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Agouti-related peptide (AGRP)-expressing neurons are activated by fasting--this causes hunger.sup.1-4, an aversive state that motivates the seeking and consumption of food.sup.5,6. Eating returns AGRP neuron activity towards baseline on three distinct timescales: rapidly and transiently following sensory detection of food cues.sup.6-8, slowly and longer-lasting in response to nutrients in the gut.sup.9,10, and even more slowly and permanently with restoration of energy balance.sup.9,11. The rapid regulation by food cues is of particular interest as its neurobiological basis and purpose are unknown. Given that AGRP neuron activity is aversive.sup.6, the sensory cue-linked reductions in activity could function to guide behaviour. To evaluate this, we first identified the circuit mediating sensory cue inhibition and then selectively perturbed it to determine function. Here, we show that a lateral hypothalamic glutamatergic [right arrow] dorsomedial hypothalamic GABAergic ([gamma]-aminobutyric acid-producing).sup.12 [right arrow] AGRP neuron circuit mediates this regulation. Interference with this circuit impairs food cue inhibition of AGRP neurons and, notably, greatly impairs learning of a sensory cue-initiated food-acquisition task. This is specific for food, as learning of an identical water-acquisition task is unaffected. We propose that decreases in aversive AGRP neuron activity.sup.6 mediated by this food-specific circuit increases the incentive salience.sup.13 of food cues, and thus facilitates the learning of food-acquisition tasks. In response to food cues, a hypothalamic circuit in the mouse brain transiently inhibits neurons expressing agouti-related peptide, and this promotes learning of cue-initiated food-seeking tasks., Author(s): Janet Berrios [sup.1] , Chia Li [sup.2] [sup.3] , Joseph C. Madara [sup.1] , Alastair S. Garfield [sup.1] [sup.5] , Jennifer S. Steger [sup.1] [sup.6] , Michael J. Krashes [...]

A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus control the most fundamental physiological needs in vertebrates.sup.1,2. Nevertheless, we lack a developmental blueprint that integrates the molecular determinants of neuronal and glial diversity along temporal and spatial scales of hypothalamus development.sup.3. Here we combine single-cell RNA sequencing of 51,199 mouse cells of ectodermal origin, gene regulatory network (GRN) screens in conjunction with genome-wide association study-based disease phenotyping, and genetic lineage reconstruction to show that nine glial and thirty-three neuronal subtypes are generated by mid-gestation under the control of distinct GRNs. Combinatorial molecular codes that arise from neurotransmitters, neuropeptides and transcription factors are minimally required to decode the taxonomical hierarchy of hypothalamic neurons. The differentiation of [gamma]-aminobutyric acid (GABA) and dopamine neurons, but not glutamate neurons, relies on quasi-stable intermediate states, with a pool of GABA progenitors giving rise to dopamine cells.sup.4. We found an unexpected abundance of chemotropic proliferation and guidance cues that are commonly implicated in dorsal (cortical) patterning.sup.5 in the hypothalamus. In particular, loss of SLIT-ROBO signalling impaired both the production and positioning of periventricular dopamine neurons. Overall, we identify molecular principles that shape the developmental architecture of the hypothalamus and show how neuronal heterogeneity is transformed into a multimodal neural unit to provide virtually infinite adaptive potential throughout life. Single-cell RNA sequencing reveals molecular determinants of the developmental programs that orchestrate the intermingling of neuronal subtypes in the hypothalamus., Author(s): Roman A. Romanov [sup.1] [sup.2] , Evgenii O. Tretiakov [sup.1] , Maria Eleni Kastriti [sup.1] [sup.3] , Maja Zupancic [sup.1] , Martin Häring [sup.1] , Solomiia Korchynska [sup.1] , [...]

This study aimed to investigate the effects of maternal viral infection during a critical time window of fetal hypothalamic development on timing of puberty in the female offspring. For that purpose, a viral mimetic (i.e., synthetic double- strand RNA, namely, polyinosinic-polycytidylic acid, poly (I:C)) or saline was injected (i.p.) to the pregnant rats during the beginning (day 12 of pregnancy, n = 5 for each group) or at the end of this time window (day 14 of pregnancy, n = 5 for each group). Four study groups were formed from the female pups (n = 9-10 pups/group). Following weaning of pups, vaginal opening and vaginal smearing was studied daily until 2 sequential estrous cycles were observed. During the second diestrus phase, blood samples were taken for progesterone, leptin, corticosterone, follicle-stimulating hormone, and luteinizing hormone. Maternal poly (I:C) injection on day 12 of pregnancy increased body mass and reduced the time to puberty in the female offspring. Neither poly (I:C) nor timing of injection affected other parameters studied (p > 0.05). It has been shown for the first time that maternal viral infection during the beginning of fetal hypothalamic development might hasten puberty by increasing body mass in rat offspring. Key words: viral, puberty, poly (I:C), hypothalamus. Ces travaux visaient a etudier les effets de l'infection virale maternelle pendant une fenetre temporelle critique du developpement foetal de l'hypothalamus sur le moment du debut de la puberte chez les rejetons femelles. A cet effet, nous avons injecte (i.p.) a des rates gravides un mime de virus (c. a d. un ARN bicatenaire synthetique, nommement l'acide polyinosinique-polycytidylique ou poly (I:C)) ou une solution saline pendant le debut (jour 12 de gestation, n = 5 pour chaque groupe) ou la fin de cette fenetre temporelle (jour 14 de gestation, n = 5 pour chaque groupe). Nous avons forme 4 groupes a l'etude a partir des rejetons femelles (n = 9-10 rejetons/groupe). A la suite du sevrage des rejetons, nous avons etudie quotidiennement l'ouverture du vagin et le frottis du vagin jusqu'a ce que nous observions 2 cycles oestraux sequentiels. Pendant la seconde phase de dioestrus, nous avons preleve des echantillons de sang pour mesurer le taux des hormones suivantes : progesterone, leptine, corticosterone, hormone folliculo-stimulante et hormone luteinisante. L'injection maternelle de poly (I:C) au jour 12 de la gestation a entraine chez les rejetons femelles une augmentation du poids corporel et une diminution du temps ecoule avant le debut de la puberte. Ni le poly (I:C) ni le moment de l'injection n'ont affecte les autres parametres etudies (p > 0,05). Nous avons montre pour la premiere fois que l'infection virale maternelle pendant le debut du developpement foetal de l'hypothalamus pourrait hater la puberte en augmentant le poids corporel chez le rejeton de rat. [Traduit par la Redaction] Mots-cles : viral, puberte, poly (I:C), hypothalamus., Introduction Microorganisms can be found almost anywhere on the earth (MacDonald and Kuehn 2012) and in the human body (Peters et al. 2012). There is a communalist or mutualistic balance [...]

