Showing papers on "Hypothalamus published in 1998"

Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems

Abstract: The novel neuropeptides called hypocretins (orexins) have recently been identified as being localized exclusively in cell bodies in a subregion of the tuberal part of the hypothalamus. The structure of the hypocretins, their accumulation in vesicles of axon terminals, and their excitatory effect on cultured hypothalamic neurons suggest that the hypocretins function in intercellular communication. To characterize these peptides further and to help understand what physiological functions they may serve, we undertook an immunohistochemical study to examine the distribution of preprohypocretin-immunoreactive neurons and fibers in the rat brain. Preprohypocretin-positive neurons were found in the perifornical nucleus and in the dorsal and lateral hypothalamic areas. These cells were distinct from those that express melanin-concentrating hormone. Although they represent a restricted group of cells, their projections were widely distributed in the brain. We observed labeled fibers throughout the hypothalamus. The densest extrahypothalamic projection was found in the locus coeruleus. Fibers were also seen in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central gray, the substantia nigra, the raphe nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Less prominent projections were found in cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. These results suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep–waking cycle.

Biological Action of Leptin as an Angiogenic Factor

Abstract: Leptin is a hormone that regulates food intake, and its receptor (OB-Rb) is expressed primarily in the hypothalamus. Here, it is shown that OB-Rb is also expressed in human vasculature and in primary cultures of human endothelial cells. In vitro and in vivo assays revealed that leptin has angiogenic activity. In vivo, leptin induced neovascularization in corneas from normal rats but not in corneas from fa/fa Zucker rats, which lack functional leptin receptors. These observations indicate that the vascular endothelium is a target for leptin and suggest a physiological mechanism whereby leptin-induced angiogenesis may facilitate increased energy expenditure.

Hypothalamic CART is a new anorectic peptide regulated by leptin

Abstract: The mammalian hypothalamus strongly influences ingestive behaviour through several different signalling molecules and receptor systems Here we show that CART (cocaine- and amphetamine-regulated transcript), a brain-located peptide, is a satiety factor and is closely associated with the actions of two important regulators of food intake, leptin and neuropeptide Y Food-deprived animals show a pronounced decrease in expression of CART messenger RNA in the arcuate nucleus In animal models of obesity with disrupted leptin signalling, CART mRNA is almost absent from the arcuate nucleus Peripheral administration of leptin to obese mice stimulates CART mRNA expression When injected intracerebroventricularly into rats, recombinant CART peptide inhibits both normal and starvation-induced feeding, and completely blocks the feeding response induced by neuropeptide Y An antiserum against CART increases feeding in normal rats, indicating that CART may be an endogenous inhibitor of food intake in normal animals

Mice lacking melanin-concentrating hormone are hypophagic and lean

Abstract: Feeding is influenced by hypothalamic neuropeptides that promote (orexigenic peptides) or inhibit feeding1. Of these, neuropeptide Y (NPY) in the arcuate nucleus2 and melanin-concentrating hormone (MCH)3 and orexins/hypocretins4,5 in the lateral hypothalamus have received attention because their expression is increased during fasting and because they promote feeding when administered centrally. Surprisingly, absence of the orexigenic neuropeptide NPY fails to alter feeding or body weight in normal mice6. As deficiency of a single component of the pathway that limits food intake (such as leptin or receptors for melanocortin-4)7,8 causes obesity, it has been suggested that orexigenic signals are more redundant than those limiting food intake7,8. To define further the physiological role of MCH and to test the redundancy of orexigenic signals, we generated mice carrying a targeted deletion of the MCH gene. MCH-deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding) and an inappropriately increased metabolic rate, despite their reduced amounts of both leptin and arcuate nucleus pro-opiomelanocortin messenger RNA. Our results show that MCH is a critical regulator of feeding and energy balance which acts downstream of leptin and the melanocortin system, and that deletion of a gene encoding a single orexigenic peptide can result in leanness.

Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons

Abstract: Neuropeptide Y (NPY) stimulates food intake and promotes weight gain, whereas melanocortins have the opposite effect. Yet both peptides are synthesized in the arcuate nucleus, a hypothalamic area involved in energy homeostasis. We report here that mRNA encoding NPY and the melanocortin precursor, proopiomelanocortin (POMC) are expressed in adjacent, but distinct, subpopulations of arcuate nucleus neurons. Moreover, these NPY neurons coexpress mRNA encoding Agouti-related protein (Agrp), an endogenous melanocortin receptor antagonist, and fasting increases the expression of both of these mRNA species. Our findings suggest that hypothalamic NPY/Agrp neurons constitute a unique cell type that is activated by fasting to stimulate food intake via a simultaneous increase of NPY and decrease of melanocortin.

Distributions of leptin receptor mRNA isoforms in the rat brain.

Abstract: Leptin, secreted by white adipocytes, has profound feeding, metabolic, and neuroendocrine effects. Leptin acts on the brain, but the specific anatomic sites and pathways responsible for mediating these effects are still unclear. We have systematically examined distributions of mRNA of leptin receptor isoforms in the rat brain by using a probe specific for the long form and a probe recognizing all known forms of the leptin receptor. The mRNA for the long form of the receptor (OB-Rb) localized to selected nuclear groups in the rat brain. Within the hypothalamus, dense hybridization was observed in the arcuate, dorsomedial, ventromedial, and ventral premamillary nuclei. Within the dorsomedial nucleus, particularly intense hybridization was observed in the caudal regions of the nucleus ventral to the compact formation. Receptors were preferentially localized to the dorsomedial division of the ventromedial nucleus. Hybridization accumulated throughout the arcuate nucleus, extending from the retrochiasmatic region to the posterior periventricular region. Moderate hybridization was observed in the periventricular hypothalamic nucleus, lateral hypothalamic area, medial mammillary nucleus, posterior hypothalamic nucleus, nucleus of the lateral olfactory tract, and within substantia nigra pars compacta. Several thalamic nuclei were also found to contain dense hybridization. These groups included the mediodorsal, ventral anterior, ventral medial, submedial, ventral posterior, and lateral dorsal thalamic nuclei. Hybridization was also observed in the medial and lateral geniculate nuclei. Intense hybridization was observed in the Purkinje and granular cell layers of the cerebellum. A probe recognizing all known forms of the leptin receptor hybridized to all of these sites within the brain. In addition, intense hybridization was observed in the choroid plexus, meninges, and also surrounding blood vessels. These findings indicate that circulating leptin may act through hypothalamic nuclear groups involved in regulating feeding, body weight, and neuroendocrine function. The localization of leptin receptor mRNA in extrahypothalamic sites in the thalamus and cerebellum suggests that leptin may act on specific sensory and motor systems. Leptin receptors localized in nonneuronal cells in the meninges, choroid plexus, and blood vessels may be involved in transport of leptin into the brain and in the clearance of leptin from the cerebrospinal fluid. J. Comp. Neurol. 395:535–547, 1998. © 1998 Wiley-Liss, Inc.

Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area

Abstract: Recent studies have identified several neuropeptide systems in the hypothalamus that are critical in the regulation of body weight. The lateral hypothalamic area (LHA) has long been considered essential in regulating food intake and body weight. Two neuropeptides, melanin-concentrating hormone (MCH) and the orexins (ORX), are localized in the LHA and provide diffuse innervation of the neuraxis, including monosynaptic projections to the cerebral cortex and autonomic preganglionic neurons. Therefore, MCH and ORX neurons may regulate both cognitive and autonomic aspects of food intake and body weight regulation. The arcuate nucleus also is critical in the regulation of body weight, because it contains neurons that express leptin receptors, neuropeptide Y (NPY), alpha-melanin-stimulating hormone (alpha-MSH), and agouti-related peptide (AgRP). In this study, we examined the relationships of these peptidergic systems by using dual-label immunohistochemistry or in situ hybridization in rat, mouse, and human brains. In the normal rat, mouse, and human brain, ORX and MCH neurons make up segregated populations. In addition, we found that AgRP- and NPY-immunoreactive neurons are present in the medial division of the human arcuate nucleus, whereas alpha-MSH-immunoreactive neurons are found in the lateral arcuate nucleus. In humans, AgRP projections were widespread in the hypothalamus, but they were especially dense in the paraventricular nucleus and the perifornical area. Moreover, in both rat and human, MCH and ORX neurons receive innervation from NPY-, AgRP-, and alpha-MSH-immunoreactive fibers. Projections from populations of leptin-responsive neurons in the mediobasal hypothalamus to MCH and ORX cells in the LHA may link peripheral metabolic cues with the cortical mantle and may play a critical role in the regulation of feeding behavior and body weight.

