Showing papers on "Hypothalamus published in 2007"
TL;DR: It is shown that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity and may be an element in neurodevelopmental disorders.
Abstract: CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders.
603 citations
TL;DR: This Review provides a synthesis of recent evidence concerning the actions of these hormones on food intake through their actions on the hypothalamus, the brain stem, and the autonomic nervous system.
565 citations
TL;DR: This article exploited RNA interference mediated by adeno-associated viral vectors to achieve focused silencing of ERα in the ventromedial nucleus of the hypothalamus, a key center of energy homeostasis.
Abstract: Estrogen receptor α (ERα) plays a pivotal role in the regulation of food intake and energy expenditure by estrogens. Although it is well documented that a disruption of ERα signaling in ERα knockout (ERKO) mice leads to an obese phenotype, the sites of estrogen action and mechanisms underlying this phenomenon are still largely unknown. In the present study, we exploited RNA interference mediated by adeno-associated viral vectors to achieve focused silencing of ERα in the ventromedial nucleus of the hypothalamus, a key center of energy homeostasis. After suppression of ERα expression in this nucleus, female mice and rats developed a phenotype characteristic for metabolic syndrome and marked by obesity, hyperphagia, impaired tolerance to glucose, and reduced energy expenditure. This phenotype persisted despite normal ERα levels elsewhere in the brain. Although an increase in food intake preceded weight gain, our data suggest that a leading factor of obesity in this model is likely a decline in energy expenditure with all three major constituents being affected, including voluntary activity, basal metabolic rate, and diet-induced thermogenesis. Together, these findings indicate that ERα in the ventromedial nucleus of the hypothalamus neurons plays an essential role in the control of energy balance and the maintenance of normal body weight.
477 citations
TL;DR: A high expression of irGPR30 is shown in the hypothalamic-pituitary axis, hippocampal formation, and brainstem autonomic nuclei; and the activation of GPR30 by G-1 is associated with a mobilization of calcium in dissociated and cultured rat hypothalamic neurons.
Abstract: The G protein-coupled receptor 30 (GPR 30) has been identified as the non-genomic estrogen receptor, and G-1, the specific ligand for GPR30. With the use of a polyclonal antiserum directed against the human C-terminus of GPR30, immunohistochemical studies revealed GPR30-immunoreactivity (irGPR30) in the brain of adult male and non-pregnant female rats. A high density of irGPR30 was noted in the Islands of Calleja and striatum. In the hypothalamus, irGPR30 was detected in the paraventricular nucleus and supraoptic nucleus. The anterior and posterior pituitary contained numerous irGPR30 cells and terminal-like endings. Cells in the hippocampal formation as well as the substantia nigra were irGPR30. In the brainstem, irGPR30 cells were noted in the area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus; a cluster of cells were prominently labeled in the nucleus ambiguus. Tissue sections processed with pre-immune serum showed no irGPR30, affirming the specificity of the antiserum. G-1 (100 nM) caused a large increase of intracellular calcium concentrations [Ca(2+) ](i) in dissociated and cultured rat hypothalamic neurons, as assessed by microfluorometric Fura-2 imaging. The calcium response to a second application of G-1 showed a marked homologous desensitization. Our result shows a high expression of irGPR30 in the hypothalamic-pituitary axis, hippocampal formation, and brainstem autonomic nuclei; and the activation of GPR30 by G-1 is associated with a mobilization of calcium in dissociated and cultured rat hypothalamic neurons.
459 citations
TL;DR: It is concluded that KiSS-1 expression in the ARC of the ewe brain is negatively regulated by chronic levels of E and P, suggesting that both steroids may exert negative feedback control on GnRH secretion through altered kisspeptin signaling.
Abstract: The KiSS-1 gene encodes a family of peptides called kisspeptins, which are endogenous ligands for the G protein-coupled receptor GPR54. Kisspeptin function appears to be critical for GnRH secretion and the initiation of puberty. To test the hypothesis that steroid hormones regulate KiSS-1 mRNA expression in the ewe, we examined the brains of ovary-intact (luteal phase) and ovariectomized (OVX) ewes, as well as OVX ewes that received estradiol (E) or progesterone (P) replacement. KiSS-1 mRNA-expressing cells were predominantly located in the arcuate nucleus (ARC). Here, expression was increased after OVX but returned to the level of gonad-intact animals with E treatment. Treatment with P partially restored KiSS-1 expression toward gonad-intact levels. Double-label immunohistochemistry revealed that approximately 86% of kisspeptin-immunoreactive cells in the ARC are also P-receptor positive. Finally, we tested the hypothesis that KiSS-1 mRNA is lower during anestrus, due to a non-steroid-dependent seasonal effect. In OVX ewes, expression in the ARC was lower at the time of year corresponding to anestrus. We conclude that KiSS-1 expression in the ARC of the ewe brain is negatively regulated by chronic levels of E and P, suggesting that both steroids may exert negative feedback control on GnRH secretion through altered kisspeptin signaling. Furthermore, a seasonal alteration in KiSS-1 expression in the ARC of OVX ewes strongly suggests that kisspeptin is fundamentally involved in the control of seasonal changes in reproductive function.
