulates arterial blood pressure (ABP) and counteracts the deleterious effect of hypertension. We tested the hypothesis that hypertension, in turn, influences the expression and trafficking of gonadal steroid receptors in central cardiovascular circuits. Thus, we examined whether ER- and progestin receptor (PR)-immunoreactivity (ir) are altered in medullary and hypothalamic autonomic areas of cycling rats following chronic infusion of the hypertensive agent, angiotensin II (AngII). After 1 week AngII-infusion, systolic ABP was elevated from 103 ± 4 to 172 ± 8 mmHg (p < 0.05; N = 8/group) and all rats were in diestrus (low estrogen). In AngII-infused rats the number of PR-immunoreactive nuclei was reduced (− 72%) compared to saline-infused controls also in diestrus (p < 0.05). Furthermore, the intensity of ERα-ir increased selectively in nuclei (16%) and cytoplasm (21%) of cells in the commissural nucleus of the solitary tract (cNTS; p < 0.05) while neither the number nor intensity of ERβ-labeled cells changed (p > 0.05). Following chronic AngII-infusion, electron microscopy showed a higher cytoplasmic-to-nuclear ratio of ERα-labeling selectively in tyrosine hydroxylase (TH)-labeled neurons in the cNTS. Furthermore, AngII-infusion increased ERα-ir in the cytosol of TH- and non-TH neuronal perikarya and increased the amount of ERα-ir associated with endoplasmic reticulum only in TH-containing perikarya. The data suggest that hypertension modulates the expression and subcellular distribution of ERα and PR in central autonomic regions involved in blood pressure control. Considering that ERα counteracts the central and peripheral effects of AngII, these receptor changes may underlie adaptive responses that protect females from the deleterious effects of hypertension.     

Intramedullary connections of the rostral nucleus of the solitary tract in the hamster

The rostral nucleus of the solitary tract (NST) figures prominently in the gustatory system, giving rise to ascending taste pathways that are well documented. Less is known of the local connections of the rostral NST with sites in the medulla. This study defines the intramedullary connections of the rostral NST in the hamster. Small iontophoretic injections of horseradish peroxidase (HRP), confined to the rostral NST, resulted in Golgi-like filling of axons that exited the NST or that interconnected cytoarchitectonic subdivisions within the NST complex. The NST efferent axons terminated sparsely in the trigeminal, facial and hypoglossal motor nuclei, but axons and endings were heavily distributed in the parvicellular reticular formation ventral to the NST. HRP injections centered in this part of the reticular formation resulted in heavy projections to the orofacial motor nuclei. Intranuclear connections, labelled after NST injections, linked NST subdivisions that receive primary afferent taste inputs to subdivisions involved in (1) projections to the preoromotor reticular formation, (2) projections to swallowing motor neurons, (3) activation of preganglionic parasympathetic neurons, and (4) general viscerosensation. In general, the connections defined in the present study provide anatomical details about the substrate for gustatory-motor and gustatory-visceral interactions.     

Oxytocin-immunoreactive innervation of identified neurons in the rat dorsal vagal complex

Background Oxytocin (OXT) has been implicated in reproduction and social interactions and in the control of digestion and blood pressure. OXT‐immunoreactive axons occur in the dorsal vagal complex (DVC; nucleus tractus solitarius, NTS, dorsal motor nucleus of the vagus, DMV, and area postrema, AP), which contains neurons that regulate autonomic homeostasis. The aim of the present work is to provide a systematic investigation of the OXT‐immunoreactive innervation of dorsal motor nucleus of the vagus (DMV) neurons involved in the control of gastrointestinal (GI) function. Methods We studied DMV neurons identified by (i) prior injection of retrograde tracers in the stomach, ileum, or cervical vagus or (ii) induction of c‐fos expression by glucoprivation with 2‐deoxyglucose. Another subgroup of DMV neurons was identified electrophysiologically by stimulation of the cervical vagus and then juxtacellularly labeled with biotinamide. We used two‐ or three‐color immunoperoxidase labeling for studies at the light microscopic level. Key Results Close appositions from OXT‐immunoreactive varicosities were found on the cell bodies, dendrites, and axons of DMV neurons that projected to the GI tract and that responded to 2‐deoxyglucose and juxtacellularly labeled DMV neurons. Double staining for OXT and choline acetyltransferase revealed that OXT innervation was heavier in the caudal and lateral DMV than in other regions. OXT‐immunoreactive varicosities also closely apposed a small subset of tyrosine hydroxylase‐immunoreactive NTS and DMV neurons. Conclusions & Inferences Our results provide the first anatomical evidence for direct OXT‐immunoreactive innervation of GI‐related neurons in the DMV.     

Conditioned c-Fos in mouse NTS during expression of a learned taste aversion depends on contextual cues

c-Fos expression in the nucleus tractus solitarius (NTS) of the rat has been found to follow administration of a variety of pharmacologically diverse unconditioned stimuli (US), and it has been proposed that NTS is a critical structure in transduction of the US during taste aversion learning. Before conditioning, the conditioned stimulus (CS) taste does not induce c-Fos in NTS, but following pairing of the CS and US, subsequent CS presentation induces c-Fos in NTS. Although it has been suggested that the shift in the c-Fos response following conditioning represents a molecular correlate of taste aversion learning, i.e. the formerly neutral CS now predicts the toxicity associated with the US, the data presented here suggest a more cautious interpretation of c-Fos expression in NTS. In mice, post-conditioning c-Fos expression to the CS depends on contextual cues: when conditioning and testing occur in a novel environment, CS saccharin causes an increase in c-Fos expression, and when conditioning and testing occur in the home cage, CS saccharin produces a decrease in c-Fos expression relative to controls. Furthermore, we show that merely placing an animal into a novel environment is sufficient to drive c-Fos expression in NTS. These data suggest that c-Fos expression in NTS can be driven by a number of different stimuli and conditions, and that these responses may depend on context-dependent activation of forebrain structures shown to drive conditioned c-Fos expression in NTS.     

The central neural connections of the area postrema of the rat

We applied the neuroanatomical tracers cholera toxin-horseradish peroxidase and wheat germ agglutinin-horseradish peroxidase to investigate the neural connections of the area postrema (AP) in the rat. We find that the AP projects to the nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus bilaterally both rostral and caudal to obex; the nucleus ambiguus; the dorsal aspect of the spinal trigeminal tract and nucelus and the paratrigeminal nucleus; the region of the ventrolateral medullary catecholaminergic column; the cerebellar vermis; and a cluster of structures in the dorsolateral pons which prominently include a discrete set of subnuclei in the lateral parabrachial nucleus. The major central afferent input to the area postrema is provided by a group of neurons in the paraventricular and dorsomedial hypothalamic nuclei whose collective dendrites describe a horizontally oriented plexus which encircles the parvocellular nucleus of the hypothalamus bilaterally. In addition, the caudal NTS may project lightly to the AP. The lateral parabrachial nucleus provides a very light input as well. These connections, when considered in the context of the known vagal afferent input and reduced blood-brain barrier of AP, place this structure in a unique position to receive and modulate ascending interoceptive information and to influence autonomic outflow as well.