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Showing papers on "Hypothalamus published in 2002"


Journal ArticleDOI
08 Aug 2002-Nature
TL;DR: In this paper, the authors showed that post-prandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.
Abstract: Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus(1). The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons(2) in the arcuate nucleus, which is accessible to peripheral hormones(3). Peptide YY3-36 (PYY3-36), a Y2R agonist(4), is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal(5-7). Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons(8). In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.

2,110 citations


Journal ArticleDOI
TL;DR: These findings provide the first direct evidence of altered brain levels of endocannabinoids, and of 2‐AG in particular, during fasting and feeding, and supports a role for endoc cannabinoidoids in the control of appetitive motivation.
Abstract: Endocannabinoids are implicated in appetite and body weight regulation. In rodents, anandamide stimulates eating by actions at central CB1 receptors, and hypothalamic endocannabinoids may be under the negative control of leptin. However, changes to brain endocannabinoid levels in direct relation to feeding or changing nutritional status have not been investigated. We measured anandamide and 2-arachidonoyl glycerol (2-AG) levels in feeding-associated brain regions of rats, during fasting, feeding of a palatable food, or after satiation. Endocannabinoid levels were compared to those in rats fed ad libitum, at a point in their daily cycle when motivation to eat was absent. Fasting increased levels of anandamide and 2-AG in the limbic forebrain and, to a lesser extent, of 2-AG in the hypothalamus. By contrast, hypothalamic 2-AG declined as animals ate. No changes were detected in satiated rats. Endocannabinoid levels in the cerebellum, a control region not directly involved in the control of food intake, were unaffected by any manipulation. As 2-AG was most sensitive to variation during feeding, and to leptin regulation in a previous study, we examined the behavioural effects of 2-AG when injected into the nucleus accumbens shell, a limbic forebrain area strongly linked to eating motivation. 2-AG potently, and dose-dependently, stimulated feeding. This effect was attenuated by the CB1 receptor antagonist SR141716. These findings provide the first direct evidence of altered brain levels of endocannabinoids, and of 2-AG in particular, during fasting and feeding. The nature of these effects supports a role for endocannabinoids in the control of appetitive motivation.

781 citations


Journal ArticleDOI
TL;DR: A dual approach in the male rat reveals that testosterone can act and interact on different aspects of basal and stress HPA function, and holds great promise in establishing further links between the neuroendocrinology of stress and the central bases of sex‐dependent disorders, including psychiatric, cardiovascular and metabolic disease.
Abstract: Under normal conditions, the adrenal glucocorticoids, the endproduct of the hypothalamic-pituitary-adrenal (HPA) axis, provide a frontline of defence against threats to homeostasis (i.e. stress). On the other hand, chronic HPA drive and glucocorticoid hypersecretion have been implicated in the pathogenesis of several forms of systemic, neurodegenerative and affective disorders. The HPA axis is subject to gonadal influence, indicated by sex differences in basal and stress HPA function and neuropathologies associated with HPA dysfunction. Functional cross-talk between the gonadal and adrenal axes is due in large part to the interactive effects of sex steroids and glucocorticoids, explaining perhaps why several disease states linked to stress are sex-dependent. Realizing the interactive nature by which the hypothalamic-pituitary-gonadal and HPA systems operate, however, has made it difficult to model how these hormones act in the brain. Manipulation of one endocrine system is not without effects on the other. Simultaneous manipulation and assessment of both endocrine systems can overcome this problem. This dual approach in the male rat reveals that testosterone can act and interact on different aspects of basal and stress HPA function. Basal adrenocorticotropic hormone (ACTH) release is regulated by testosterone-dependent effects on arginine vasopressin synthesis, and corticosterone-dependent effects on corticotropin-releasing hormone (CRH) synthesis in the paraventricular nucleus (PVN) of the hypothalamus. In contrast, testosterone and corticosterone interact on stress-induced ACTH release and drive to the PVN motor neurones. Candidate structures mediating this interaction include several testosterone-sensitive afferents to the HPA axis, including the medial preoptic area, central and medial amygdala and bed nuclei of the stria terminalis. All of these relay homeostatic information and integrate reproductive and social behaviour. Because these modalities are affected by stress in humans, a dual systems approach holds great promise in establishing further links between the neuroendocrinology of stress and the central bases of sex-dependent disorders, including psychiatric, cardiovascular and metabolic disease.