Dysfunction of primary cilia is related to dyshomeostasis, leading to a wide range of disorders. The ventromedial hypothalamus (VMH) is known to regulate several homeostatic processes, but those modulated specifically by VMH primary cilia are not yet known. In this study, we identify VMH primary cilia as an important organelle that maintains energy and skeletal homeostasis by modulating the autonomic nervous system. We established loss-of-function models of primary cilia in the VMH by either targeting IFT88 (IFT88-K[O.sup.SF-1]) using steroidogenic factor 1-Cre (SF-1-Cre) or injecting an adeno-associated virus Cre (AAV-Cre) directly into the VMH. Functional impairments of VMH primary cilia were linked to decreased sympathetic activation and central leptin resistance, which led to marked obesity and bone-density accrual. Obesity was caused by hyperphagia, decreased energy expenditure, and blunted brown fat function and was also associated with insulin and leptin resistance. The effect of bone-density accrual was independent of obesity, as it was caused by decreased sympathetic tone resulting in increased osteoblastic and decreased osteoclastic activities in the IFT88-K[O.sup.SF-1] and VMH primary cilia knockdown mice. Overall, our current study identifies VMH primary cilia as a critical hypothalamic organelle that maintains energy and skeletal homeostasis., Introduction Homeostatic regulation in the CNS is a complex process that is critical for systemic physiological balance. Therefore, identifying the brain systems integrating internal and external signals is paramount to [...]

Activation of glucose-sensing neurons in the ventromedial hypothalamic nucleus using radio waves or magnetic fields remotely and non-invasively in vivo increases plasma glucose and glucagon, and suppresses plasma insulin; conversely, remote inhibition of glucose-sensing neurons decreased blood glucose and increased plasma insulin. Remote control of animal behaviour This study describes a new technology that allows neurons to be activated or inhibited remotely in freely moving animals using radio waves or magnetic fields. Jeffrey Friedman and colleagues used an iron-binding protein tethered to a heat-sensitive protein to excite or inhibit neurons in the ventromedial hypothalamic nucleus in mice. Activation of glucose-sensing neurons increased plasma glucose and glucagon, suppressed plasma insulin and increased feeding. Inhibition decreased blood glucose, increased plasma insulin and suppressed the response to hypoglycaemia. As well as enabling remote control of cellular activity in basic research, this approach has potential therapeutic implications as a minimally invasive alternative to deep brain stimulation. Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP-TRPV1).sup.1. Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase-Cre mice, which express Cre in glucose-sensing neurons.sup.2. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types., Author(s): Sarah A. Stanley [sup.1] , Leah Kelly [sup.1] , Kaamashri N. Latcha [sup.1] , Sarah F. Schmidt [sup.1] , Xiaofei Yu [sup.1] , Alexander R. Nectow [sup.1] , Jeremy [...]

Ageing is a result of gradual and overall functional deteriorations across the body; however, it is unknown whether an individual tissue primarily works to mediate the ageing progress and control lifespan. Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IκB kinase-β (IKK-β), nuclear factor κB (NF-κB) and related microglia-neuron immune crosstalk. Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-β and NF-κB activation. Mechanistic studies further revealed that IKK-β and NF-κB inhibit gonadotropin-releasing hormone (GnRH) to mediate ageing-related hypothalamic GnRH decline, and GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing. In conclusion, the hypothalamus has a programmatic role in ageing development via immuneneuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems., Ageing is characterized by the gradual and overall loss of various physiological functions, leading to the end of lifespan. Although the search for resolution of ageing pathology is continuing (1,6), [...]

Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3'-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone [...]

Thyroid hormone is a well-known regulator of metabolic and cardiovascular functions, and signaling through thyroid receptors has differential effects on cells depending on the receptor isoform that they express. In [...]

Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity., Introduction The pathophysiological function of glial cells has become a primary focus in the investigation of numerous diseases. Astrocytes appeared evolutionarily subsequent to neurons, augmenting in abundance and complexity in [...]

Simultaneous exposure of explants of the hypothalamo-neurohypophyseal system (HNS) to ATP and the [[alpha].sub.1]-adrenergic receptor ([[alpha].sub.1]-R) agonist, phenylephrine (ATP+PE) induces a synergistic stimulation of vasopressin and oxytocin (VP/OT) release that is sustained for hours (23). The current studies confirm that the synergism is dependent upon activation of [[alpha].sub.1]-R by demonstrating that an [[alpha].sub.1]-R antagonist prevents the response. The role of the [[alpha].sub.1]A, B, and D-adrenergic receptor subtypes in the synergistic effect of ATP+PE on intracellular calcium ([[[Ca.sup.2+]].sub.i]) in supraoptic nucleus (SON) neurons and VP/OT release from neural lobe was evaluated. The increase in [[[Ca.sup.2+]].sub.i] induced by PE in SON predominantly reflects release from intracellular stores and is mediated by activation of the [[alpha].sub.1]A adrenergic receptor subtype. The [[alpha].sub.1]A subtype is also required for the sustained elevation in [[[Ca.sup.2+]].sub.i] induced by ATP+PE. In contrast, although synergistic stimulation of VP/OT release was eliminated by removal of PE and was blunted by benoxathian, an [[alpha].sub.1]-R antagonist that is not subtype selective, no single [[alpha].sub.1]-R subtype selective antagonist prevented sustained stimulation of VP/OT release by ATP+PE. Thus, sustained activation of [[alpha].sub.1]-R is essential for the synergistic VP and OT response to ATP+PE, but multiple [[alpha].sub.1]-R subtypes can support the response. Redundancy amongst the [[alpha].sub.1]-R subunits in supporting this response is consistent with the predicted importance of the response for sustaining the elevated VP release required to prevent cardiovascular collapse during hemorrhage and sepsis. hypothalamus; neurohypophysis; supraoptic nucleus doi: 10.1152/ajpregu.00532.2010.

To maintain homeostasis autonomic control centers in the hypothalamus and medulla must respond appropriately to both external and internal stimuli. Although protected behind the blood-brain barrier, neurons in these autonomic control centers are known to be influenced by changing levels of important signaling molecules in the systemic circulation (e.g., osmolarity, glucose concentrations, and regulatory peptides). The subfornical organ belongs to a group of specialized central nervous system structures, the circumventricular organs, which are characterized by the lack of the normal blood-brain barrier, such that circulating lipophobic substances may act on neurons within this region and via well-documented efferent neural projections to hypothalamic autonomic control centers, influence autonomic function. This review focuses on the role of the subfornical organ in sensing peripheral signals and transmitting this information to autonomic control centers in the hypothalamus. autonomic; cardiovascular; satiety signals; immune regulation; blood-brain barrier doi: 10.1152/ajpregu.00103.2010.