374 citations
TL;DR: The cynomolgus monkey experiments provide strong evidence that the increase in KiSS-1 neuronal size and gene expression in postmenopausal women is secondary to ovarian failure, and suggest that kisspeptin neurons regulate estrogen negative feedback in the human.
Abstract: Context: Human menopause is characterized by ovarian failure, gonadotropin hypersecretion, and neuronal hypertrophy in the hypothalamic infundibular (arcuate) nucleus. Recent studies have demonstrated a critical role for kisspeptins in reproductive regulation, but it is not known whether menopause is accompanied by changes in hypothalamic kisspeptin neurons. Objectives: Our objective was to map the location of neurons expressing kisspeptin gene (KiSS-1) transcripts in the human hypothalamus and determine whether menopause is associated with changes in the size and gene expression of kisspeptin neurons. In monkeys, our objective was to evaluate the effects of ovariectomy and hormone replacement on neurons expressing KiSS-1 mRNA in the infundibular nucleus. Subjects: Hypothalamic tissues were collected at autopsy from eight premenopausal and nine postmenopausal women and from 42 young cynomolgus monkeys in various endocrine states. Methods: We used hybridization histochemistry, quantitative autoradiography,...
350 citations
TL;DR: The circulating thyroid hormone levels of M CT8-null mice closely resemble those of humans with MCT8 mutations, yet in the mice, CNS development is only partially affected, indicating the hypothyroid state of this tissue.
Abstract: In humans, inactivating mutations in the gene of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8; SLc16A2) lead to severe forms of psychomotor retardation combined with imbalanced thyroid hormone serum levels. The MCT8-null mice described here, however, developed without overt deficits but also exhibited distorted 3,5,3'-triiodothyronine (T3) and thyroxine (T4) serum levels, resulting in increased hepatic activity of type 1 deiodinase (D1). In the mutants' brains, entry of T4 was not affected, but uptake of T3 was diminished. Moreover, the T4 and T3 content in the brain of MCT8-null mice was decreased, the activity of D2 was increased, and D3 activity was decreased, indicating the hypothyroid state of this tissue. In the CNS, analysis of T3 target genes revealed that in the mutants, the neuronal T3 uptake was impaired in an area-specific manner, with strongly elevated thyrotropin-releasing hormone transcript levels in the hypothalamic paraventricular nucleus and slightly decreased RC3 mRNA expression in striatal neurons; however, cerebellar Purkinje cells appeared unaffected, since they did not exhibit dendritic outgrowth defects and responded normally to T3 treatment in vitro. In. conclusion, the circulating thyroid hormone levels of MCT8-null mice closely resemble those of humans with MCT8 mutations, yet in the mice, CNS development is only partially affected.
321 citations
TL;DR: It is reported that selective genetic deletion of the EP3Rs in the median preoptic nucleus of mice resulted in abrogation of the fever response, demonstrating that the EP 3R-bearing neurons in the Median preoptIC nucleus are required for fever responses.
Abstract: Fever is a result of the action of prostaglandin E2 (PGE2) on the brain and appears to require EP3 prostaglandin receptors (EP3Rs), but the specific neurons on which PGE2 acts to produce fever have not been definitively established. Here we report that selective genetic deletion of the EP3Rs in the median preoptic nucleus of mice resulted in abrogation of the fever response. These observations demonstrate that the EP3R-bearing neurons in the median preoptic nucleus are required for fever responses.
300 citations
TL;DR: Observations support the view that several classical transmitters, relatively neglected feeding transmitters candidates, are present in key neurons that regulate body weight and consequently may represent important orexigenic/anorexigenic mediators that convey information to other neurons within the hypothalamic area as well as from the hypothalamus to other brain regions that participate in regulation of energy balance.
289 citations
TL;DR: This review will focus on feeding behaviour and link it in with the neuroanatomy of the POMC neurones in the hypothalamus and brainstem, which has other functions, including regulation of sexual behaviour, lactation, the reproductive cycle and possibly central cardiovascular control.