The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice

Abstract: Neuropeptide Y (NPY) and the endogenous melanocortin receptor antagonist, agouti gene-related protein (AGRP), coexist in the arcuate nucleus, and both exert orexigenic effects. The present study aimed primarily at determining the brain distribution of AGRP. AGRP mRNA-expressing cells were limited to the arcuate nucleus, representing a major subpopulation (95%) of the NPY neurons, which also was confirmed with immunohistochemistry. AGRP-immunoreactive (-ir) terminals all contained NPY and were observed in many brain regions extending from the rostral telencephalon to the pons, including the parabrachial nucleus. NPY-positive, AGRP-negative terminals were observed in many areas. AGRP-ir terminals were reduced dramatically in all brain regions of mice treated neonatally with monosodium glutamate as well as of mice homozygous for the anorexia mutation. Terminals immunoreactive for the melanocortin peptide alpha-melanocyte-stimulating hormone formed a population separate from, but parallel to, the AGRP-ir terminals. Our results show that arcuate NPY neurons, identified by the presence of AGRP, project more extensively in the brain than previously known and indicate that the feeding regulatory actions of NPY may extend beyond the hypothalamus.

Leptin Receptor Immunoreactivity in Chemically Defined Target Neurons of the Hypothalamus

Abstract: The adipose tissue-derived hormone leptin regulates body weight homeostasis by decreasing food intake and increasing energy expenditure. The weight-reducing action of leptin is thought to be mediated primarily by signal transduction through the leptin receptor (LR) in the hypothalamus. We have used immunohistochemistry to localize LR-immunoreactive (LR-IR) cells in the rat brain using an antiserum against a portion of the intracellular domain of LR that is common to all LR isoforms. The antiserum recognized the short and long isoforms of LR in transfected hematopoietic BaF3 cells. To examine the chemical nature of target cells for leptin, direct double-labeling immunofluorescence histochemistry was applied. The results show extensive distribution of LR-like immunoreactivity (LR-LI) in the brain with positively stained cells present, e.g., in the choroid plexus, cerebral cortex, hippocampus, thalamus, and hypothalamus. In the hypothalamus, strongly LR-IR neurons were present in the supraoptic nucleus (SON) and paraventricular nucleus (PVN), periventricular nucleus, arcuate nucleus, and lateral hypothalamus. Weaker LR-IR neurons were also demonstrated in the lateral and medial preoptic nuclei, suprachiasmatic nucleus, ventromedial and dorsomedial nuclei, and tuberomammillary nucleus. Confocal laser scanning microscopy showed LR-LI in the periphery of individual cells. In magnocellular neurons of the SON and PVN, LR-LI was demonstrated in vasopressin- and oxytocin-containing neurons. In parvocellular neurons of the PVN, LR-LI was demonstrated in many corticotropin-releasing hormone-containing neurons. LR-IR neurons were mainly seen in the ventromedial aspect of the arcuate nucleus, where LR-LI co-localized with neuropeptide Y. In the ventrolateral part of the arcuate nucleus, LR-LI was present in many large adrenocorticotropic hormone-IR proopiomelanocortin-containing neurons and in a few galanin-, neurotensin-, and growth hormone-releasing hormone-containing neurons. In the dorsomedial arcuate nucleus, few tyrosine hydroxylase (dopamine)-containing neurons were seen to have LR-LI. Melanin-concentrating hormone-containing neurons in the lateral hypothalamus had LR-LI. Based on the immunohistochemical results, possible interactions of leptin with brain mechanisms are discussed.

Expression and neuropeptidergic characterization of estrogen receptors (ERalpha and ERbeta) throughout the rat brain: anatomical evidence of distinct roles of each subtype.