The sympathetic nerve activity is elevated in cardiovascular diseases such as hypertension. Enhanced glutamatergic inputs in the paraventricular nucleus (PVN) of the hypothalamus contribute to heightened sympathetic outflow in spontaneously hypertensive rats (SHR). We determined the role of group I metabotropic glutamate receptors (mGluR) in the PVN in the control of sympathetic vasomotor tone in hypertension. Lumbar sympathetic nerve activity (LSNA), arterial blood pressure (ABP), and heart rate (HR) were recorded in anesthetized SHR and Wistar-Kyoto (WKY) rats. Bilateral microinjection of 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), a selective mGluR5 receptor antagonist, or (S)-(+)-[alpha]-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), a selective mGluR1 receptor antagonist, into the PVN had no significant effect on LSNA and ABP in WKY rats. Strikingly, MPEP and LY367385 dose dependently decreased LSNA, ABP, and HR in SHR. The MPEP-induced decreases in LSNA and ABP were significantly greater than those inhibited by LY367385 in SHR. Furthermore, bilateral microinjection of (S)-3,5-dihydroxyphenylglycine (S-DHPG), a selective group I mGluR agonist, into the PVN caused a similar dose-dependent increase in LSNA, ABP, and HR in both groups. S-DHPG-induced responses were attenuated by MPEP or LY367385 alone and were abolished by a combination of MPEP and LY367385 in WKY rats and SHR. In addition, microinjection of the NMDA receptor antagonist attenuated the sympathoexcitatory responses induced by S-DHPG in both WKY rats and SHR. Collectively, this study provides important new evidence that the resting sympathetic vasomotor tone is maintained by tonic activation of group I mGluRs in the PVN in hypertension. Activation of NMDA receptors are involved in the sympathoexcitatory effect of group I mGluRs in the PVN. hypothalamus; sympathetic activity doi: 10.1152/ajpregu.00195.2010.

An emerging literature attests to the ability of psychological stress to alter the inflammatory cytokine environment of the body. While the ability of stress to cause cytokine release is well established, the neural pathways involved in this control have yet to be identified. This study tests the hypothesis that IL-6 neurons of the hypothalamo-neurohypophyseal system (HNS), a neural pathway proposed to secrete IL-6 into the circulation, are activated in response to psychological stress. Colocalization studies confirm robust expression of IL-6 in cell bodies and fibers of vasopressin (but not oxytocin) neurons of the paraventricular (PVN) and supraoptic nucleus (SON) of the rat hypothalamus. In response to restraint, there was a greater increase in c-Fos expression in SON IL-6-positive (IL-6+) neurons. In addition, both psychogenic (restraint) or systemic stress (hypoxia) lead to phosphorylated ERK induction only in IL-6+ magnocellular neurons, indicating selective activation of the MAPK signaling pathway in the IL-6 subset of magnocellular neurons. Finally, restraint upregulated IL-6 mRNA expression in both the PVN and SON, which was accompanied by a four-fold increase in circulating IL-6. The data indicate that noninflammatory stressors selectively activate IL-6 magnocellular neurons, upregulate IL-6 gene expression in the PVN and SON, and increase plasma IL-6. In summary, results show that IL-6 neurons of the HNS are a recruited component of the response to psychological stress. cytokine; magnocellular; supraoptic nucleus; paraventricular nucleus; hypothalamo-neurohypophyseal system doi: 10.1152/ajpregu.00131.2010.

Riediger T, Eisele N, Scheel C, Lutz TA. Effects of glucagon-like peptide 1 and oxyntomodulin on neuronal activity of ghrelin-sensitive neurons in the hypothalamic arcuate nucleus. Am J Physiol Regul Integr Comp Physiol 298: R 1061-R1067, 2010. First published February 10, 2010; doi:10.1152/ajpregu.00438.2009.--Glucagon-like peptide 1 (GLP-1) and oxyntomodulin (OXM) are structurally related gastrointestinal hormones that are secreted in response to food intake. They reduce food intake and body weight and exert partly overlapping actions on glucose homeostasis and gastrointestinal function. The hypothalamic arcuate (ARC) nucleus is among the central structures expressing a high density of GLP-1 receptors (GLP-lR), which are known to be activated by both peptides, It was the aim of our electrophysiological studies to characterize the effects of GLP-1 and OXM on functionally defined ghrelin-sensitive ARC neurons. GLP-I and OXM ([10.sup.-7] M) exerted excitatory effects in about two-thirds of ghrelin-inhibited neurons and in approximately one-third of ghrelinexcited cells. In addition, a minor fraction of the ghrelin-excited cells was inhibited by both peptides. There was a high degree of cosensitivity to GLP-1 and OXM, and the effects of both hormones were blocked by the GLP-IR antagonist exendin(9-39). The GLP-lRmediated excitations and inhibitions persisted under synaptic blockade, indicating a direct postsynaptic mode of action. Our results demonstrate that GLP-1 and OXM directly and similarly alter neuronal activity in the ARC, probably via a common GLP-lR-mediated mechanism. Ghrelin-antagonistic effects on neuronal activity, which might be implicated in ghrelin-antagonistic in vivo actions, resulting from GLP-lR stimulation (e.g., GLP-IR dependent supression of food intake), predominated in ghrefin-inhibited ARC neurons. However, a subset of ghrelin-excited ARC neurons showed responses to OXM or GLP-1, suggesting the existence of a common mode of action for these hormones; the functional relevance of this effect remains to be elucidated. electrophysiology; glucagon-like peptide I receptor: exendin; hypothalamus doi: 10.1152/ajpregu.00438.2009.

Infection causes the production of proinflammatory cytokines, which act on the central nervous system (CNS) and can result in fever, sleep disorders, depression-like behavior, and even anorexia, although precisely how cytokines regulate the functions of the CNS remain unclear. In the present study, we investigated the regulatory-molecular mechanisms by which cytokines affect hypothalamic function in a state of infection. The intraperitoneal administration of lipopolysaccharide (LPS), a ligand of Toll-like receptor 4 (TLR4), time-dependently (2-24 h) increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in the hypothalamus and liver, which corresponded with anorexia observed within 24 h. Interestingly, the pattern of phosphorylation in response to LPS differed between the hypothalamus and liver. In the hypothalamus, LPS increased STAT3 phosphorylation from 2 h, with a peak at 4 h and a decline thereafter, whereas, in the liver, the peak activation of STAT3 persisted from 2 to 8 h. The time course of the LPS-induced expression of suppressor of cytokine signaling 3 (SOCS3), a STAT3-induced negative regulator of the Janus kinase-STAT pathway, was similar to that of STAT3 phosphorylation. Using mice deficient in myeloid differentiation primary-response protein 88 (MyD88), an adapter protein of TLR4, we found that LPS-induced STAT3 phosphorylation and SOCS3 expression in the hypothalamus and liver were predominantly mediated through MyD88. Moreover, we observed that MyD88-deficient mice were resistant to LPS-induced anorexia. Taken together, our findings reveal a novel mechanism, i.e., MyD88 plays a key role in mediating STAT3 phosphorylation and anorexia in the CNS in a state of infection and inflammation. inflammation; anorexia; central nervous system; liver; Toll-like receptor 4; myeloid differentiation primary-response protein 88; signal transducer and activator of transcription 3; lipopolysaccharide doi: 10.1152/ajpregu.00395.2009