Abstract: The precursor protein, proopiomelanocortin (POMC), produces many biologically active peptides via a series of enzymatic steps in a tissue-specific manner, yielding the melanocyte-stimulating hormones (MSHs), corticotrophin (ACTH) and β-endorphin. The MSHs and ACTH bind to the extracellular G-protein coupled melanocortin receptors (MCRs) of which there are five subtypes. The MC3R and MC4R show widespread expression in the central nervous system (CNS), whilst there is low level expression of MC1R and MC5R. In the CNS, cell bodies for POMC are mainly located in the arcuate nucleus of the hypothalamus and the nucleus tractus solitarius of the brainstem. Both of these areas have well defined functions relating to appetite and food intake. Mouse knockouts (ko) for pomc, mc4r and mc3r all show an obese phenotype, as do humans expressing mutations of POMC and MC4R. Recently, human subjects with specific mutations in β-MSH have been found to be obese too, as have mice with engineered β-endorphin deficiency. The CNS POMC system has other functions, including regulation of sexual behaviour, lactation, the reproductive cycle and possibly central cardiovascular control. However, this review will focus on feeding behaviour and link it in with the neuroanatomy of the POMC neurones in the hypothalamus and brainstem.
284 citations
TL;DR: The result shows that irNEF is distributed to several discrete nuclei in the brainstem, in addition to the hypothalamus and NTS reported earlier, and that the peptide interacts with a G protein-coupled receptor, leading to an increase of [Ca(2+)](i), which is linked to protein kinase A activation in cultured rat hypothalamic neurons.
Abstract: Nesfatin-1 is a recently identified satiety molecule detectable in neurons of the hypothalamus and nucleus of solitary tract (NTS). Immunohistochemical studies revealed nesfatin-1-immunoreactive (irNEF) cells in the Edinger-Westphal nucleus, dorsal motor nucleus of vagus, and caudal raphe nuclei of the rats, in addition to the hypothalamus and NTS reported in the initial study. Double-labeling immunohistochemistry showed that irNEF cells were vasopressin or oxytocin positive in the paraventricular and supraoptic nucleus; cocaine-amphetamine-regulated transcript or tyrosine hydroxylase positive in arcuate nucleus; cocaine-amphetamine-regulated transcript or melanin concentrating hormone positive in the lateral hypothalamus. In the brainstem, irNEF neurons were choline acetyltransferase positive in the Edinger-Westphal nucleus and dorsal motor nucleus of vagus; tyrosine hydroxylase positive in the NTS; and 5-hydroxytryptamine positive in the caudal raphe nucleus. The biological activity of rat nesfatin-1 (1...
TL;DR: The present data further characterize the functional relevance and putative key mediators (such as leptin and NPY) of the metabolic regulation of the hypothalamic KiSS-1 system in the mouse.
Abstract: It is well established that reproductive function is metabolically gated. However, the mechanisms whereby energy stores and metabolic cues influence fertility are yet to be completely deciphered. Recently, the hypothalamic KiSS-1/GPR54 system has emerged as a fundamental regulator of the gonadotropic axis, which conveys the modulatory actions of sex steroids to GnRH neurons. Evidence is also mounting that KiSS-1 neurons may also represent the link between systemic metabolic signals and central control of reproduction. To further explore this possibility, we examined the impact of changes in energy status and key metabolic regulators on the hypothalamic expression of KiSS-1 and GPR54 genes, using different mouse models and the hypothalamic cell line N6. Time-course analysis of the effects of short-term fasting revealed a rapid (12- and 24-h) decline in KiSS-1 and GPR54 mRNA levels, which preceded that of GnRH (48 h). In contrast, diet-induced obesity or obesity associated with leptin deficiency (ob/ob vs. wild-type mice) failed to induce overt changes in hypothalamic expression of KiSS-1 and GPR54 genes. However, leptin infusion of ob/ob mice evoked a significant increase in KiSS-1 and GPR54 mRNA levels compared with pair-fed controls. Moreover, leptin, but not insulin or IGF-I, stimulated KiSS-1 mRNA expression in the mouse hypothalamic cell line N6. In addition, neuropeptide Y (NPY) null mice showed decreased KiSS-1 mRNA levels at the hypothalamus, whereas exposure to NPY increased expression of KiSS-1 in hypothalamic N6 cells. In sum, our present data further characterize the functional relevance and putative key mediators (such as leptin and NPY) of the metabolic regulation of the hypothalamic KiSS-1 system in the mouse.
TL;DR: Findings provide a mechanistic explanation for the longstanding observation of HPA axis stimulation in response to 5-HT and thereby give insight into the neural circuitry mediating the complex neuroendocrine responses to stress.
