Showing papers on "Hypothalamus published in 2006"

Identification of nesfatin-1 as a satiety molecule in the hypothalamus

Abstract: The brain hypothalamus contains certain secreted molecules that are important in regulating feeding behaviour. Here we show that nesfatin, corresponding to NEFA/nucleobindin2 (NUCB2), a secreted protein of unknown function, is expressed in the appetite-control hypothalamic nuclei in rats. Intracerebroventricular (i.c.v.) injection of NUCB2 reduces feeding. Rat cerebrospinal fluid contains nesfatin-1, an amino-terminal fragment derived from NUCB2, and its expression is decreased in the hypothalamic paraventricular nucleus under starved conditions. I.c.v. injection of nesfatin-1 decreases food intake in a dose-dependent manner, whereas injection of an antibody neutralizing nesfatin-1 stimulates appetite. In contrast, i.c.v. injection of other possible fragments processed from NUCB2 does not promote satiety, and conversion of NUCB2 to nesfatin-1 is necessary to induce feeding suppression. Chronic i.c.v. injection of nesfatin-1 reduces body weight, whereas rats gain body weight after chronic i.c.v. injection of antisense morpholino oligonucleotide against the gene encoding NUCB2. Nesfatin-1-induced anorexia occurs in Zucker rats with a leptin receptor mutation, and an anti-nesfatin-1 antibody does not block leptin-induced anorexia. In contrast, central injection of alpha-melanocyte-stimulating hormone elevates NUCB2 gene expression in the paraventricular nucleus, and satiety by nesfatin-1 is abolished by an antagonist of the melanocortin-3/4 receptor. We identify nesfatin-1 as a satiety molecule that is associated with melanocortin signalling in the hypothalamus.

Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons.

Abstract: The neuropeptide kisspeptin has recently been implicated as having a critical role in the activation of the GnRH neurons to bring about puberty. We examined here the postnatal development of kisspeptin neuronal populations and their projections to GnRH neurons in the mouse. Three populations of kisspeptin neurons located in the 1) anteroventral periventricular nucleus (AVPV) and the preoptic periventricular nucleus (PeN), 2) dorsomedial hypothalamus, and 3) arcuate nucleus were identified using an antisera raised against mouse kisspeptin-10. A marked 10-fold (P<0.01), female-dominant sex difference in the numbers of kisspeptin neurons existed in the AVPV/PeN but not elsewhere. Kisspeptin neurons in the AVPV/PeN of both sexes displayed a similar pattern of postnatal development with no cells detected at postnatal day (P) 10, followed by increases from P25 to reach adult levels by puberty onset (P<0.01; P31 females and P45 males). This pattern was not found in the dorsomedial hypothalamus or arcuate nucleus. Dual immunofluorescence experiments demonstrated close appositions between kisspeptin fibers and GnRH neuron cell bodies that were first apparent at P25 and increased across postnatal development in both sexes. These studies demonstrate kisspeptin peptide expression in the mouse hypothalamus and reveal the postnatal development of a sexually dimorphic continuum of kisspeptin neurons within the AVPV and PeN. This periventricular population of kisspeptin neurons reaches adult-like proportions at the time of puberty onset and is the likely source of the kisspeptin inputs to GnRH neurons.