Abstract: The recent cloning of a second estrogen receptor (ER) provided a new tool to investigate and clarify how estrogens are capable of communicating with the brain and influence gene expression and neural function. The purpose of the present study was to define the neuroanatomical organization of each receptor subtype using a side-by-side approach and to characterize the cellular population (s) expressing the ERbeta transcript in the endocrine hypothalamus using immunohistochemistry combined with in situ hybridization. Axonal transport inhibition was accomplished to cause neuropeptide accumulation into the cytoplasm and thus facilitate the detection of all positive luteinizing hormone-releasing hormone (LHRH), corticotropin-releasing factor (CRF), vasopressin (AVP), oxytocin (OT), gastrin-related peptide (GRP), and enkephalin (ENK) neurons. The genes encoding either ERalpha or -beta were expressed in numerous limbic-associated structures, and fine differences were found in terms of intensity and positive signal. Such phenomenon is best represented by the bed nucleus of the stria terminalis (BnST) and preoptic area/anterior hypothalamus, where the expression pattern of both transcripts differed across subnuclei. The novel ER was also found to be expressed quite exclusively in other hypothalamic nuclei, including the supraoptic (SON) and selective compartments (magnocellular and autonomic divisions) of the paraventricular nucleus (PVN). A high percentage of the ERbeta-expressing neurons located in the ventro- and dorsomedial PVN are of OT type; 40% of the OT-ir cells forming the medial magnocellular and ventromedial parvocellular PVN showed a clear hybridization signal for ERbeta mRNA, whereas a lower percentage (15-20%) of OT neurons were positive in the caudal parvocellular PVN and no double-labeled cells were found in the rostral PVN and other regions of the brain with the exception of the SON. Very few AVP-ir neurons expressing ERbeta transcript were found throughout the rat brain, although the medial PVN displayed some scattered double-labeled cells (<5%). Quite interestingly, the large majority of the ERbeta-positive cells in the caudal PVN were colocalized within CRF-ir perikarya. Indeed, more than 60-80% of the CRF-containing cells located in the caudolateral division of the parvocellular PVN exhibited a positive hybridization signal for ERbeta mRNA, whereas very few (<5%) neuroendocrine CRF-ir parvocellular neurons of the medial PVN expressed the gene encoding ERbeta. A small percentage of ERbeta-expressing cells in the dorsocaudal and ventromedial zones of the parvocellular PVN were also ENK positive. The ventral zone of the medial parvocellular PVN also displayed GRP-ir neurons, but no convincing hybridization signal for ERbeta was detected in this neuronal population. Finally, as previously described for the gene encoding the classic ER, LHRH neurons of both intact and colchicine-pretreated animals did not express the novel estrogen receptor. This study shows a differential pattern of expression of both receptors in the brain of intact rats and that ERbeta is expressed at various levels in distinct neuropeptidergic populations, including OT, CRF, and ENK. The influence of estrogen in mediating genomic and neuronal responses may therefore take place within these specific cellular groups in the brains of cycling as well as intact male mammals.

Exposure to acute stress induces brain interleukin-1beta protein in the rat

Abstract: Peripheral immune stimulation such as that provided by lipopolysaccharide (LPS) has been reported to increase brain levels of IL-1β mRNA, immunoreactivity, and bioactivity. Stressors produce many of the same neural and endocrine responses as those that follow LPS, but the impact of stressors on brain interleukin-1β (IL-1β) has not been systematically explored. An ELISA designed to detect IL-1β was used to measure levels of IL-1β protein in rat brain. Brain IL-1β was explored after exposure to inescapable shock (IS; 100 1.6 mA tail shocks for 5 sec each) and LPS (1 mg/kg) as a positive control. Rats were killed either immediately or 2, 7, 24, or 48 hr after IS. Brains were dissected into hypothalamus, hippocampus, cerebellum, posterior cortex, and nucleus tractus solitarius regions. LPS produced widespread increases in brain IL-1β, but IS did not. Adrenal glucocorticoids are known to suppress IL-1β production in both the periphery and brain. Thus, it was possible that the stressor did provide stimulus input to the brain IL-1β system(s), but that the production of IL-1β protein was suppressed by the rapid and prolonged high levels of glucocorticoids produced by IS. To test this possibility rats were adrenalectomized or given sham surgery, with half of the adrenalectomized rats receiving corticosterone replacement to maintain basal corticosterone levels. IS produced large increases in brain IL-1β protein in the adrenalectomized subjects 2 hr after stress, whether basal corticosterone levels had been maintained. Thus elimination of the stress-induced rise in corticosterone unmasked a robust and widespread increase in brain IL-1β.

Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei

Abstract: Leptin has profound effects on feeding, metabolism, and neuroendocrine status. Evidence indicates that the hypothalamus coordinates these responses, though the specific brain pathways engaged by leptin remain obscure. The paraventricular nucleus of the hypothalamus (PVH) regulates pituitary gland function and feeding, and innervates autonomic preganglionic neurons, making it a candidate to regulate many of the responses to leptin. The subparaventricular zone, an anterior hypothalamic region receiving dense innervation from the suprachiasmatic nucleus, is thought to integrate circadian and metabolic information. We investigated the distribution of neurons in the rat brain activated by leptin administration that also project to the PVH or the subparaventricular zone by coupling immunohistochemistry for Fos with retrograde transport of cholera toxin-b. Intravenous leptin characteristically activated several cell groups including the ventromedial hypothalamic nucleus, the dorsomedial hypothalamic nucleus (DMH), and the PVH. When tracer injections were centered in the subparaventricular zone, many double-labeled cells were observed in the dorsomedial subdivision of the ventromedial hypothalamic nucleus. This projection may provide an anatomic substrate for integration of metabolic and circadian information to regulate the hypothalamo-pituitary axis. When cholera toxin-b injections were centered in the PVH, many double-labeled cells were found within the caudal DMH. Hence, activation of specific neuroendocrine and autonomic elements of the PVH may be triggered by leptin-activated afferents arising in the DMH. Our results demonstrate that a discrete set of hypothalamic pathways may underlie leptin's autonomic, endocrine, and behavioral effects.

Development of neuroendocrine lineages requires the bHLH–PAS transcription factor SIM1

Abstract: The bHLH‐PAS transcription factor SIM1 is expressed during the development of the hypothalamic‐pituitary axis in three hypothalamic nuclei: the paraventricular nucleus (PVN), the anterior periventricular nucleus (aPV), and the supraoptic nucleus (SON). To investigate Sim1 function in the hypothalamus, we produced mice carrying a null allele of Sim1 by gene targeting. Homozygous mutant mice die shortly after birth. Histological analysis shows that the PVN and the SON of these mice are hypocellular. At least five distinct types of secretory neurons, identified by the expression of oxytocin, vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin, are absent in the mutant PVN, aPV, and SON. Moreover, we show that SIM1 controls the development of these secretory neurons at the final stages of their differentiation. A subset of these neuronal lineages in the PVN/SON are also missing in mice bearing a mutation in the POU transcription factor BRN2. We provide evidence that, during development of the Sim1 mutant hypothalamus, the prospective PVN/SON region fails to express Brn2. Our results strongly indicate that SIM1 functions upstream to maintain Brn2 expression, which in turn directs the terminal differentiation of specific neuroendocrine lineages within the PVN/SON.

Dendritic Release of Vasopressin and Oxytocin

Abstract: In addition to the release of neurotransmitters from their axon terminals, several neuronal populations are able to release their products from their dendrites. The cell bodies and dendrites of vasopressin- and oxytocin-producing neurones are mainly located within the hypothalamic supraoptic and paraventricular nuclei and neuropeptide release within the magnocellular nuclei has been shown in vitro and in vivo. Local release is induced by a range of physiological and pharmacological stimuli, and is regulated by a number of brain areas; locally released peptides are mainly involved in pre- and postsynaptic modulation of the electrical activity of magnocellular neurones. Spatial and temporal differences between peptide release within the nuclei and that from the distant axonal varicosities indicate that the release mechanisms are at least partially independent, supporting the hypothesis of locally regulated dendritic release of vasopressin and oxytocin. In this respect, magnocellular neurones show similarities to other neuronal populations and thus autoregulation of neuronal activity by dendritic neuromodulator release may be a general phenomenon within the brain.

Expression of leptin receptor isoforms in rat brain microvessels.