Abstract: The dynamic interplay between serotonin [5-hydroxytryptamine (5-HT)] neurotransmission and the hypothalamic-pituitary-adrenal (HPA) axis has been extensively studied over the past 30 years, but the underlying mechanism of this interaction has not been defined. A possibility receiving little attention is that 5-HT regulates upstream corticotropin-releasing hormone (CRH) signaling systems via activation of serotonin 2C receptors (5-HT(2C)Rs) in the paraventricular nucleus of the hypothalamus (PVH). Through complementary approaches in wild-type rodents and 5-HT(2C)R-deficient mice, we determined that 5-HT(2C)Rs are necessary for 5-HT-induced HPA axis activation. We used laser-capture PVH microdissection followed by microarray analysis to compare the expression of 13 5-HTRs. Only 5-HT(2C)R and 5-HT(1D)R transcripts were consistently identified as present in the PVH, and of these, the 5-HT(2C)R was expressed at a substantially higher level. The abundant expression of 5-HT(2C)Rs in the PVH was confirmed with in situ hybridization histochemistry. Dual-neurohistochemical labeling revealed that approximately one-half of PVH CRH-containing neurons coexpressed 5-HT(2C)R mRNA. We observed that PVH CRH neurons consistently depolarized in the presence of a high-affinity 5-HT(2C)R agonist, an effect blocked by a 5-HT(2C)R antagonist. Supporting the importance of 5-HT(2C)Rs in CRH neuronal activity, genetic inactivation of 5-HT(2C)Rs produced a downregulation of CRH mRNA and blunted CRH and corticosterone release after 5-HT compound administration. These findings thus provide a mechanistic explanation for the longstanding observation of HPA axis stimulation in response to 5-HT and thereby give insight into the neural circuitry mediating the complex neuroendocrine responses to stress.
TL;DR: Data suggest that the NPS system may play a key role in modulating a variety of physiological functions, especially arousal, anxiety, learning and memory, and energy balance, as well as regulate energy homeostasis.
Abstract: Neuropeptide S (NPS) and its receptor (NPSR) constitute a novel neuropeptide system that is involved in regulating arousal and anxiety. The NPS precursor mRNA is highly expressed in a previously undescribed group of neurons located between the locus coeruleus (LC) and Barrington's nucleus. We report here that the majority of NPS-expressing neurons in the LC area and the principal sensory trigeminal nucleus are glutamatergic neurons, whereas many NPS-positive neurons in the lateral parabrachial nucleus coexpress corticotropin-releasing factor (CRF). In addition, we describe a comprehensive map of NPSR mRNA expression in the rat brain. High levels of expression are found in areas involved in olfactory processing, including the anterior olfactory nucleus, the endopiriform nucleus, and the piriform cortex. NPSR mRNA is expressed in several regions mediating anxiety responses, including the amygdaloid complex and the paraventricular hypothalamic nucleus. NPSR mRNA is also found in multiple key regions of sleep neurocircuitries, such as the thalamus, the hypothalamus, and the preoptic region. In addition, NPSR mRNA is strongly expressed in major output and input regions of hippocampus, including the parahippocampal regions, the lateral entorhinal cortex, and the retrosplenial agranular cortex. Multiple hypothalamic nuclei, including the dorsomedial and the ventromedial hypothalamic nucleus and the posterior arcuate nucleus, express high levels of NPSR mRNA, indicating that NPS may regulate energy homeostasis. These data suggest that the NPS system may play a key role in modulating a variety of physiological functions, especially arousal, anxiety, learning and memory, and energy balance. J. Comp. Neurol. 500:84–102, 2007. © 2006 Wiley-Liss, Inc.
TL;DR: It is shown that the availability of thyroid hormone within the hypothalamus is a key determinant of seasonal transitions, and a pivotal role for hypothalamic DIO3 and T(3) catabolism in seasonal cycles of body weight and reproduction in mammals.
Abstract: Seasonal adaptations in physiology exhibited by many animals involve an interface between biological timing and specific neuroendocrine systems, but the molecular basis of this interface is unknown. In this study of Siberian hamsters, we show that the availability of thyroid hormone within the hypothalamus is a key determinant of seasonal transitions. The expression of the gene encoding type III deiodinase (Dio3) and Dio3 activity in vivo (catabolism of T4 and T3) is dynamically and temporally regulated by photoperiod, consistent with the loss of hypothalamic T3 concentrations under short photoperiods. Chronic replacement of T3 in the hypothalamus of male hamsters exposed to short photoperiods, thus bypassing synthetic or catabolic deiodinase enzymes located in cells of the ependyma of the third ventricle, prevented the onset of short-day physiology: hamsters maintained a long-day body weight phenotype and failed to undergo testicular and epididymal regression. However, pelage moult to a winter coat was n...
TL;DR: It is demonstrated that orexin signaling in the ventral tegmental area is important for this reward-driven appetite to override metabolic repletion signals in presatiated rats, and it is suggested that direct accumbens–hypothalamic projections can stimulate hypothalamic orexIn neurons, which in turn through Orexin-1 receptor signaling inThe ventral Te segmental area and possibly other sites interfaces with the motivational and motor systems to increase intake of palatable food.