700 citations


Journal ArticleDOI
TL;DR: Insulin receptors in discrete areas of the hypothalamus have a physiological role in the control of food intake, fat mass and hepatic action of insulin.
Abstract: We investigated the role of hypothalamic insulin signaling in the regulation of energy balance and insulin action in rats through selective decreases in insulin receptor expression in discrete hypothalamic nuclei. We generated an antisense oligodeoxynucleotide directed against the insulin receptor precursor protein and administered this directly into the third cerebral ventricle. Immunostaining of rat brains after 7-day administration of the oligodeoxynucleotide showed a selective decrease of insulin receptor protein within cells in the medial portion of the arcuate nucleus (decreased by ∼80% as compared to rats treated with a control oligodeoxynucleotide). Insulin receptors in other hypothalamic and extra-hypothalamic areas were not affected. This selective decrease in hypothalamic insulin receptor protein was accompanied by rapid onset of hyperphagia and increased fat mass. During insulin-clamp studies, physiological hyperinsulinemia decreased glucose production by 55% in rats treated with control oligodeoxynucleotides but by only 25% in rats treated with insulin receptor antisense oligodeoxynucleotides. Thus, insulin receptors in discrete areas of the hypothalamus have a physiological role in the control of food intake, fat mass and hepatic action of insulin.

689 citations


Journal ArticleDOI
TL;DR: The results indicate that the brain contains multiple, damped circadian oscillators outside the SCN, and the phasing of these oscillators to one another may play a critical role in coordinating brain activity and its adjustment to changes in the light cycle.
Abstract: The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus has been referred to as the master circadian pacemaker that drives daily rhythms in behavior and physiology. There is, however, evidence for extra-SCN circadian oscillators. Neural tissues cultured from rats carrying the Per-luciferase transgene were used to monitor the intrinsic Per1 expression patterns in different brain areas and their response to changes in the light cycle. Although many Per-expressing brain areas were arrhythmic in culture, 14 of the 27 areas examined were rhythmic. The pineal and pituitary glands both expressed rhythms that persisted for >3 d in vitro, with peak expression during the subjective night. Nuclei in the olfactory bulb and the ventral hypothalamus expressed rhythmicity with peak expression at night, whereas other brain areas were either weakly rhythmic and peaked at night, or arrhythmic. After a 6 hr advance or delay in the light cycle, the pineal, paraventricular nucleus of the hypothalamus, and arcuate nucleus each adjusted the phase of their rhythmicity with different kinetics. Together, these results indicate that the brain contains multiple, damped circadian oscillators outside the SCN. The phasing of these oscillators to one another may play a critical role in coordinating brain activity and its adjustment to changes in the light cycle.

625 citations


Journal ArticleDOI
TL;DR: A detailed quantitative analysis of the organization of the SCN core and shell in the rat is presented and place this in the context of the functional significance of the subdivisions in the circadian control of regulatory systems.
Abstract: The suprachiasmatic nucleus (SCN) of the hypothalamus is a dominant circadian pacemaker in the mammalian brain controlling the rest-activity cycle and a series of physiological and endocrine functions to provide a foundation for the successful elaboration of adaptive sleep and waking behavior. The SCN is anatomically and functionally organized into two subdivisions: (1) a core that lies adjacent to the optic chiasm, comprises predominantly neurons producing vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP) colocalized with GABA and receives dense visual and midbrain raphe afferents, and (2) a shell that surrounds the core, contains a large population of arginine vasopressin (AVP)-producing neurons in its dorsomedial portion, and a smaller population of calretinin (CAR)-producing neurons dorsally and laterally, colocalized with GABA, and receives input from non-visual cortical and subcortical regions. In this paper, we present a detailed quantitative analysis of the organization of the SCN core and shell in the rat and place this in the context of the functional significance of the subdivisions in the circadian control of regulatory systems.

591 citations


Journal ArticleDOI
TL;DR: Robust pathways examined in afferents to the ventrolateral preoptic nucleus (VLPO) suggest candidate mechanisms by which sleep may be influenced by brain systems regulating arousal, autonomic, limbic, and circadian functions.
Abstract: Sleep is influenced by diverse factors such as circadian time, affective states, ambient temperature, pain, etc., but pathways mediating these influences are unknown. To identify pathways that may influence sleep, we examined afferents to the ventrolateral preoptic nucleus (VLPO), an area critically implicated in promoting sleep. Injections of the retrograde tracer cholera toxin B subunit (CTB) into the VLPO produced modest numbers of CTB-labeled monoaminergic neurons in the tuberomammillary nucleus, raphe nuclei, and ventrolateral medulla, as well as a few neurons in the locus coeruleus. Immunohistochemistry for monoaminergic markers showed dense innervation of the VLPO by histaminergic, noradrenergic, and serotonergic fibers. Along with previous findings, these results suggest that the VLPO and monoaminergic nuclei may be reciprocally connected. Retrograde and anterograde tracing showed moderate or heavy inputs to the VLPO from hypothalamic regions including the median preoptic nucleus, lateral hypothalamic area, and dorsomedial hypothalamic nucleus (DMH), autonomic regions including the infralimbic cortex and parabrachial nucleus, and limbic regions including the lateral septal nucleus and ventral subiculum. Light to moderate inputs arose from orexin and melanin concentrating hormone neurons, but cholinergic or dopaminergic inputs were extremely sparse. Suprachiasmatic nucleus (SCN) projections to the VLPO were sparse, but the heavy input to the VLPO from the DMH, which receives direct and indirect SCN inputs, could provide an alternate pathway regulating the circadian timing of sleep. These robust pathways suggest candidate mechanisms by which sleep may be influenced by brain systems regulating arousal, autonomic, limbic, and circadian functions.