ACTH and [alpha]-melanocyte-stimulating hormone ([alpha]-MSH) are both consecutively processed from proopiomelanocortin (POMC), which is synthesized in hypothalamic arcuate neurons innervating the paraventricular nuclei (PVN). POMC secretion/synthesis is regulated by energy availability. ACTH and [alpha]-MSH bind with equal affinity to melanocortin-4 receptors and elicit similar effects on signal transduction in-vitro. Endogenous [alpha]-MSH thus far is believed to be the major physiological agonist and to act in an anorexigenic manner. Until now, it was fully unknown whether endogenous ACTH is also involved in the regulation of appetite and food intake. In this study in rats, we now show that icy ACTH as well as [alpha]-MSH possess anorexigenic effects in the PVN or areas in close proximity in vivo and that the effect of ACTH is direct and not mediated via [alpha]-MSH. We investigated the roles of endogenous ACTH and ct-MSH by PVN application of the respective antibodies under different physiological conditions. In satiated rats with high levels of ACTH and [alpha]-MSH in the PVN, antibody administration increased food intake and body weight gain; hungry animals were unaffected. Finally, repeated injections of ACTH antibodies into PVN resulted in persistently increased food intake during the light period. These data now provide robust evidence that endogenous ACTH without further processing acts in the PVN or areas in close proximity to reduce food intake under conditions of feeding-induced satiety. adrenocorticotropic hormone; appetite; hypothalamus; paraventricular nucleus; melanocortin-4 receptor doi: 10.1152/ajpendo.00408.2009

Am J Physiol Regul Integr Comp Physiol 298: R147-R156, 2010. First published November 4, 2009; doi: 10.1152/ajpregu.00494.2009.--We examined whether growth hormone-releasing hormone (GHRH) may promote non-rapid eye movement (NREM) sleep via activation of GABAergic neurons in the preoptic area. Male Sprague-Dawley rats were implanted with EEG, EMG electrodes and a unilateral intracerebroventricular cannula. Groups of rats received injections (3 [micro]l icv) with gonadotropin-releasing hormone (GHRH) (0.1 nmol/100 g body wt) or equal volume of physiological saline at the onset of the dark period and were permitted spontaneous sleep for 90 min. Separate groups of rats were sleep deprived by gentle handling for 90 min, beginning at the time of GHRH or saline injection, at the onset of the dark period. Other groups of rats received intracerebroventricular octreotide (somatostatin analog OCT) injections, intracerebroventricular injection of one of two doses of competitive GHRH antagonist, or intracerebroventricular saline injection at light onset and were then permitted 90 min spontaneous sleep-waking. Rats were killed immediately after the 90-min sleep/wake monitoring period. Brain tissue was processed for immunohistochemistry for c-Fos protein and glutamic acid decarboxylase (GAD). Single c-Fos and dual Fos-GAD cell counts were determined in the median preoptic nucleus (MnPN), and in the core and the extended parts of the ventrolateral preoptic nucleus (cVLPO and exVLPO). Intracerebroventricular GHRH elicited a significant increase in NREM sleep amount. Double-labeled Fos+GAD cell counts were significantly elevated after GHRH injection in the MnPN and VLPO in both undisturbed and sleep-deprived groups. OCT and GHRH antagonist significantly decreased NREM sleep amount compared with control rats. OCT injection increased single c-Fos-labeled cell counts in the MnPN, but not in the VLPO. Double-labeled cell counts were significantly reduced after OCT and the high dose of GHRH antagonist injection in all areas examined. These findings identify GABAergic neurons in the MnPN and VLPO as potential targets of the sleep-regulatory actions of GHRH. preoptic area; growth hormone-releasing hormone; somatostatin; octreotide; median preoptic nucleus; ventrolateral preoptic nucleus

Am J Physiol Regul Integr Comp Physiol 298: R130-R140, 2010. First published November 18, 2009; doi: 10.1152/ajpregu.00574.2009.--Previous studies suggest that sympathetic responses evoked from the preoptic area in anesthetized rats require activation of neurons in the dorsomedial hypothalamus. Disinhibition of neurons in the dorsomedial hypothalamus in conscious rats produces physiological and behavioral changes resembling those evoked by microinjection of muscimol, a [GABA.sub.A] receptor agonist and neuronal inhibitor, into the medial preoptic area. We tested the hypothesis that all of these effects evoked from the medial preoptic area are mediated through neurons in the dorsomedial hypothalamus by assessing the effect of bilateral microinjection of muscimol into the DMH on these changes. After injection of vehicle into the dorsomedial hypothalamus, injection of muscimol into the medial preoptic area elicited marked increases in heart rate, arterial pressure, body temperature, plasma ACTH, and locomotor activity and also increased c-Fos expression in the hypothalamic paraventricular nucleus, a region known to control the release of ACTH from the adenohypophysis. Prior bilateral microinjection of muscimol into the dorsomedial hypothalamus produced a modest depression of baseline heart rate and body temperature but completely abolished all changes evoked from the medial preoptic area. Microinjection of muscimol just anterior to the dorsomedial hypothalamus had no effect on autonomic and neuroendocrine changes evoked from the medial preoptic area. Thus, activity of neurons in the dorsomedial hypothalamus mediates a diverse array of physiological and behavioral responses elicited from the medial preoptic area, suggesting that the latter region represents an important source of inhibitory tone to key neurons in the dorsomedial hypothalamus. paraventricular nucleus; heart rate; body temperature; adrenocorticotropic hormone; rats

Neural centers in the hypothalamus regulate food Intake and body weight In response to hormones and other neural stimuli, and dysfunctional communication between the brain and gut underlies metabolic disorders, including obesity. In this issue of the JCI, Steculorum and colleagues present evidence that the gastric peptide ghrelin mediates neural fiber growth in the arcuate nucleus of the hypothalamus during the neonatal period. Neonatal mice subjected to either increased or decreased ghrelin action during this developmental period had an increased risk of obesity in adulthood. Together, the results of this study support a model whereby neural organization at key stages of development sets the foundation for metabolic health later in life., Ghrelin: how the stomach talks to the brain Ghrelin is the only known circulating factor that stimulates appetite and promotes adiposity (1, 2). Unlike many other gastrointestinal (GI) peptides that [...]