Abstract: The overriding of satiety and homeostatic control mechanisms by cognitive, rewarding, and emotional aspects of palatable foods may contribute to the evolving obesity crisis, but little is known about neural pathways and mechanisms responsible for crosstalk between the "cognitive" and "metabolic" brain in the control of appetite. Here we show that neural connections between the nucleus accumbens and hypothalamus might be part of this link. Using the well known model of selective stimulation of high-fat intake induced by intra-accumbens injection of the mu-opioid receptor agonist D-Ala2-N-Me-Phe4-gly5-ol-enkephalin (DAMGO), we demonstrate that orexin signaling in the ventral tegmental area is important for this reward-driven appetite to override metabolic repletion signals in presatiated rats. We further show that accumbens DAMGO in the absence of food selectively increases the proportion of orexin neurons expressing c-Fos in parts of the perifornical hypothalamus and that neural projections originating in DAMGO-responsive sites of the nucleus accumbens make close anatomical contacts with hypothalamic orexin neurons. These findings suggest that direct accumbens-hypothalamic projections can stimulate hypothalamic orexin neurons, which in turn through orexin-1 receptor signaling in the ventral tegmental area and possibly other sites interfaces with the motivational and motor systems to increase intake of palatable food.
TL;DR: A hypothalamus-pituitary-gonads pathway, in which d-Asp is involved, has been formulated and a summary of previous and current research done on the role of d- aspartic acid in the nervous and endocrine systems of invertebrates and vertebrates, including mammals is summary.
TL;DR: Variations in hormone bioactivity allow the animals to adapt their metabolic balance to different environmental conditions, changes in nutrient requirements and availability, and to homeorhetic changes during different physiological stages.
Abstract: Appropriate thyroid gland function and thyroid hormone activity are considered crucial to sustain the productive performance in domestic animals (growth, milk or hair fibre production). Changes of blood thyroid hormone concentrations are an indirect measure of the changes in thyroid gland activity and circulating thyroid hormones can be considered as indicators of the metabolic and nutritional status of the animals. Thyroid hormones play a pivotal role in the mechanisms permitting the animals to live and breed in the surrounding environment. Variations in hormone bioactivity allow the animals to adapt their metabolic balance to different environmental conditions, changes in nutrient requirements and availability, and to homeorhetic changes during different physiological stages. This is particularly important in the free-ranging and grazing animals, such as traditionally reared small ruminants, whose main physiological functions (feed intake, reproduction, hair growth) are markedly seasonal. Many investigations dealt with the involvement of thyroid hormones in the expression of endogenous seasonal rhythms, such as reproduction and hair growth cycles in fibre-producing (wool, mohair, cashmere) sheep and goats. Important knowledge about the pattern of thyroid hormone metabolism and their role in ontogenetic development has been obtained from studies in the ovine foetus and in the newborn. Many endogenous (breed, age, gender, physiological state) and environmental factors (climate, season, with a primary role of nutrition) are able to affect thyroid activity and hormone concentrations in blood, acting at the level of hypothalamus, pituitary and/or thyroid gland, as well as on peripheral monodeiodination. Knowledge on such topics mirror physiological changes and possibly allows the monitoring and manipulation of thyroid physiology, in order to improve animal health, welfare and production.
TL;DR: Data is presented that shows that ERα and mGluR1a directly interact to mediate a rapid estradiol-induced activation of MOR in the medial preoptic nucleus, leading to female sexual receptivity, demonstrating the physiological importance of ERα-to-mGlu R1a signaling.
Abstract: In rats, female sexual behavior is regulated by a well defined limbic–hypothalamic circuit that integrates sensory and hormonal information. Estradiol activation of this circuit results in μ-opioid receptor (MOR) internalization in the medial preoptic nucleus, an important step for full expression of sexual receptivity. Estradiol acts through both membrane and intracellular receptors to influence neuronal activity and behavior, yet the mechanism(s) and physiological significance of estradiol-mediated membrane responses in vivo have remained elusive. Recent in vitro evidence found that stimulation of membrane-associated estrogen receptor-α (ERα) led to activation of metabotropic glutamate receptor 1a (mGluR1a). Furthermore, mGluR1a signaling was responsible for the observed downstream effects of estradiol. Here we present data that show that ERα and mGluR1a directly interact to mediate a rapid estradiol-induced activation of MOR in the medial preoptic nucleus, leading to female sexual receptivity. In addition, blockade of mGluR1a in the arcuate nucleus of the hypothalamus resulted in a significant attenuation of estradiol-induced MOR internalization, leading to diminished female sexual behavior. These results link membrane-initiated estradiol actions to neural events modulating behavior, demonstrating the physiological importance of ERα-to-mGluR1a signaling.
TL;DR: It is demonstrated that CB1 deficiency enhances the circadian HPA axis activity peak and leads to central impairment of glucocorticoid feedback, thus further outlining the essential role of the endocannabinoid system in the modulation of neuroendocrine functions.