Leptin Signaling, Adiposity, and Energy Balance

Abstract: A chronic minor imbalance between energy intake and energy expenditure may lead to obesity. Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure. The cloning of the ob gene and the identification of its encoded protein, leptin, have provided a system signaling the amount of adipose energy stores to the brain. Leptin, a hormone secreted by fat cells, acts in rodents via hypothalamic receptors to inhibit feeding and increase thermogenesis. A feedback regulatory loop with three distinct steps has been identified: (1) a sensor (leptin production by adipose cells) monitors the size of the adipose tissue mass; (2) hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors (LRb); (3) effector systems, including the sympathetic nervous system, control the two main determinants of energy balance-energy intake and energy expenditure. While this feedback regulatory loop is well established in rodents, there are many unsolved questions about its applicability to body weight regulation in humans. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness. Gender is an important factor determining plasma leptin, with women having markedly higher leptin concentrations than men for any given degree of fat mass. The ob mRNA expression is also upregulated by glucocorticoids, whereas stimulation of the sympathetic nervous system results in its inhibition. Furthermore, leptin is not a satiety factor in humans because changes in food intake do not induce short-term increases in plasma leptin levels. After its binding to LRb in the hypothalamus, leptin stimulates a specific signaling cascade that results in the inhibition of several orexigenic neuropeptides, while stimulating several anorexigenic peptides. The orexigenic neuropeptides that are downregulated by leptin are NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-related peptide). The anorexigenic neuropeptides that are upregulated by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone), which acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone). Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected responses (i.e., a reduction in food intake and an increase in energy expenditure). This suggests that obese humans are resistant to the effects of endogenous leptin. This resistance is also shown by the lack of effect of exogenous leptin administration to induce weight loss in obese patients. The mechanisms that may account for leptin resistance in human obesity include a limitation of the blood-brain-barrier transport system for leptin and an inhibition of the leptin signaling pathways in leptin-responsive hypothalamic neurons. During periods of energy deficit, the fall in leptin plasma levels exceeds the rate at which fat stores are decreased. Reduction of the leptin signal induces several neuroendocrine responses that tend to limit weight loss, such as hunger, food-seeking behavior, and suppression of plasma thyroid hormone levels. Conversely, it is unlikely that leptin has evolved to prevent obesity when plenty of palatable foods are available because the elevated plasma leptin levels resulting from the increased adipose tissue mass do not prevent the development of obesity. In conclusion, in humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit. Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal (mutations of the leptin gene or of the leptin receptor gene), which produces an internal perception of starvation and results in a chronic stimulation of excessive food intake.

Afferents to the Orexin Neurons of the Rat Brain

Abstract: Emotions, stress, hunger, and circadian rhythms all promote wakefulness and behavioral arousal. Little is known about the pathways mediating these influences, but the orexin-producing neurons of the hypothalamus may play an essential role. These cells heavily innervate many wake-promoting brain regions, and mice lacking the orexin neurons have narcolepsy and fail to rouse in response to hunger (Yamanaka et al. [2003] Neuron 38:701-713). To identify the afferents to the orexin neurons, we first injected a retrograde tracer into the orexin neuron field of rats. Retrogradely labeled neurons were abundant in the allocortex, claustrum, lateral septum, bed nucleus of the stria terminalis, and in many hypothalamic regions including the preoptic area, dorsomedial nucleus, lateral hypothalamus, and posterior hypothalamus. Retrograde labeling in the brainstem was generally more modest, but labeling was strong in the periaqueductal gray matter, dorsal raphe nucleus, and lateral parabrachial nucleus. Injection of an anterograde tracer confirmed that most of these regions directly innervate the orexin neurons, with some of the heaviest input coming from the lateral septum, preoptic area, and posterior hypothalamus. In addition, hypothalamic regions preferentially innervate orexin neurons in the medial and perifornical parts of the field, but most projections from the brainstem target the lateral part of the field. Inputs from the suprachiasmatic nucleus are mainly relayed via the subparaventricular zone and dorsomedial nucleus. These observations suggest that the orexin neurons may integrate a variety of interoceptive and homeostatic signals to increase behavioral arousal in response to hunger, stress, circadian signals, and autonomic challenges.

KiSS-1 neurones are direct targets for leptin in the ob/ob mouse.

Abstract: Leptin is an adipocyte-derived hormone that acts on the hypothalamus to influence feeding, metabolism and reproduction, but the cellular and molecular targets for the action of leptin in the brain have yet to be fully elucidated. Kisspeptins are encoded by the Kiss1 gene, which is expressed in the hypothalamus and has been implicated in the neuroendocrine regulation of gonadotrophin-releasing hormone secretion. We tested the hypothesis that kisspeptin-expressing neurones are targets for leptin. First, we examined whether leptin regulates the expression of Kiss1 by comparing levels of KiSS-1 mRNA in the arcuate nucleus among groups of mice having different circulating levels of leptin: (i) wild-type (WT); (ii) leptin-deficient ob/ob; and (iii) ob/ob mice treated with leptin. All mice were castrated to control for endogenous concentrations of gonadal steroids. KiSS-1 mRNA was significantly reduced in ob/ob compared to WT mice and levels of KiSS-1 mRNA in ob/ob mice treated with leptin were increased, but not fully restored to that found in WT animals. Second, we performed double-label in situ hybridisation for KiSS-1 mRNA and the leptin receptor (Ob-Rb) mRNA and found that almost one-half (approximately 40%) of KiSS-1 mRNA-expressing cells in the arcuate nucleus expressed Ob-Rb mRNA. These results demonstrate that KiSS-1 neurones are direct targets for regulation by leptin and suggest that the reproductive deficits associated with leptin-deficient states may be attributable, in part, to diminished expression of Kiss1.