452 citations


Journal ArticleDOI
TL;DR: It is suggested that the leptin receptor-deficient animals show impaired LTP in CA1 and poor spatial memory due, at least in part, to a deficiency in leptin receptors in the hippocampus.

428 citations


Journal ArticleDOI
TL;DR: The lack of any changes in plasma total calcium, leptinemia, or hypothalamo-pituitary-corticotropic, -thyrotropic, -somatotropic, or -gonadotropic output suggests that Y2 receptors do not modulate bone formation by humoral mechanisms, and that alteration of autonomic function through hypothalamic Y1 receptors may play a key role in a major central regulatory circuit of bone formation.
Abstract: Neuropeptide Y (NPY) is a downstream modulator of leptin action, possibly at the level of the arcuate nucleus where NPY neurons are known to express both leptin receptors and Y2 receptors. In addition to the well-described role of NPY and leptin in energy balance and obesity, intracerebroventricular administration of NPY or leptin also causes bone loss. Here we show that Y2 receptor-deficient mice have a twofold increase in trabecular bone volume as well as greater trabecular number and thickness compared with control mice. We also demonstrate that central Y2 receptors are crucial for this process, since selective deletion of hypothalamic Y2 receptors in mature conditional Y2 knockout mice results in an identical increase in trabecular bone volume within 5 weeks. This hypothalamus-specific Y2 receptor deletion stimulates osteoblast activity and increases the rate of bone mineralization and formation, with no effect on osteoblast or osteoclast surface measurements. The lack of any changes in plasma total calcium, leptinemia, or hypothalamo-pituitary-corticotropic, -thyrotropic, -somatotropic, or -gonadotropic output suggests that Y2 receptors do not modulate bone formation by humoral mechanisms, and that alteration of autonomic function through hypothalamic Y2 receptors may play a key role in a major central regulatory circuit of bone formation.

417 citations


Journal ArticleDOI
TL;DR: Ghrelin induces Fos expression selectively in the ventromedial part of the hypothalamic arcuate nucleus (Arc) and indicates that NPY neurons in the Arc are likely the primary target mediating i.p. ghrelin induced orexigenic effect.

336 citations


Journal ArticleDOI
TL;DR: The neurotropic virus pseudorabies has been utilised in conjunction with the immunocytochemical localisation of a variety of neuroactive peptides and receptors to better define the pathways in the rat hypothalamus directed polysynaptically to the major thermogenic endpoint, brown adipose tissue.

Journal ArticleDOI
TL;DR: The results suggest that GHS-R in the Arc is involved in the regulation of GH secretion, food intake, and adiposity.
Abstract: Growth hormone secretagogues (GHSs) stimulate GH secretion and food intake. GHS receptor (GHS-R) mRNA has been identified mainly in the arcuate nucleus (Arc) and ventromedial nucleus of the hypothalamus and in the pituitary. Ghrelin, an endogenous ligand for GHS-R, has recently been purified from rat stomach. Although ghrelin is also expressed in the hypothalamus, the physiological significance of the ghrelin/GHS-R system is still unknown. We have created transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the promoter for tyrosine hydroxylase (TH), thus selectively attenuating GHS-R protein expression in the Arc. Tg rats had lower body weight and less adipose tissue than did control rats. Daily food intake was reduced, and the stimulatory effect of GHS treatment on feeding was abolished in Tg rats. GH secretion and plasma insulin-like growth factor-I levels were reduced in female Tg rats. These results suggest that GHS-R in the Arc is involved in the regulation of GH secretion, food intake, and adiposity.

Journal ArticleDOI
TL;DR: In vitro, apelin-13 stimulated the release of CRH and AVP from hypothalamic explants, but had no effect on NPY release, suggesting that apelin may play an important role in the hypothalamic regulation of water intake and endocrine axes.