Abstract: The endocannabinoid system affects the neuroendocrine regulation of hormone secretion, including the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, the mechanisms by which endocannabinoids regulate HPA axis function have remained unclear. Here we demonstrate that mice lacking cannabinoid receptor type 1 (CB1-/-) display a significant dysregulation of the HPA axis. Although circadian HPA axis responsiveness is preserved, CB1-/- mice are characterized by an enhanced circadian drive on the HPA axis, resulting in elevated plasma corticosterone concentrations at the onset of the dark as compared with wild-type (CB1+/+) littermates. Moreover, CB1-/--derived pituitary cells respond with a significantly higher ACTH secretion to CRH and forskolin challenges as compared with pituitary cells derived from CB1+/+ mice. Both CBL-/- and CB1+/+ mice properly respond to a high-dose dexamethasone test, but response to low-dose dexamethasone is influenced by genotype. In addition, CB1-/- mice show increased CRH mRNA levels in the paraventricular nucleus of the hypothalamus but not in other extrahypothalamic areas, such as the amygdala and piriform cortex, in which CB1 and CRH mRNA have been colocalized. Finally, CB1-/- mice have selective glucocorticoid receptor mRNA down-regulation in the CA1 region of the hippocampus but not in the dentate gyrus or paraventricular nucleus. Conversely, mineralocorticoid receptor mRNA expression levels were found unchanged in these brain areas. In conclusion, our findings indicate that CB1 deficiency enhances the circadian HPA axis activity peak and leads to central impairment of glucocorticoid feedback, thus further outlining the essential role of the endocannabinoid system in the modulation of neuroendocrine functions.
TL;DR: Results provide unequivocal evidence that kisspeptins exert direct pituitary effects in peripubertal male and female rats and suggest a possible autocrine/paracrine mode of action.
Abstract: Recent, compelling evidence indicates that kisspeptins, the products of KiSS-1 gene, and their receptor GPR54, represent key elements in the neuroendocrine control of reproduction, and that they act primarily by regulating gonadotrophin-releasing hormone (GnRH) secretion at the hypothalamus. Conversely, and despite earlier reports showing GPR54 expression in the pituitary, the potential physiological roles of kisspeptins at this gland have remained elusive. To clarify this issue, cultures of rat pituitary cells were used to evaluate expression of KiSS-1 and GPR54, and to monitor the ability of kisspeptin-10 to stimulate Ca(2+) responses in gonadotrophs and to elicit luteinising hormone (LH) secretion in vitro. The results obtained show that both GPR54 and KiSS-1 are expressed in the pituitary of peripubertal male and female rats. Moreover, kisspeptin-10 induced a rise in free cytosolic Ca(2+) concentration ([Ca(2+)](i)) in approximately 10% of male rat pituitary cells. Intriguingly, kisspeptin-responsive cells included not only gonadotrophs, in which a 62.8 +/- 16.0%[Ca(2+)](i) rise was observed, but also somatotrophs, wherein kisspeptin induced a 60.3 +/- 5.5%[Ca(2+)](i) increase. Accordingly, challenge of dispersed pituitary cells with increasing kisspeptin-10 concentrations induced dose-related LH and growth hormone (GH) secretory responses, which were nevertheless of lower magnitude than those evoked by the primary regulators GnRH and GH-releasing hormone, respectively. In particular, 10(-8) M kisspeptin caused maximal increases in LH release (218.7 +/- 23.6% and 180.4 +/- 7.2% in male and female rat pituitary cells, respectively), and also stimulated maximally GH secretion (181.9 +/- 14.9% and 260.2 +/- 15.9% in male and female rat pituitary cells, respectively). Additionally, moderate summation of kisspeptin- and GnRH-induced LH responses was observed after short-term incubation of male rat pituitary cells. In conclusion, our results provide unequivocal evidence that kisspeptins exert direct pituitary effects in peripubertal male and female rats and suggest a possible autocrine/paracrine mode of action. The precise relevance and underlying mechanisms of this potential new actions of kisspeptins (i.e. the direct modulation of gonadotrophic and somatotrophic axis at the pituitary) deserve further analysis.
TL;DR: Infusions of a fluorescent retrograde tracer, fluorogold, into the VTA region, combined with fluorescent immunocytochemistry for CRF to identify sources of this input point to diffusely distributed sources of CRF-containing fibers in the Vta.
TL;DR: Exogenous circulating leptin results in detectable levels of baseline activated signal transducer and activator of transcription 3 (STAT3) phosphorylation in a population of ARC/LRb neurons, consistent with increased sensing of circulating leptin in these neurons compared with other LRb neurons.