Leptin: A potential novel antidepressant

Abstract: Leptin, a hormone secreted from adipose tissue, was originally discovered to regulate body weight. The localization of the leptin receptor in limbic structures suggests a potential role for leptin in emotional processes. Here, we show that rats exposed to chronic unpredictable stress and chronic social defeat exhibit low leptin levels in plasma. Systemic leptin treatment reversed the hedonic-like deficit induced by chronic unpredictable stress and improved behavioral despair dose-dependently in the forced swim test (FST), a model widely used for screening potential antidepressant efficacy. The behavioral effects of leptin in the FST were accompanied by increased neuronal activation in limbic structures, particularly in the hippocampus. Intrahippocampal infusion of leptin produced a similar antidepressant-like effect in the FST as its systemic administration. By contrast, infusion of leptin into the hypothalamus decreased body weight but had no effect on FST behavior. These findings suggest that: (i) impaired leptin production and secretion may contribute to chronic stress-induced depression-like phenotypes, (ii) the hippocampus is a brain site mediating leptin's antidepressant-like activity, and (iii) elevating leptin signaling in brain may represent a novel approach for the treatment of depressive disorders.

Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor.

Abstract: Ghrelin, an acylated peptide produced predominantly in the stomach, stimulates feeding and GH secretion via interactions with the GH secretagogue type 1a receptor (GHS-R1a), the functionally active form of the GHS-R. Ghrelin molecules exist in the stomach and hypothalamus as two major endogenous forms, a form acylated at serine 3 (ghrelin) and a des-acylated form (des-acyl ghrelin). Acylation is indispensable for the binding of ghrelin to the GHS-R1a. Ghrelin enhances feeding via the neuronal pathways of neuropeptide Y and orexin, which act as orexigenic peptides in the hypothalamus. We here studied the effect of des-acyl ghrelin on feeding behavior. Intracerebroventricular (icv) administration of rat des-acyl ghrelin to rats or mice fed ad libitum stimulated feeding during the light phase; neither ip nor icv administration of des-acyl ghrelin to fasting mice suppressed feeding. The icv administration of des-acyl ghrelin induced the expression of Fos, a marker of neuronal activation, in orexin-expressing ...

Gastrointestinal hormones regulating appetite

Abstract: The role of gastrointestinal hormones in the regulation of appetite is reviewed. The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones function to optimize the process of digestion and absorption of nutrients by the gut. In this capacity, their local effects on gastrointestinal motility and secretion have been well characterized. By altering the rate at which nutrients are delivered to compartments of the alimentary canal, the control of food intake arguably constitutes another point at which intervention may promote efficient digestion and nutrient uptake. In recent decades, gut hormones have come to occupy a central place in the complex neuroendocrine interactions that underlie the regulation of energy balance. Many gut peptides have been shown to influence energy intake. The most well studied in this regard are cholecystokinin (CCK), pancreatic polypeptide, peptide YY, glucagon-like peptide-1 (GLP-1), oxyntomodulin and ghrelin. With the exception of ghrelin, these hormones act to increase satiety and decrease food intake. The mechanisms by which gut hormones modify feeding are the subject of ongoing investigation. Local effects such as the inhibition of gastric emptying might contribute to the decrease in energy intake. Activation of mechanoreceptors as a result of gastric distension may inhibit further food intake via neural reflex arcs. Circulating gut hormones have also been shown to act directly on neurons in hypothalamic and brainstem centres of appetite control. The median eminence and area postrema are characterized by a deficiency of the blood-brain barrier. Some investigators argue that this renders neighbouring structures, such as the arcuate nucleus of the hypothalamus and the nucleus of the tractus solitarius in the brainstem, susceptible to influence by circulating factors. Extensive reciprocal connections exist between these areas and the hypothalamic paraventricular nucleus and other energy-regulating centres of the central nervous system. In this way, hormonal signals from the gut may be translated into the subjective sensation of satiety. Moreover, the importance of the brain-gut axis in the control of food intake is reflected in the dual role exhibited by many gut peptides as both hormones and neurotransmitters. Peptides such as CCK and GLP-1 are expressed in neurons projecting both into and out of areas of the central nervous system critical to energy balance. The global increase in the incidence of obesity and the associated burden of morbidity has imparted greater urgency to understanding the processes of appetite control. Appetite regulation offers an integrated model of a brain-gut axis comprising both endocrine and neurological systems. As physiological mediators of satiety, gut hormones offer an attractive therapeutic target in the treatment of obesity.