Abstract: Leptin acts on specific brain regions to affect body weight regulation. As leptin is made by white adipose tissue, it is thought that leptin must cross the blood-brain barrier or the blood-cerebrospinal fluid barrier to reach key sites of action within the brain. High expression of a short form leptin receptor has been reported in the choroid plexus. However, whether one or more of the known leptin receptor isoforms is expressed in brain capillaries is unknown. To identify and quantitate leptin receptor isoforms in rat brain microvessels, we applied quantitative RT-PCR to RNA from purified rat brain microvessels in parallel with in situ hybridization. The results show that the amount of short form leptin receptor messenger RNA (mRNA) in brain microvessels is extremely high, exceeding that in choroid plexus. In contrast, low levels of this mRNA were detected in the cerebellum, hypothalamus, and meninges. The long form leptin receptor mRNA is only present at low levels in the microvessels, but surprisingly, its level in cerebellum is 5 times higher than that in the hypothalamus. In situ hybridization experiments confirmed strong expression of short leptin receptors in microvessels, choroid plexus, and leptomeninges. The distribution and type of leptin receptor mRNA isoforms in brain microvessels are consistent with the possibility that receptor-mediated transport of leptin across the blood-brain barrier is mediated by the short leptin receptor isoform.

Comparative distribution of vasopressin v1b and oxytocin receptor messenger ribonucleic acids in brain

Abstract: The comparative distributions of the vasopressin V1b receptor (V1bR) and the oxytocin receptor (OTR) messenger RNAs (mRNAs) are described in male rat brain using in situ hybridization histochemistry V1bR transcripts were present in forebrain and hypothalamus and were less abundant in mid- and hindbrain regions, similar to the gradient observed with OTR transcripts Microscopic analyses indicated that V1bR expressing cells typically demonstrated the morphology of neurons and confirmed V1bR gene expression in regions including the olfactory bulb, supraoptic, suprachiasmatic, and dorsomedial hypothalamic nuclei, piriform and entorhinal cortices, hippocampus, substantia nigra, and dorsal motor nucleus of the vagus Most regions that expressed V1bR mRNA also expressed OTR mRNA, although OTR gene expression was much more extensive than that of the V1bR V1bR and OTR mRNA distributions were distinct from each other and from that of the V1a receptor mRNA in brain A few brain regions express only V1bR transcripts such as the dorsomedial hypothalamic nucleus and the external plexiform layer of the olfactory bulb Other brain regions, such as the fields of Ammon's horn, the suprachiasmatic nucleus, the substantia nigra pars compacta, and the piriform cortex express mRNAs that encode all three receptor subtypes (V1a, V1b, and OTR), whereas brain areas including the red nucleus and supraoptic nucleus express V1bR and OTR transcripts only These data suggest functional specialization of the V1b, OTR and V1a receptors in brain

Structural bases of vasopressin/oxytocin receptor function.

Abstract: The neurohypophyseal hormones vasopressin and oxytocin are two closely related nonapeptides, synthesized mainly by the magnocellular neurons of the hypothalamus. Their peptide sequences differ only in the amino acids at positions 3 and 8, but, for both hormones, the formation of a disulfide bond between Cys residues at the 1 and 6 positions results in a peptide constituted of a 6 amino acid cyclic part and a 3 amino acid C-terminal part. Both peptides exert various hormonal effects. Circulating oxytocin is mostly known for its ability to elicit the contraction of uterine smooth muscle at term and that of myoepithelial cells that surround the alveoli of the mammary gland during lactation. The main endocrine functions of arginine vasopressin (AVP) are the facilitation of water reabsorption by the kidney and the contraction of smooth muscle cells in arteries. AVP released in the portal blood in the median eminence acts as a potent secretagogue of adrenocorticotropin. In addition, it has become clear that vasopressin and oxytocin, besides mediating well-documented functions at the periphery, are also critically involved in numerous central processes including higher cognitive functions such as memory and learning (see Barberis & Tribollet 1996 for review). Vasopressin and oxytocin were the first biologically active peptides to be synthesized. This achievement, by Du Vigneaud and coworkers, 40 years ago, ushered in the modern era of peptide chemistry. During the subsequent decades, many structural analogues of the neurohypophyseal hormones have been synthesized and pharmacologically characterized (Manning & Sawyer 1993). Peripheral vasopressin and oxytocin receptors have been classified on the basis of both the second messenger system coupled to the receptors and the affinity of a series of vasopressin and oxytocin analogues with enhanced selectivity for a certain receptor type. These classification criteria have led to the distinction of V1a vasopressin (liver, smooth muscle cells from blood vessels, and most peripheral tissues expressing vasopressin receptors), V1b vasopressin (adenohypophysis), V2 vasopressin (kidney) and oxytocin (uterus, mammary gland) receptors ( Jard et al. 1988). To date central receptors have been identified as being of the vasopressin V1a and oxytocin subtypes. Moreover, a great number of molecular probes have been developed, including agonists and antagonists, and radiolabelled, fluorescent or photosensitive ligands. These make this receptor family a good model with which to study structure–function relationships. Today, the four different receptor subtypes have been cloned in mammals, lower vertebrates and invertebrates. Molecular cloning studies have renewed interest in these neurohormone receptors. Vasopressin V1b receptor mRNA has been detected in peripheral tissues (kidney, thymus, heart, lung, spleen, uterus and breast) and numerous areas of the brain in the rat (Lolait et al. 1995), and this receptor subtype has also been characterized in rat adrenal (Grazzini et al. 1996). These studies suggest that the vasopressin V1b receptor may serve additional and unknown functions in the brain and at the periphery. The primary focus of this review is to summarize recent studies that have led to novel insights into the molecular bases of vasopressin and oxytocin receptor functions.