Journal ArticleDOI
TL;DR: The present review focuses on the physiological properties of the cells that secrete or respond to orexins, which appear to be controlled by feeding- and sleep-related signals via a variety of neurotransmitters/hormones from the brain and other tissues.
Abstract: Orexin A and orexin B are hypothalamic peptides that act on their targets via two G protein-coupled receptors (OX1 and OX2 receptors). In the central nervous system, the cell bodies producing orexins are localized in a narrow region within the lateral hypothalamus and project mainly to regions involved in feeding, sleep, and autonomic functions. Via putative pre- and postsynaptic effects, orexins increase synaptic activity in these regions. In isolated neurons and cells expressing recombinant receptors orexins cause Ca2+ elevation, which is mainly dependent on influx. The activity of orexinergic cells appears to be controlled by feeding- and sleep-related signals via a variety of neurotransmitters/hormones from the brain and other tissues. Orexins and orexin receptors are also found outside the central nervous system, particularly in organs involved in feeding and energy metabolism, e.g., gastrointestinal tract, pancreas, and adrenal gland. In the present review we focus on the physiological properties of the cells that secrete or respond to orexins.

Journal ArticleDOI
TL;DR: It is suggested that GLP‐1 (7–36) amide may modulate both food and drink intake in the rat through a central mechanism.
Abstract: This study was designed to determine the possible role of brain glucagon-like peptide-1 (GLP-1) receptors in feeding behavior. In situ hybridization showed colocalization of the mRNAs for GLP-1 receptors, glucokinase, and GLUT-2 in the third ventricle wall and adjacent arcuate nucleus, median eminence, and supraoptic nucleus. These brain areas are considered to contain glucose-sensitive neurons mediating feeding behavior. Because GLP-1 receptors, GLUT-2, and glucokinase are proteins involved in the multistep process of glucose sensing in pancreatic beta cells, the colocalization of specific GLP-1 receptors and glucose sensing-related proteins in hypothalamic neurons supports a role of this peptide in the hypothalamic regulation of macronutrient and water intake. This hypothesis was confirmed by analyzing the effects of both systemic and central administration of GLP-1 receptor ligands. Acute or subchronic intraperitoneal administration of GLP-1 (7-36) amide did not modify food and water intake, although a dose-dependent loss of body weight gain was observed 24 h after acute administration of the higher dose of the peptide. By contrast, the intracerebroventricular (i.c.v.) administration of GLP-1 (7-36) amide produced a biphasic effect on food intake characterized by an increase in the amount of food intake after acute i.c.v. delivery of 100 ng of the peptide. There was a marked reduction of food ingestion with the 1,000 and 2,000 ng doses of the peptide, which also produced a significant decrease of water intake. These effects seemed to be specific because i.c.v. administration of GLP-1 (1-37), a peptide with lower biological activity than GLP-1 (7-36) amide, did not change feeding behavior in food-deprived animals. Exendin-4, when given by i.c.v. administration in a broad range of doses (0.2, 1, 5, 25, 100, and 500 ng), proved to be a potent agonist of GLP-1 (7-36) amide. It decreased, in a dose-dependent manner, both food and water intake, starting at the dose of 25 ng per injection. Pretreatment with an i.c.v. dose of a GLP-1 receptor antagonist [exendin (9-39); 2,500 ng] reversed the inhibitory effects of GLP-1 (7-36) amide (1,000 ng dose) and exendin-4 (25 ng dose) on food and water ingestion. These findings suggest that GLP-1 (7-36) amide may modulate both food and drink intake in the rat through a central mechanism.

Journal ArticleDOI
TL;DR: It is hypothesized that shrinkage of the VLPO with advancing age may explain sleep deficits in elderly humans, and galanin expression may serve to identify sleep-active neurons in the ventrolateral preoptic area of the mammalian brain.

Journal ArticleDOI
TL;DR: It is suggested that ghrelin acts to regulate food intake through synaptic connections in hypothalamic neuronal networks through synapses with unknown immunonegative neurons.

Journal ArticleDOI
TL;DR: Limbic neurocircuits play a central role in regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis, and are likely the primary integrators of anticipatory stress responses as discussed by the authors.
Abstract: Limbic neurocircuits play a central role in regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis Limbic influences on adrenocortical hormone secretion are mediated by transynaptic activation or inhibition of hypophysiotrophic neurons in the medial parvocellular paraventricular nucleus (PVN) Projections from the ventral subiculum, prefrontal cortex, medial amygdala, lateral septum, paraventricular thalamus and suprachiasmatic nucleus (SN) terminate in the immediate surround of the PVN, an area heavily populated by GABAergic interneurons As such, these regions are positioned to modulate paraventricular output via excitation or inhibition of interneuronal projections into the PVN In addition, the same limbic and diencephalic regions have projections to local PVN-projecting hypothalamic and basal telencephalic nuclei, including the dorsomedial and medial preoptic nuclei and the bed nucleus of the stria terminalis These regions are involved in both inhibitory and excitatory regulation of the stress axis, indicating that they contain heterogeneous neuronal populations whose relative impact on the PVN is determined by the nature of afferent stimuli Thus, limbic modulation of the pituitary-adrenocortical system appears to be a multisynaptic process integrated at the level of local PVN-projecting neurocircuits Local circuits are likely the primary integrators of anticipatory stress responses, and may indeed be the focus of HPA dysfunction seen with aging or affective disease