Maternal presence serves as a switch between learning fear and attraction in infancy

Abstract: Odor-shock conditioning produces either olfactory preference or aversion in preweanling (12–15 days old) rats, depending on the context. In the mother's absence, odor-shock conditioning produces amygdala activation and learned odor avoidance. With maternal presence, this same conditioning yields an odor preference without amygdala activation. Maternal presence acts through modulation of pup corticosterone and corticosterone's regulation of amygdala activity. Over-riding maternal suppression of corticosterone through intra-amygdala corticosterone infusions permits fear conditioning and amygdala activation.

The TRH neuron: a hypothalamic integrator of energy metabolism.

Abstract: Thyrotropin-releasing hormone (TRH) has an important role in the regulation of energy homeostasis not only through effects on thyroid function orchestrated through hypophysiotropic neurons in the hypothalamic paraventricular nucleus (PVN), but also through central effects on feeding behavior, thermogenesis, locomotor activation and autonomic regulation Hypophysiotropic TRH neurons are located in the medial and periventricular parvocellular subdivisions of the PVN and receive direct monosynaptic projections from two, separate, populations of leptin-responsive neurons in the hypothalamic arcuate nucleus containing either alpha-melanocyte-stimulating hormone (alpha-MSH) and cocaine- and amphetamine-regulated transcript (CART), peptides that promote weight loss and increase energy expenditure, or neuropeptide Y (NPY) and agouti-related protein (AGRP), peptides that promote weight gain and reduce energy expenditure During fasting, the reduction in TRH mRNA in hypophysiotropic neurons mediated by suppression of alpha-MSH/CART simultaneously with an increase in NPY/AGRP gene expression in arcuate nucleus neurons contributes to the fall in circulating thyroid hormone levels, presumably by increasing the sensitivity of the TRH gene to negative feedback inhibition by thyroid hormone Endotoxin administration, however, has the paradoxical effect of increasing circulating levels of leptin and melanocortin signaling and CART gene expression in arcuate nucleus neurons, but inhibiting TRH gene expression in hypophysiotropic neurons This may be explained by an overriding inhibitory effect of endotoxin to increase type 2 iodothyroine deiodinase (D2) in a population of specialized glial cells, tanycytes, located in the base and infralateral walls of the third ventricle By increasing the conversion of T4 into T3, tanycytes may increase local tissue concenetrations of thyroid hormone, and thereby induce a state of local tissue hyperthyroidism in the region of hypophysisotrophic TRH neurons Other regions of the brain may also serve as metabolic sensors for hypophysiostropic TRH neurons including the ventrolateral medulla and dorsomedial nucleus of the hypothalamus that have direct monosynaptic projections to the PVN TRH also exerts a number of effects within the central nervous system that may contribute to the regulation of energy homeostasis Included are an increase in core body temperature mediated through neurons in the anterior hypothalamic-preoptic area that coordinate a variety of autonomic responses; arousal and locomotor activation through cholinergic and dopaminergic mechanisms on the septum and nucleus accumbens, respectively; and regulation of the cephalic phase of digestion While the latter responses are largely mediated through cholinergic mechanisms via TRH neurons in the brainstem medullary raphe and dorsal motor nucleus of the vagus, effects of TRH on autonomic loci in the hypothalamic PVN may also be important Contrary to the actions of T3 to increase appetite, TRH has central effects to reduce food intake in normal, fasting and stressed animals The precise locus where TRH mediates this response is unknown However, evidence that an anatomically separate population of nonhypophysiotropic TRH neurons in the anterior parvocellular subdivision of the PVN is integrated into the leptin regulatory control system by the same arcuate nucleus neuronal populations that innervate hypophysiotropic TRH neurons, raises the possibility that anterior parvocellular TRH neurons may be involved, possibly through interactions with the limbic nervous system