Epidemiological data and results from animal studies indicate that imbalances in maternal nutrition impact the expression of metabolic disorders in the offspring. We tested the hypothesis that consumption of excess saturated fats during pregnancy and lactation contributes to adult metabolic dysfunction and that these disturbances can be further influenced by the postweaning diet. Adult male offspring from chowfed dams were compared with males from dams fed a diet high in saturated fat (45 kcal/100 kcal) before mating, pregnancy, and lactation. Offspring were weaned to a standard chow diet or high fat diet. Animals were killed at 120 days after a 24-h fast. Body weight, energy intake, fat deposition, serum leptin, and insulin were significantly higher in offspring from control or high-fat dams if fed a high-fat diet from weaning to adulthood. Only fat-fed offspring from fat-fed dams were hyperglycemic. Leptin receptor, proopiomelanocortin, and neuropeptide Y (NPY) were also significantly increased in offspring exposed to excess saturated fat during gestation and into adulthood, whereas [NPY.sub.1] receptor was downregulated. Signal transducer and activator of transcription 3 mRNA level was significantly higher in offspring from high-fat-fed dams compared with controls; however, no change was detected in cocaine and amphetamine-regulated transcript or suppressor of cytokine signaling 3. An increase in agouti-related protein expression did not reach significance. A significant reduction in phosphatidylinositol 3-kinase regulatory subunit (p85[alpha]) coupled to an upregulation of protein kinase B was observed in offspring from high-fat-fed dams transitioned to chow food, whereas p85[alpha] expression was significantly increased in high-fat offspring weaned to the high-fat diet. These data support the hypothesis that early life exposure to excess fat is associated with changes in hypothalamic regulation of body weight and energy homeostasis and that postweaning diet influences development of metabolic dysfunction and obesity. development; hypothalamus; obesity doi: 10.1152/ajpregu.90585.2008

The median preoptic nucleus (MnPO) is densely innervated by efferent projections from the subfornical organ (SFO) and, therefore, is an important relay for the peripheral chemosensory and humoral information (osmolality and serum levels ANG II). In this context, controlling the excitability of MnPO neuronal populations is a major determinant of body fluid homeostasis and cardiovascular regulation. Using a brain slice preparation and patch-clamp recordings, our study sought to determine whether endogenous ANG II modulates the strength of the SFO-derived GABAergic inputs to the MnPO. Our results showed that the amplitude of the inhibitory postsynaptic currents (IPSCs) were progressively reduced by 44 [+ or -] 2.3% by (Sar (1), Ile (8))-ANG II, a competitive ANG type 1 receptor ([AT.sub.1]R) antagonist. Similarly, losartan, a nonpeptidergic [AT.sub.1]R antagonist decreased the IPSC amplitude by 40.4 [+ or -] 5.6%. The facilitating effect of endogenous ANG II on the GABAergic input to the MnPO was not attributed to a change in GABA release probability and was mimicked by exogenous ANG II, which potentiated the amplitude of the muscimol-activated [GABA.sub.A]/ [Cl.sup.-] current by 53.1 [+ or -] 11.4%. These results demonstrate a postsynaptic locus of action of ANG II. Further analysis reveals that ANG II did not affect the reversal potential of the synaptic inhibitory response, thus privileging a cross talk between postsynaptic [AT.sub.1] and [GABA.sub.A] receptors. Interestingly, facilitation of GABAergic neurotransmission by endogenous ANG II was specific to neurons responding to changes in the ambient [Na.sup.+] level. This finding, combined with the ANG II-mediated depolarization of non-[Na.sup.+]-responsive neurons reveals the dual actions of ANG II to modulate the excitability of MnPO neurons. hydromineral homeostasis; sodium homeostasis; neuropeptides; hypothalamus

The hypothalamus has historically been subdivided into nuclei, agglomerations of cell bodies that are visually distinct in histological sections. Regulatory functions of metabolism have been assigned to the various hypothalamic nuclei principally by analysis of animals with lesions of individual nuclei (39) but also via various means of stimulation, such as cooling or heating probes. Biochemical and molecular specificity of these studies became possible with the identification and synthesis of neurotransmitters (7, 38) as well as the means to manipulate the expression of endogenous neurotransmitters (35, 37) and their receptors by genetic means (6, 21). The arcuate nucleus (ARC) is likely to be the primary site for neurons that sense circulating fuels and energy reserves (POMC/CART neurons, NPY/AGRP neurons), whereas the paraventricular nucleus (PVN) receives input from the ARC and harbors many of the releasing factors (CRF, TRH, vasopressin, and oxytocin) that control pituitary hormone release. The ventromedial nucleus (VMN) receives input from the ARC and plays a critical role in energy balance in parallel with the ARC. The VMN and PVN also send descending projections to the autonomic nervous system and other pathways that control ingestive behavior and metabolism. Developmental analyses have revealed that the neurons that comprise the hypothalamic nuclei arise by differentiation and migration from stem cells within the ventricular zone. Based on recent work, it is becoming clear that coordination between numerous transcription factors that determine specification, survival, and migration is necessary for the formation of the hypothalamus, with each nucleus being determined by its own unique set of factors. In this minireview, we will provide a selective view of the roles that transcription factors play in the developing hypothalamus.

Nesfatin-1 is a recently discovered hypothalamic peptide that was shown to suppress food intake through a melanocortin-3/4 receptor-dependent mechanism. Since nesfatin-1 mRNA is detected in the paraventricular nucleus of the hypothalamus, and because many peptides that alter food intake also influence cardiovascular function, we tested the ability of centrally administered nesfatin-1 to affect mean arterial pressure (MAP) in conscious, freely moving rats. Significant increases in MAP were observed following intracerebroventricular administration of nesfatin-1. Pretreatment with either the melanocortin-3/4 receptor antagonist, SHU9119 (intracerebroventricular), or the [alpha]-adrenergic antagonist, phentolamine (intra-arterial), abrogated the rise in MAP induced by nesfatin-1, indicating that nesfatin-1 may interact with the central melanocortin system to increase sympathetic nerve activity and lead to an increase in MAP. Thus we have identified a novel action of nesfatin-l, in addition to its anorexigenic effects, to stimulate autonomic nervous system activity. autonomics; hypothalamus: appetite