Abstract: Hypothalamic neurons expressing the long form of the leptin receptor (LRb) mediate important leptin actions. Although it has been suggested that leptin crosses the blood-brain barrier (BBB) via a specific transport system, we hypothesized the existence of a population of hypothalamic arcuate nucleus (ARC) neurons that senses leptin independently of this transport system. Indeed, endogenous circulating leptin results in detectable levels of baseline activated signal transducer and activator of transcription 3 (STAT3) phosphorylation in a population of ARC/LRb neurons, consistent with increased sensing of circulating leptin in these neurons compared with other LRb neurons. Furthermore, a population of ARC/LRb neurons that responds more rapidly and sensitively to circulating leptin compared with other hypothalamic LRb neurons detected by leptin activated phosphorylated STAT3. In addition, peripheral application of the BBB-impermeant retrograde tracer fluorogold revealed a population of ARC/LRb neurons that directly contact the circulation (e.g. via neuronal processes reaching outside the BBB). Taken together, these data suggest that a population of ARC/LRb neurons directly contacts the circulation and displays increased sensitivity to circulating leptin compared with neurons residing entirely behind the BBB elsewhere in the hypothalamus.
TL;DR: The findings suggest that isolation in a socially monogamous rodent model induces both behavioral and neuroendocrine changes that are relevant to depression, which may provide insight into the mechanisms that underlie the development and/or maintenance of depressive disorders in humans.
Abstract: Objective—Previous evidence suggests that responses to social stressors may play a mechanistic role in the behavioral and physiological changes associated with affective disorders such as depression. Prairie voles (Microtus ochrogaster) are socially monogamous rodents that share features of social behavior with humans, and therefore might provide a useful model for examining social regulation of behaviors and physiological responses related to depression. In the present study we hypothesized that social isolation in female prairie voles would induce depression-relevant behaviors and altered neuroendocrine responses to an acute social stressor. Methods—Twenty adult female prairie voles were exposed to either 60 days of social isolation or paired (control) housing, and tested for a depression-like behavior (anhedonia), numbers of corticotropin-releasing factor- and oxytocin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and circulating levels of hormones and peptide in response to an acute social stressor (resident-intruder test). Results—Chronic social isolation produced anhedonia, measured by a reduction in sucrose intake and sucrose preference relative to paired animals. Compared to paired animals, isolated prairie voles displayed increased plasma hormone and peptide levels (oxytocin, arginine vasopressin, and corticosterone) following a 5-minute resident-intruder test, mirrored by an increased number of oxytocin- and corticotropin-releasing factor-immunoreactive cells in the hypothalamic paraventricular nucleus. Conclusions—These findings suggest that isolation in a socially monogamous rodent model induces both behavioral and neuroendocrine changes that are relevant to depression, and may provide insight into the mechanisms that underlie the development and/or maintenance of depressive disorders in humans.
TL;DR: Results provide further support for the existence of a neural circuit in which dopamine and oxytocin influence both the consummatory and motivational/rewarding aspects of sexual behaviour.
Abstract: The neuropeptide oxytocin (20-100 ng), induces penile erection when injected unilaterally into the caudal but not rostral mesencephalic ventral tegmental area (VTA) of male Sprague-Dawley rats. Such pro-erectile effect started 30 min after treatment and was abolished by the prior injection of d(CH2)5Tyr(Me)(2)-Orn(8)-vasotocin (1 microg), an oxytocin receptor antagonist injected into the same caudal ventral tegmental area or of haloperidol (1 microg), a dopamine receptor antagonist, injected either into the nucleus accumbens shell (NAs) or into the paraventricular nucleus of the hypothalamus (PVN) ipsilateral to the injected ventral tegmental area. Penile erection was seen 15 min after the occurrence of, or concomitantly to, an increase in extracellular dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the dialysate obtained from the nucleus accumbens or the paraventricular nucleus, which was also abolished by d(CH2)5Tyr(Me)(2)-Orn(8)-vasotocin (1 microg), injected into the ventral tegmental area before oxytocin. In the caudal ventral tegmental area oxytocin-containing axons/fibres (originating from the paraventricular nucleus) appeared to closely contact cell bodies of mesolimbic dopaminergic neurons retrogradely labelled with Fluorogold injected into the nucleus accumbens shell, suggesting that oxytocin effects are mediated by the activation of mesolimbic dopaminergic neurons, followed in turn by that of incerto-hypothalamic dopaminergic neurons impinging on oxytocinergic neurons mediating penile erection. As the stimulation of paraventricular dopamine receptors not only induces penile erection, but also increases mesolimbic dopamine neurotransmission by activating oxytocinergic neurons, these results provide further support for the existence of a neural circuit in which dopamine and oxytocin influence both the consummatory and motivational/rewarding aspects of sexual behaviour.