Journal ArticleDOI
TL;DR: A differential involvement of adrenergic, glutamatergic and GABAergic mechanisms in regulating neurosecretory populations of the PVH is supported and involvement of local circuit neurons must be carefully considered in the interpretation of microinjection studies.
Abstract: Norepinephrine (NE), glutamate (Glu), and GABA have been identified as important neurotransmitters governing neuroendocrine mechanisms represented in the paraventricular nucleus of the hypothalamus (PVH). Microinjection studies were used to compare the efficacy of these transmitter mechanisms in stimulating PVH output neurons. Local administration of NE provoked an increase in plasma corticosterone levels and Fos induction in the both the parvocellular and magnocellular divisions of the nucleus. This treatment also stimulated a robust increase in corticotropin-releasing factor (CRF) heteronuclear (hn) RNA in the parvocellular PVH and a more subtle, although reliable, increase in arginine vasopressin (AVP) hnRNA in this same compartment. Local administration of the GABA(A) receptor antagonist bicuculline methiodide (BMI) resulted in increased plasma corticosterone and, in contrast to NE treatment, Fos induction limited primarily to the parvocellular PVH. BMI elicited marked increases in both CRH and AVP hnRNAs within the parvocellular division of the nucleus. Over a wide range of concentrations, Glu failed to produce reliable increases in corticosterone secretion and induced only weak activational responses limited primarily to non-neurosecretory regions of the PVH. Local Glu administration did, however, provoke Fos induction in identified GABAergic neurons immediately adjoining the PVH, suggesting that the muted response to Glu may be a consequence of concurrent activation of local inhibitory interneurons. These results support a differential involvement of adrenergic, glutamatergic and GABAergic mechanisms in regulating neurosecretory populations of the PVH and suggest that involvement of local circuit neurons must be carefully considered in the interpretation of microinjection studies.

Journal ArticleDOI
TL;DR: The transience of the observed effects on food intake and body weight in the hypothalamus-specific Y2 knockout mice, and the difference of this model from germ-line Y2 deletion mice, underline the importance of conditional models of gene deletion, because developmental, secondary, or extrahypothalamic mechanisms may mask such effects in germ- line knockouts.
Abstract: Neuropeptide Y is implicated in energy homeostasis, and contributes to obesity when hypothalamic levels remain chronically elevated. To investigate the specific role of hypothalamic Y2 receptors in this process, we used a conditional Y2 knockout model, using the Cre-lox system and adenoviral delivery of Cre-recombinase. Hypothalamus-specific Y2-deleted mice showed a significant decrease in body weight and a significant increase in food intake that was associated with increased mRNA levels for the orexigenic NPY and AgRP, as well as the anorexic proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the arcuate nucleus. These hypothalamic changes persisted until at least 34 days after Y2 deletion, yet the effect on body weight and food intake subsided within this time. Plasma concentrations of pancreatic polypeptide and corticosterone were 3- to 5-fold increased in hypothalamus-specific Y2 knockout mice. Germ-line Y2 receptor knockout also produced a significant increase in plasma levels of pancreatic polypeptide. However, these mice differed from conditional knockout mice in that they showed a sustained reduction in body weight and adiposity associated with increased NPY and AgRP but decreased POMC and CART mRNA levels in the arcuate nucleus. The transience of the observed effects on food intake and body weight in the hypothalamus-specific Y2 knockout mice, and the difference of this model from germ-line Y2 knockout mice, underline the importance of conditional models of gene deletion, because developmental, secondary, or extrahypothalamic mechanisms may mask such effects in germ-line knockouts.