Insulin signaling is dysfunctional in obesity and diabetes. Moreover, central glucose-sensing mechanisms are impaired in these diseases. This is associated with abnormalities in hypothalamic glucose-sensing neurons. Glucose-sensing neurons reside in key areas of the brain involved in glucose and energy homeostasis, such as the ventromedial hypothalamus (VMH). Our results indicate that insulin opens the [K.sub.ATP] channel on VMH GE neurons in 5, 2.5, and 0.1 mM glucose. Furthermore, insulin reduced the sensitivity of VMH GE neurons to a decrease in extracellular glucose level from 2.5 to 0.1 mM. This change in the glucose sensitivity in the presence of insulin was reversed by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (10 nM) but not by the mitogen-activated kinase (MAPK) inhibitor PD-98059 (PD; 50 [micro]M). Finally, neither the AMPK inhibitor compound C nor the AMPK activator AICAR altered the activity of VMH GE neurons. These data suggest that insulin attenuates the ability of VMH GE neurons to sense decreased glucose via the PI3K signaling pathway. Furthermore, these data are consistent with the role of insulin as a satiety factor. That is, in the presence of insulin, glucose levels must decline further before GE neurons respond. Thus, the set point for detection of glucose deficit and initiation of compensatory mechanisms would be lowered. adenosine 5'-triphosphate-sensitive [K.sup.+] channel; adenosine 5'-monophosphate-activated protein kinase; phosphatidylinositol 3-kinase; electrophysiology

The role of the medial basal hypothalamus (MBH) and the anterior hypothalamus/preoptic area (AH/POA) in sleep regulation was investigated using the Halasz knife technique to sever MBH anterior and lateral projections in rats. If both lateral and anterior connections of the MBH were cut, rats spent less time in non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). In contrast, if the lateral connections remained intact, the duration of NREMS and REMS was normal. The diurnal rhythm of NREMS and REMS was altered in all groups except the sham control group. Changes in NREMS or REMS duration were not detected in a group with pituitary stalk lesions. Water consumption was enhanced in three groups of rats, possibly due to the lesion of vasopressin fibers entering the pituitary. EEG delta power during NREMS and brain temperatures (Tbr) were not affected by the cuts during baseline or after sleep deprivation. In response to 4 h of sleep deprivation, only one group, that with the most anterior-to-posterior cuts, failed to increase its NREMS or REMS time during the recovery sleep. After deprivation, Tbr returned to baseline in most of the treatment groups. Collectively, results indicate that the lateral projections of the MBH are important determinants of duration of NREMS and REMS, while more anterior projections are concerned with the diurnal distribution of sleep. Further, the MBH projections involved in sleep regulation are distinct from those involved in EEG delta activity, water intake, and brain temperature. anterior hypothalamus/preoptic area; sleep regulation; non-rapid eye movement sleep

To investigate the role of serotonin 2C receptors (2CR), which are expressed only in the central nervous system, in the satiating actions of the gut peptides CCK and glucagon-like peptide 1 (GLP-1), we examined 1) the effect of null mutations of serotonin 2CR (2CR KO) on the eating-inhibitory potencies of dark-onset intraperitoneal injections of 0.9, 1.7, or 3.5 nmol/kg (1, 2, or 4 [micro]g/kg) CCK and 100, 200, and 400 nmol/kg (33, 66, or 132 [micro]g/kg) GLP-1, and 2) the effects of intra-peritoneal injections of 1.7 nmol//kg CCK and 100 nmol/kg GLP-1 on neuronal activation in the brain, as measured by c-Fos expression. All CCK and GLP-1 doses decreased 30-min food intake in wild-type (WT) mice, but none of them did in 2CR KO mice. CCK increased the number of cells expressing c-Fos in the nucleus tractus solitarii (NTS) of WT, but not 2CR KO mice. CCK induced similar degrees of c-Fos expression in the paraventricular (PVN) and arcuate (Arc) nuclei of the hypothalamus of both genotypes. GLP-1, on the other hand, increased c-Fos expression similarly in the NTS of both genotypes and increased c-Fos expression more in the PVN and Arc of 2CR KO mice, but not WT mice. These results indicate that serotonin signaling via serotonin 2CR is necessary for the full satiating effects of CCK and GLP-I. In addition, they suggest that the satiating effects of the two peptides are mediated by different neural mechanisms. endocrine; eating; hormone; neural; immunocytochemistry; 5HT

The histamine-containing posterior hypothalamic region (PH-TMN) plays a key role in sleep-wake regulation. We investigated rapid changes in glutamate release in the PH-TMN across the sleep-wake cycle with a glutamate biosensor that allows the measurement of glutamate levels at 1- to 4-s resolution. In the PH-TMN, glutamate levels increased in active waking (AW) and rapid eye movement (REM) sleep compared with quiet waking and nonrapid eye movement (NREM) sleep. There was a rapid (0.6 [+ or -] 1.8 s) and progressive increase in glutamate levels at REM sleep onset. A reduction in glutamate levels consistently preceded the offset of REM sleep by 8 [+ or -] 3 s. Short-duration sleep deprivation resulted in a progressive increase in glutamate levels in the PH-TMN, perifornical-lateral hypothalamus (PF-LH), and cortex. We found that in the PF-LH, glutamate levels took a longer time to return to basal values compared with the time it took for glutamate levels to increase to peak values during AW onset. This is in contrast to other regions we studied in which the return to baseline values after AW was quicker than their rise with waking onset. In summary, we demonstrated an increase in glutamate levels in the PH-TMN with REM/AW onset and a drop in glutamate levels before the offset of REM. High temporal resolution measurement of glutamate levels reveals dynamic changes in release linked to the initiation and termination of REM sleep. rapid eye movement sleep; histamine; microdialysis; biosensor; cortex

A reduction of heat loss to the environment through increased cutaneous vasoconstrictor (CVC) sympathetic outflow contributes to elevated body temperature during fever. We determined the role of neurons in the dorsomedial hypothalamus (DMH) in increases in CVC sympathetic tone evoked by [PGE.sub.2] into the preoptic area (POA) in chloralose/urethane-anesthetized rats. The frequency of axonal action potentials of CVC sympathetic ganglion cells recorded from the surface of the tail artery was increased by 1.8 Hz following nanoinjections of bicuculline (50 pmol) into the DMH. [PGE.sub.2] nanoinjection into the POA elicited a similar excitation of tail CVC neurons (+2.1 Hz). Subsequent to [PGE.sub.2] into the POA, muscimol (400 pmol/side) into the DMH did not alter the activity of tail CVC neurons. Inhibition of neurons in the rostral raphe pallidus (rRPa) eliminated the spontaneous discharge of tail CVC neurons but only reduced the [PGE.sub.2]-evoked activity. Residual activity was abolished by subsequent muscimol into the rostral ventrolateral medulla. Transections through the neuraxis caudal to the POA increased the activity of tail CVC neurons, which were sustained through transections caudal to DMH. We conclude that while activation of neurons in the DMH is sufficient to activate tail CVC neurons, it is not necessary for their [PGE.sub.2]-evoked activity. These results support a CVC component of increased core temperature elicited by [PGE.sub.2] in POA that arises from relief of a tonic inhibition from neurons in POA of CVC sympathetic premotor neurons in rRPa and is dependent on the excitation of CVC premotor neurons from a site caudal to DMH. rostral raphe pallidus; thermoregulation; fever; dorsomedial hypothalamus; preoptic hypothalamus