TL;DR: Characterisation of these novel actions of leptin is providing valuable insights into the role of this hormone in the regulation of diverse neuronal functions in health and disease.
TL;DR: The findings suggest that leptin is a legitimate candidate for the treatment of ischemic stroke, and showed that leptin protected primary cortical neurons against death induced by oxygen-glucose deprivation in a concentration-dependent manner.
Abstract: Background and Purpose— Leptin is the major adipose hormone that regulates body weight and energy expenditure by activating leptin receptors in the hypothalamus. Leptin receptors are also present in other cell types, and a potent antiapoptotic effect for leptin has recently been reported. We investigated whether leptin was neuroprotective against ischemic brain injury. Methods— In vitro ischemic injury was induced in rat primary neuronal culture by oxygen-glucose deprivation for 90 minutes. In vivo ischemic brain injury was induced by middle cerebral artery occlusion in mice for 60 minutes. Results— Leptin receptors were detected in cultured rat cortical neurons, as well as in the mouse cortex, striatum, and hippocampus. In vitro results showed that leptin, 50 to 100 μg/mL, protected primary cortical neurons against death induced by oxygen-glucose deprivation in a concentration-dependent manner. In vivo studies in the mouse brain demonstrated that the intraperitoneal administration of leptin, 2 to 8 mg/kg...
TL;DR: It is demonstrated that leptin action in the arcuate nucleus of the hypothalamus is important for the control of sympathetic outflow to both brown adipose tissue and the kidney and suggested that the cardiovascular effects of leptin might be evoked by the action of this hormone in the arcsuate nucleus.
Abstract: Leptin is an adipocyte-derived hormone that plays an important role in the regulation of energy homeostasis through its action in the central nervous system. Leptin decreases body weight by promoting satiety and increasing thermogenesis via increasing sympathetic nerve activity (SNA) to brown adipose tissue. Leptin also increases renal SNA and arterial pressure. The arcuate nucleus is considered as a major nucleus for leptin action on energy homeostasis. We tested whether leptin action in the arcuate nucleus simultaneously activates SNA to brown adipose tissue and the kidney. The sympathetic and cardiovascular responses to intra-arcuate injection of leptin were compared with those evoked by intracerebroventricular administration of leptin in rat. Intracerebroventricular administration of leptin (10 μg) caused a significant increase in SNA to brown adipose tissue and the kidney. Intracerebroventricular leptin also increased mean arterial pressure. Direct injection of leptin (500 ng) into the arcuate nucleus increased both brown adipose tissue (254±49%; P <0.001 versus vehicle) and renal SNA (111±31%; P <0.001 versus vehicle). Microinjection of leptin into the arcuate nucleus also produced a substantial increase in mean arterial pressure (from 82±3 to 100±7 mm Hg; P =0.02). These data demonstrate that leptin action in the arcuate nucleus of the hypothalamus is important for the control of sympathetic outflow to both brown adipose tissue and the kidney. These results also suggest that the cardiovascular effects of leptin might be evoked by the action of this hormone in the arcuate nucleus of the hypothalamus.
TL;DR: Cumulative evidence indicates that preoptic area neurons function to promote sleep onset and sleep maintenance by inhibitory modulation of multiple arousal systems.
TL;DR: These discoveries make oxytocin a promising neuromodulator of the brain for psychotherapeutic intervention and treatment of numerous psychiatric illnesses, for example, anxiety-related diseases, social phobia, autism and postpartum depression.
Abstract: The brain oxytocin system has served as a distinguished model system in neuroendocrinology to study detailed mechanisms of intracerebral release, in particular of somatodendritic release, and its behavioural and neuroendocrine consequences. It has been shown that oxytocin is released within various brain regions, but evidence for dendritic release is limited to the main sites of oxytocin synthesis, i.e. the hypothalamic SON (supraoptic nucleus) and PVN (paraventricular nucleus). In the present paper, stimuli of dendritic release of oxytocin and the related neuropeptide vasopressin are discussed, including parturition and suckling, i.e. the period of a highly activated brain oxytocin system. Also, exposure to various pharmacological, psychological or physical stressors triggers dendritic oxytocin release, as monitored by intracerebral microdialysis within the SON and PVN during ongoing behavioural testing. So far, dendritic release of the neuropeptide has only been demonstrated within the hypothalamus, but intracerebral oxytocin release has also been found within the central amygdala and the septum in response to various stimuli including stressor exposure. Such a locally released oxytocin modulates physiological and behavioural reproductive functions, emotionality and hormonal stress responses, as it exerts, for example, pro-social, anxiolytic and antistress actions within restricted brain regions. These discoveries make oxytocin a promising neuromodulator of the brain for psychotherapeutic intervention and treatment of numerous psychiatric illnesses, for example, anxiety-related diseases, social phobia, autism and postpartum depression.