Journal ArticleDOI
TL;DR: The present study takes advantage of the specificity of the vesicular transporters to afford the first detailed map of putative glutamatergic neurons in the rat hypothalamus, supporting a major role for hypothalamic glutamaters in regulation of all aspects of hypothalamic function.
Abstract: Two isoforms of the vesicular glutamate transporter, VGLUT1 and VGLUT2, were recently cloned and biophysically characterized. Both VGLUT1 and VGLUT2 specifically transport glutamate into synaptic vesicles, making them definitive markers for neurons using glutamate as a neurotransmitter. The present study takes advantage of the specificity of the vesicular transporters to afford the first detailed map of putative glutamatergic neurons in the rat hypothalamus. In situ hybridization analysis was used to map hypothalamic distributions of VGLUT1 and VGLUT2 mRNAs. VGLUT2 is clearly the predominant vesicular transporter mRNA found in the hypothalamus; rich expression can be documented in regions regulating energy balance (ventromedial hypothalamus), neuroendocrine function (preoptic nuclei), autonomic tone (posterior hypothalamus), and behavioral/homeostatic integration (lateral hypothalamus, mammillary nuclei). Expression of VGLUT1 is decidedly more circumspect and is confined to relatively weak labeling in lateral hypothalamic regions, neuroendocrine nuclei, and the suprachiasmatic nucleus. Importantly, dual-label analysis revealed no incidence of colocalization of VGLUT1 or VGLUT2 mRNAs in glutamic acid decarboxylase (GAD) 65-positive neurons, indicating that GABA neurons do not express either transporter. Our data support a major role for hypothalamic glutamatergic neurons in regulation of all aspects of hypothalamic function.

Journal ArticleDOI
TL;DR: In this article, the distribution of Urocortin (Ucn) III neurons and fibers was examined by in situ hybridization and immunohistochemistry in the rat brain and it was found that Ucn III-positive neurons were found predominately within the hypothalamus and medial amygdala.
Abstract: Urocortin (Ucn) III, or stresscopin, is a new member of the corticotropin-releasing factor (CRF) peptide family identified in mouse and human. Pharmacological studies showed that Ucn III is a high-affinity ligand for the type 2 CRF receptor (CRF-R2). To further understand physiological functions the peptide may serve in the brain, the distribution of Ucn III neurons and fibers was examined by in situ hybridization and immunohistochemistry in the rat brain. Ucn III-positive neurons were found predominately within the hypothalamus and medial amygdala. In the hypothalamus, Ucn III neurons were observed in the median preoptic nucleus and in the rostral perifornical area lateral to the paraventricular nucleus. The Ucn III fibers were distributed mainly in the hypothalamus and limbic structures. Hypothalamic regions that were innervated prominently by Ucn III fibers included the ventromedial nucleus, medial preoptic nucleus, and ventral premammillary nucleus. Outside the hypothalamus, the densest projections were found in the intermediate part of the lateral septum, posterior division of the bed nucleus stria terminalis, and the medial nucleus of the amygdala. Several major Ucn III terminal fields identified in the present study, including the lateral septum and the ventromedial hypothalamus, are known to express high levels of CRF-R2. Thus, these anatomical data strongly support the notion that Ucn III is an endogenous ligand for CRF-R2 in these areas. These results also suggest that Ucn III is positioned to play a role in mediating physiological functions, including food intake and neuroendocrine regulation.

Journal ArticleDOI
TL;DR: The widespread distribution of PACAP in the brain and spinal cord suggests that PACAP is involved in the control of many autonomic and sensory functions as well as higher cortical processes.
Abstract: In the present study the localization of pituitary adenylate cyclase-activating peptide (PACAP)-expressing cell bodies and PACAP projections were mapped in the adult rat brain and spinal cord by using immunohistochemistry and in situ hybridization histochemistry. A widespread occurrence of PACAP-containing cell bodies was found, with the greatest accumulation in several hypothalamic nuclei and in several brainstem nuclei, especially the habenular nuclei, the pontine nucleus, the lateral parabrachial nucleus (LPB), and the vagal complex. PACAP was also present in cell bodies in the olfactory areas, in neocortical areas, in the hippocampus, in the vestibulo- and cochlear nuclei, in cell bodies of the intermediolateral cell column of the spinal cord and in Purkinje cells of the cerebellum, in the subfornical organ, and in the organum vasculosum of the lamina terminalis. An intense accumulation of PACAP-immunoreactive (-IR) nerve fibers was observed throughout the hypothalamus, in the amydaloid and extended amygdaloid complex, in the anterior and paraventricular thalamic nuclei, in the intergeniculate leaflet, in the pretectum, and in several brainstem nuclei, such as the parabrachial nucleus, the sensory trigeminal nucleus, and the nucleus of the solitary tract. PACAP-IR nerve fibers were also found in the area postrema, the posterior pituitary and the choroid plexus, and the dorsal and ventral horn of the spinal cord. The widespread distribution of PACAP in the brain and spinal cord suggests that PACAP is involved in the control of many autonomic and sensory functions as well as higher cortical processes.