The genes encoding prokineticin 2 polypeptide (Prok2) and its cognate receptor (Prokr2/ Gpcr7311) are widely expressed in both the suprachiasmatic nucleus and its hypothalamic targets, and this signaling pathway has been implicated in the circadian regulation of behavior and physiology. We have previously observed that the targeted null mutation of Prokr2 disrupts circadian coordination of cycles of locomotor activity and thermoregulation. We have now observed spontaneous but sporadic bouts of torpor in the majority of these transgenic mice lacking Prokr2 signaling. During these torpor bouts, which lasted for up to 8 h, body temperature and locomotor activity decreased markedly. Oxygen consumption and carbon dioxide production also decreased, and there was a decrease in respiratory quotient. These spontaneous torpor bouts generally began toward the end of the dark phase or in the early light phase when the mice were maintained on a 12:12-h light-dark cycle and persisted when mice were exposed to continuous darkness. Periods of food deprivation (16-24 h) induced a substantial decrease in body temperature in all mice, but the duration and depth of hypothermia was significantly greater in mice lacking Prokr2 signaling compared with heterozygous and wild-type littermates. Likewise, when tested in metabolic cages, food deprivation produced greater decreases in oxygen consumption and carbon dioxide production in the transgenic mice than controls. We conclude that Prokr2 signaling plays a role in hypothalamic regulation of energy balance, and loss of this pathway results in physiological and behavioral responses normally only detected when mice are in negative energy balance. metabolic rate; thermoregulation; CLAMS; radiotelemetry

It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs., Author(s): Yalin Zhang [1]; Min Soo Kim [1]; Baosen Jia [1]; Jingqi Yan [1]; Juan Pablo Zuniga-Hertz [1]; Cheng Han [1]; Dongsheng Cai (corresponding author) [1] Although the nervous system [...]

Author(s): Marta Carus-Cadavieco [1]; Maria Gorbati [1]; Li Ye [2, 3]; Franziska Bender [1]; Suzanne van der Veldt [1]; Christin Kosse [4]; Christoph Brgers [5]; Soo Yeun Lee [2]; Charu [...]

Neurons within the dorsomedial hypothalamus (DMH) play a critical role in subserving the cardiovascular and neuroendocrine response to psychological stress. An increase in respiratory activity is also a characteristic feature of the physiological response to psychological stress, but there have been few studies of the role of DMH neurons in regulating respiratory activity. In this study we determined the effects of activation of DMH neurons on respiratory activity (assessed by measuring phrenic nerve activity, PNA) and the relationship between evoked changes in respiratory activity and changes in sympathetic vasomotor activity in spontaneously breathing urethane-anesthetized rats. Microinjections of bicuculline (4-40 pmol in 20 nl) into the DMH evoked dose-dependent increases in PNA burst frequency and amplitude. These were accompanied by dose-dependent decreases in mean tracheal CO2 levels, indicative of hyperventilation. In control experiments, microinjections of bicuculline into sites adjacent to the DMH evoked much smaller or no changes in PNA. In experiments where renal sympathetic nerve activity (RSNA) was also measured, cycle-triggered averaging revealed that RSNA under resting conditions was partly correlated with the PNA, but in response to DMH disinhibition there was no consistent change in the amplitude of the respiratory-related variations in RSNA. The results indicate that DMH neurons can exert a powerful stimulatory effect on respiratory activity, causing hyperventilation. This is not associated with an increase in the degree of coupling between PNA and RSNA, indicating that the DMH-evoked increase in RSNA is not a consequence of increased central respiratory drive. arterial pressure; renal sympathetic nerve activity; heart rate; psychological stress

Water-restricted (WR) rats exhibit a rapid suppression of plasma corticosterone following drinking. The present study monitored Fos-like immunoreactivity (Fos) to assess the effect of WR-induced drinking on the activity of vasopressin (VP)-positive magnocellular and parvocellular neurons and corticotropin-releasing hormone (CRH)-positive parvocellular neurons in the paraventricular nucleus of the hypothalamus. Adult male rats received water for 30 min (WR) in the post meridiem (PM) each day for 6 days and were killed without receiving water or at 1 h after receiving water for 15 min. In WR rats, Fos increased in VP magnocellular and parvocellular neurons but not CRH neurons. After drinking, Fos was reduced in VP magnocellular and parvocellular neurons but did not change in CRH neurons. To assess the severity of osmotic stress, rats were sampled throughout the final day of WR. Plasma osmolality, hematocrit and plasma VP were increased throughout the day before PM rehydration, and plasma ACTH and corticosterone were elevated at 1230 and 1430, respectively, showing that WR activates hypothalamic-pituitary-adrenal activity during the early PM before the time of rehydration. To determine the effects of WR-induced drinking on CRH neurons activated by acute stress, WR rats underwent restraint. Restraint increased plasma ACTH and corticosterone and Fos in CRH neurons; although rehydration reduced plasma ACTH and Fos expression in VP neurons, Fos in CRH neurons was not affected. These results suggest that inhibition of VP magnocellular and parvocellular neurons, but not CRH parvocellular neurons, contributes to the suppression of corticosterone after WR-induced drinking. Fos; dehydration; rehydration; magnocellular neurons; parvocellular neurons

Hypertension is a prominent underlying factor in the genesis of cardiovascular-related morbidity and mortality. A major impediment to the investigation into the causes of the disease is the paucity of naturally occurring animal models of the disease. There is evidence that some species of New World primates spontaneously become hypertensive. We used chronically implanted pressure transducers to assess normally occurring blood pressure and heart rate levels at rest and during routine laboratory procedures in a group of one of these New World primates (Aotus sp.). Resting mean arterial pressure ranged from 72 to 130 mmHg. Three animals were judged to have resting mean arterial pressure levels in the hypertensive range ([greater than or equal to] 110 mmHg). In all of the animals, pressor responses to routine laboratory events were exaggerated (average highest mean pressure during 1 min from any session was 97-196 mmHg). Subsequently, the region of the perifornical/lateral hypothalamus known to produce elevated blood pressure and heart rate responses to electrical stimulation was removed, and the blood pressure responses to the laboratory routines were significantly decreased and, in some cases, eliminated. Control lesions in nearby tissue had no effect on these responses. This region may play a critical role in initiating or exacerbating cardiovascular responses that contribute to the development of essential hypertension. essential hypertension; environment; perifornical/lateral hypothalamus