The Stimulatory Effect of Leptin on the Neuroendocrine Reproductive Axis of the Monkey

Abstract: Leptin acts as a metabolic activator of the neuroendocrine reproductive axis in several rodent species, but whether leptin plays a similar role in primates is unknown. To explore this question, we examined the effects of leptin on gonadotropin and testosterone secretion in male rhesus monkeys that were fasted for 2 days. Mean plasma levels of LH and FSH, LH pulse frequency, and LH pulse amplitude were significantly higher in leptin-treated animals compared with saline-treated controls during the second day of the fast. To identify targets for leptin’s action, we used in situ hybridization and computerized imaging to map leptin receptor (Ob-R) messenger RNA (mRNA) distribution. Ob-R mRNA was observed in the anterior pituitary and several areas of the brain, including the arcuate and ventromedial nuclei of the hypothalamus. Ob-R mRNA was coexpressed in both POMC and neuropeptide Y neurons in the arcuate nucleus, whereas little or no coexpression of Ob-R mRNA was evident in GnRH neurons. These results sugges...

Evidence Suggesting That Galanin (GAL), Melanin-Concentrating Hormone (MCH), Neurotensin (NT), Proopiomelanocortin (POMC) and Neuropeptide Y (NPY) Are Targets of Leptin Signaling in the Hypothalamus

Abstract: Leptin (OB protein) reduces food intake by acting at the hypothalamic level. The purpose of the present study was to identify potential targets of leptin signaling in the hypothalamus in ad-lib fed rats. Central administration of leptin (5 microg) for 3 days decreased food intake and body weight gain in association with a decrease in hypothalamic galanin (GAL), melanin-concentrating hormone (MCH), proopiomelanocortin (POMC) and neuropeptide Y (NPY) gene expression and with an increase in neurotensin (NT) gene expression. In pair-fed rats, NPY gene expression was increased and there was no change in either MCH, GAL, POMC or NT gene expression. This study identifies GAL, MCH, POMC and NT as non-NPY targets of leptin signaling and suggests that leptin's action on food intake and body weight is most likely mediated by inhibiting excitatory (e.g. NPY, MCH, GAL, POMC) and stimulating inhibitory (e.g., NT) signals in the feeding circuitry.

Estradiol upregulates Bcl-2 expression in adult brain neurons.

Abstract: Bcl-2, a protein which negatively modulates apoptosis, is up-regulated by estrogen in several tissues To determine the effect of estradiol on Bcl-2 in the adult brain, its immunoreactive distribution was examined in the hypothalamic arcuate nucleus of female rats under different endocrine conditions The number of Bcl-2-immunoreactive neurons was significantly increased (p < 0001) on the day of estrus compared with proestrus, diestrus and metestrus, was decreased by ovariectomy and showed a dose-response increase after estradiol administration to ovariectomized rats Progesterone, when injected simultaneously with estradiol, reduced the effect of estradiol These findings indicate that ovarian hormones regulate Bcl-2 in hypothalamic neurons and suggest that this protein may be involved in the neuroprotective effects of estrogen