Journal ArticleDOI
TL;DR: Old and recent data implicating insulin and leptin as key circulating signals to the central nervous system, particularly the ventral hypothalamus, in communicating the size and the distribution of body fat stores are summarized.
Abstract: Body adiposity is known to be carefully regulated and to remain relatively stable for long periods of time in most mammalian species. This review summarizes old and recent data implicating insulin and leptin as key circulating signals to the central nervous system, particularly the ventral hypothalamus, in communicating thesizeand thedistribution of body fat stores. This input ultimately alters food intake and energy expenditure to maintain constancy of the adipose depot. The key primary neurons in the arcuate nucleus containing NPY/AgRP and POMC/CART appear be critical constituents of the CNS regulating system, and are shown to contribute to anabolic and catabolic signaling systems to complete the feedback loop. New data to indicate shared intracellular signaling from leptin and insulin is provided. The satiety system for meals, consisting of neural afferents to the hind-brain from the gastrointestinal tract, is described and its effectiveness is shown to vary with the strength of the insulin and leptin signals. This provides anefferent mechanism that plays a key role in a complex feedback system that allows intermittent meals to vary from day to day, but provides appropriate long-term adjustment to need. Recently described contributions of this system to obesity are described and potential therapeutic implications are discussed.

Journal ArticleDOI
TL;DR: It is shown that the CRH-receptor antagonist Antalarmin blocks stress-induced 99Tc extravasation, whereas site-specific injection of CRH in the paraventricular nucleus of the hypothalamus mimics acute stress.
Abstract: Stress activates the hypothalamic-pituitary-adrenal axis through release of corticotropin releasing hormone (CRH), lead- ing to production of glucocorticoids that down-regulate im- mune responses. Acute stress, however, also has proinflam- matory effects that seem to be mediated through the activation of mast cells. Stress and mast cells have been implicated in the pathophysiology of various inflammatory conditions, including some in the central nervous system, such as multiple sclerosis in which disruption of the blood-brain barrier (BBB) precedes clinical symptoms. We previously showed that acute restraint stress increases rat BBB permeability to intravenous 99 Tc glu- ceptate and that administration of the "mast cell stabilizer" disodium cromoglycate (cromolyn) inhibits this effect. In this study, we show that the CRH-receptor antagonist Antalarmin blocks stress-induced 99 Tc extravasation, whereas site-spe- cific injection of CRH in the paraventricular nucleus (PVN) of the hypothalamus mimics acute stress. This latter effect is blocked by pretreatment of the PVN with cromolyn; moreover, restraint stress cannot disrupt the BBB in the diencephalon and cere- bellum of W/W v mast cell-deficient mice. These results dem-

Journal ArticleDOI
TL;DR: The results support the idea that orexins have important actions on hypothalamic neurons that control food intake and fluid balance, but also that oxins may regulate other neuroendocrine systems.
Abstract: The neuropeptides orexin-A and orexin-B are produced in neurons of the lateral hypothalamic area and have been implicated to be involved in the regulation of food/water intake and sleep-wake control. The orexins act at two different G-protein-coupled orexin receptors (OX-R1 and OX-R2) that are derived from separate genes and expressed differentially throughout the central nervous system. In the present study, we have used a polyclonal antipeptide antiserum to analyse in detail the distribution of OX-R1-immunoreactive neurons in the rat hypothalamus. In order to identify the chemical mediators of orexin action in the hypothalamus, the OX-R1-containing neurons were characterized with regard to the content of peptides shown previously to affect ingestive and drinking behaviour. Neurons containing OX-R1 immunoreactivity were widely distributed in the hypothalamus with cell bodies located in the suprachiasmatic, periventricular, paraventricular (both magno- and parvocellular division), supraoptic, arcuate, ventromedial, dorsomedial and tuberomammillary nuclei and the lateral hypothalamic area. In magnocellular neurons of the paraventricular and supraoptic nuclei, OX-R1 immunoreactivity was seen in both vasopressin- and oxytocin-containing neurons. OX-R1 immunoreactivity was demonstrated in vasopressin and vasoactive intestinal polypeptide (VIP) neurons of the suprachiasmatic nucleus, in somatostatin neurons of the periventricular nucleus and in corticotropin-releasing hormone (CRH) neurons of the parvocellular paraventricular nucleus. In the arcuate nucleus, OX-R1 immunoreactivity was present in neuropeptide Y (NPY) and agouti-related peptide (AGRP) neurons of the ventromedial part as well as in proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neurons of the ventrolateral division. In the lateral hypothalamic area, OX-R1 immunoreactivity was demonstrated in melanin-concentrating hormone (MCH)- and orexin-containing neurons. In the hypothalamic tuberomammillary nucleus, OX-R1-immunoreactivity was shown in many histamine-containing neurons. The results support the idea that orexins have important actions on hypothalamic neurons that control food intake and fluid balance, but also that orexins may regulate other neuroendocrine systems.