Many gastrointestinal meal-related signals are transmitted to the central nervous system via the vagus nerve and thereby control changes in meal size. The c-Fos-positive neuron has been used as a marker of neuronal activation after lipid meals to examine the contribution of a selective macronutrient on brain neurocircuit activity. In rats fed Intralipid, the c-Fos-positive neurons were highly stimulated in the nucleus of the solitary tract (NTS) and in the hypothalamus, including the paraventricular nucleus (PVN), arcuate nucleus of the hypothalamus (ARC), and ventromedial hypothalamus at 4 h lipid feeding. However, c-Fos-like immunoreactivity was markedly attenuated in these brain regions when chylomicron formation/secretion was blocked by Pluronic L-81. After lymph was diverted from the lymph cannulated animals, the rats had a lower number of c-Fos-positive cells in the NTS and ARC. In contrast, the rats had higher c-Fos-positive neurons in PVN. The present study also revealed that c-Fos-positive neurons induced by feeding of Intalipid were abolished by CCK type I receptor antagonist, Lorglumide. We conclude that the formation and/or secretion of chylomicron are critical steps for initiating neuronal activation in the brain. cholecystokinin type 1 receptor antagonist; chylomicron; hindbrain; hypothalamus

The prohormone convertases (PCs), PC1/3 and PC2, are involved in the tissuespecific endoproteolytic posttranslational processing of many hormonal precursors within the secretory pathway. One important prohormone, pro-thyrotropin-releasing hormone (TRH), is expressed in both hypophysiotropic (where it regulates the secretion of thyroid-stimulating hormone) and nonhypophysiotropic regions of the brain. Pro-TRH is processed at specific sites in the secretory pathway, primarily by PC1/3 followed by PC2. We hypothesized that thyroid hormone status in specific nuclei of the brain would alter pro-TRH processing by inducing changes in PC1/3 and PC2 expression. Therefore, we examined pro-TRH, PC1/3, and PC2 coexpression and coregulation in the paraventricular nucleus (PVN), lateral hypothalamus (LH), and ventromedial nucleus (VMN) of hypothyroid and euthyroid rats. Our results show that 6-n-propyl-2-thiouracil (PTU) treatment producing hypothyroidism induced a significant increase in the expression of PC1/3, PC2, and pro-TRH in the PVN and LH, but not VMN. When confocal studies were performed, an increase in colocalization of PC1/3 or PC2 in pro-TRH was observed only in PVN, a response that was especially prominent in the ventral and medial areas of the PVN. PTU did not regulate colocalization in the VMH or LH. Regulation of colocalization of processing enzyme and prohormone expression is a novel mechanism to alter hormonal biosynthesis. posttranslational processing; hyperthyroidism; hypothyroidism; prohormone convertase; hypothalamus; pro-thyrotropin-releasing hormone; peptide

Consumption of nutrients rich in hydroxystilbenes has been promoted because of their health benefits, including dampening of inflammatory responses. However, few studies have examined their effects in vivo. Here, we show that the hydroxystilbene oxyresveratrol (trans-2,3',4,5'-tetrahydroxystilbene: o-RES) blocked hypothermia but caused no significant effect on the febrile response to the immune stimulus, bacterial LPS in rats. This was associated with a reduction in the LPS-induced plasma cytokine, tumor necrosis factor (TNF)-[alpha], but not IL-6. Both IL-6-stimulated STAT-3 and LPS-induced cycoloxygenase-2 expression in the hypothalamus were not affected by o-RES. These data strongly suggest that the o-RES-induced dampening of neuroimmune responses is largely due to its inhibitory effect on TNF-[alpha] production. In contrast to in vitro experiments, o-RES has no direct effect on NF-[kappa]B signaling pathway in vivo. The specific inhibitory effect of o-RES on TNF-[alpha] opens new avenues for the clinical use of o-RES in pathological conditions where excessive production of TNF-[alpha] is deleterious. hypothalamus; liver; nuclear factor-[kappa]B; STAT-3; cyclooxygenase-2

Lesions of the amygdala have long been known to produce hyperphagia and obesity in cats, dogs, and monkeys, but only recently have studies with rats determined that the effective site is the posterodorsal amygdala (PDA)--the posterodorsal medial amygdaloid nucleus and the intraamygdaloid bed nucleus of the stria terminalis. There is a sex difference; female rats with PDA lesions display greater weight gain than male rats. In the brains of female rats with obesity-inducing PDA lesions, there is a dense pattern of axonal degeneration in the capsule of the ventromedial hypothalamus (VMH) and other targets of the stria terminalis. Transections of the dorsal component of the stria terminalis also result in hyperphagia and obesity in female rats. Similar to rats with VMH lesions, rats with PDA lesions are hyperinsulinemic during food restriction and greatly prefer high-carbohydrate diets. The PDA is also a critical site for some aspects of rodent sexual behavior, particularly those that depend on olfaction, and the pattern of degeneration observed after obesity-inducing PDA lesions is remarkably parallel to the circuit that has been proposed to mediate sexual behavior. Medial amygdaloid lesions disrupt the normal feeding pattern and result in impaired responses to caloric challenges, and there is evidence that these behavioral changes are also due to a disruption of olfactory input. With its input from the olfactory bulbs and connections to the VMH, the PDA may be a nodal point at which olfactory and neuroendocrine stimuli are integrated to affect feeding behavior. amygdala; olfactory bulb; stria terminalis; serotonin; food intake; body weight

The intracerebroventricular injection of endothelin-1 (ET-1) induces fever and increases PG levels in the cerebrospinal fluid of rats. Likewise, the injection of IL-1 into the preoptic area (POA) of the rat hypothalamus causes both fever and increased PG production. In this study, we conducted in vivo and in vitro experiments in the rat to investigate 1) the hypothalamic region involved in ET-1-induced fever and PG biosynthesis and 2) whether hypothalamic IL-1 plays a role as a mediator of the above ET-1 activities. One hundred femtomoles of ET-1 increased body temperature when injected in the POA of conscious Wistar rats; this effect was significantly counteracted by the coinjection of 600 pmol IL-1 receptor antagonist (IL-1ra). In experiments on rat hypothalamic explants, 100 nM ET-1 caused a significant increase in [PGE.sub.2] production and release from the whole hypothalamus and from the isolated POA, but not from the retrochiasmatic region, in 1-h incubations. Six nanomoles of IL-1ra or 10 nM of a cell-permeable interleukin-1 converting enzyme inhibitor completely counteracted the effect of ET-1 on [PGE.sub.2] release from the POA. One hundred nanomoles ET-1 also caused a significant increase in IL-1[beta] immunoreactivity released into the bath solution of hypothalamic explants after 1 h of incubation, although during such time ET-1 failed to modify the gene expression of IL-1[beta] and other pyrogenic cytokines within the hypothalamus. In conclusion, our results show that ET-1 increases IL-1 production in the POA, and this effect appears to be correlated to ET-1-induced fever in vivo, as well as to PG production in vitro. prostaglandin [E.sub.2]; interleukin-1 receptor antagonist; interleukin-1-converting enzyme inhibitor; posterior hypothalamus; hypothalamic explants