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TL;DR: It is demonstrated that the paraventricular nucleus exerts a powerful, tonic effect on the control of sympathetic vasomotor tone under basal conditions in anesthetized rats and that this is enhanced in spontaneously hypertensive rats.
Abstract: Experimental evidence indicates that the hypothalamic paraventricular nucleus modulates sympathetic vasomotor tone and blood pressure and that this modulation is altered in some cardiovascular diseases. This study tested the hypothesis that this nucleus exerts a more significant tonic excitatory modulation of basal sympathetic vasomotor activity in spontaneously hypertensive rats. In anesthetized, artificially-ventilated rats, bilateral microinjections of the GABA A receptor agonist, muscimol (1 to 1.5 nmoles per side), into the paraventricular nucleus produced a depressor and sympathoinhibitory response that did not recover. When compared with normotensive rats, this response was more marked in spontaneously hypertensive rats, where lumbar sympathetic nerve discharge was reduced by 75±3% and mean arterial pressure fell from 119±7 mm Hg to 58±3 mm Hg. Blockade of excitatory and inhibitory amino acid receptors in the rostral ventrolateral medulla significantly attenuated this response. Microinjections of small volumes (

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TL;DR: The above results provide the first detailed evidence that ER-beta protein is widely distributed in both male and female rat brains, but that distinctive sex differences also exist.

Journal ArticleDOI
Toru Hosoi1, Toru Kawagishi1, Yasunobu Okuma1, Jun Tanaka1, Yasuyuki Nomura1 
TL;DR: It is reported here that peripherally applied leptin increased STAT3 phosphorylation not only in the hypothalamus but also in the brain stem as assessed by Western blotting, and suggested that circulating leptin may directly act in thebrain stem to elicit autonomic and neuroendocrine control of food intake and energy expenditure.
Abstract: Leptin is a circulating molecule for the regulation of food intake and body weight suggested to be mediated in the hypothalamus via Ob-Rb receptor, which activates Janus kinase-signal transducer and activator of transcription (STAT) pathways. Although leptin receptors exist in many regions of the brain, there have been few in vivo functional studies of leptin’s target site other than the hypothalamus. We report here that peripherally applied leptin increased STAT3 phosphorylation not only in the hypothalamus but also in the brain stem as assessed by Western blotting. Moreover, administration of leptin induced expression of the suppressor of cytokine signaling 3 mRNA, a negative feedback regulator of leptin signaling, in the brain stem as well as in the hypothalamus. Using immunohistochemistry, we observed phosphorylated STAT3-immunoreactive cells in the arcuate nucleus, ventromedial hypothalamus, lateral hypothalamic area of the hypothalamus, and the nucleus of the tractus solitarius, dorsal motor nucleus...

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TL;DR: It is hypothesize that these vlPOA and MnPN neuronal populations act as parts of a GABAergic/galaninergic sleep‐promoting (‘anti‐waking’) network which exercises inhibitory control over waking‐promoted systems.
Abstract: Several lines of evidence show that the preoptic area (POA) of the hypothalamus is critically implicated in the regulation of sleep. Functionally heterogeneous cell groups with sleep-related discharge patterns are located both in the medial and lateral POA. Recently a cluster of neurons showing sleep-related c-Fos immunoreactivity was found in the median preoptic nucleus (MnPN). To determine the specificity of the state-related behaviour of MnPN neurons we have undertaken the first study of their discharge patterns across the sleep-waking cycle. Nearly 76% of recorded cells exhibited elevated discharge rates during sleep. Sleep-related units showed several distinct types of activity changes across sleep stages. Two populations included cells displaying selective activation during either non-rapid eye movement (NREM) sleep (10%) or REM sleep (8%). Neurons belonging to the predominant population (58%) exhibited activation during both phases of sleep compared to wakefulness. Most of these cells showed a gradual increase in their firing rates prior to sleep onset, elevated discharge during NREM sleep and a further increase during REM sleep. This specific sleep-waking discharge profile is opposite to that demonstrated by wake-promoting monoaminergic cell groups and was previously found in cells localized in the ventrolateral preoptic area (vlPOA). We hypothesize that these vlPOA and MnPN neuronal populations act as parts of a GABAergic/galaninergic sleep-promoting (‘anti-waking’) network which exercises inhibitory control over waking-promoting systems. MnPN neurons that progressively increase activity during sustained waking and decrease activity during sustained sleep states may be involved in homeostatic regulation of sleep.