An N-terminal variant of Trpv1 channel is required for osmosensory transduction

Abstract: Body fluid homeostasis requires the release of arginine-vasopressin (AVP, an antidiuretic hormone) from the neurohypophysis. This release is controlled by specific and highly sensitive 'osmoreceptors' in the hypothalamus. Indeed, AVP-releasing neurons in the supraoptic nucleus (SON) are directly osmosensitive, and this osmosensitivity is mediated by stretch-inhibited cation channels. However, the molecular nature of these channels remains unknown. Here we show that SON neurons express an N-terminal splice variant of the transient receptor potential vanilloid type-1 (Trpv1), also known as the capsaicin receptor, but not full-length Trpv1. Unlike their wild-type counterparts, SON neurons in Trpv1 knockout (Trpv1−/−) mice could not generate ruthenium red–sensitive increases in membrane conductance and depolarizing potentials in response to hyperosmotic stimulation. Moreover, Trpv1−/− mice showed a pronounced serum hyperosmolality under basal conditions and severely compromised AVP responses to osmotic stimulation in vivo. These results suggest that the Trpv1 gene may encode a central component of the osmoreceptor.

The dorsomedial hypothalamic nucleus as a putative food-entrainable circadian pacemaker

Abstract: Temporal restriction of feeding can phase-shift behavioral and physiological circadian rhythms in mammals. These changes in biological rhythms are postulated to be brought about by a food-entrainable oscillator (FEO) that is independent of the suprachiasmatic nucleus. However, the neural substrates of FEO have remained elusive. Here, we carried out an unbiased search for mouse brain region(s) that exhibit a rhythmic expression of the Period genes in a feeding-entrainable manner. We found that the compact part of the dorsomedial hypothalamic nucleus (DMH) demonstrates a robust oscillation of mPer expression only under restricted feeding. The oscillation persisted for at least 2 days even when mice were given no food during the expected feeding period after the establishment of food-entrained behavioral rhythms. Moreover, refeeding after fasting rapidly induced a transient mPer expression in the same area of DMH. Taken in conjunction with recent findings (i) that behavioral expression of food-entrainable circadian rhythms is blocked by cell-specific lesions of DMH in rats and (ii) that DMH neurons directly project to orexin neurons in the lateral hypothalamus, which are essential for proper expression of food-entrained behavioral rhythms, the present study suggests that DMH plays a key role as a central FEO in the feeding-mediated regulation of circadian behaviors.

The vasopressin system: physiology and clinical strategies.

Abstract: Vasopressin, synthesized in the hypothalamus, is released by increased plasma osmolality, decreased arterial pressure, and reductions in cardiac volume. Three subtypes of vasopressin receptors, V1, V2, and V3, have been identified, mediating vasoconstriction, water reabsorption, and central nervous system effects, respectively. Vasopressin and its analogs have been studied intensively for the treatment of states of "relative vasopressin deficiency," such as sepsis, vasodilatory shock, intraoperative hypotension, and cardiopulmonary resuscitation. Infusion of vasopressin (0.01-0.04 U/min) decreases catecholamine requirements in patients with sepsis and other types of vasodilatory shock. Bolus application of 1 mg terlipressin, the V1 agonist, reverses refractory hypotension in anesthetized patients and has been studied in patients with septic shock and chronic liver failure. During cardiopulmonary resuscitation, a 40-U bolus dose of vasopressin may be considered to replace the first or second bolus of epinephrine regardless of the initial rhythm. The side effects of vasopressin and its analogs must be further characterized.

Stress history and pubertal development interact to shape hypothalamic-pituitary-adrenal axis plasticity.

Abstract: Both the magnitude and the duration of the hormonal stress response change dramatically during neonatal development and aging as well as with prior experience with a stressor. However, surprisingly little is known with regard to how pubertal maturation and experience with stress interact to affect hypothalamic-pituitary-adrenal axis responsiveness. Because adolescence is a period of neurodevelopmental vulnerabilities and opportunities that may be especially sensitive to stress, it is imperative to more fully understand these interactions. Thus, we examined hormonal and neural responses in prepubertal (28 d of age) and adult (77 d of age) male rats after exposure to acute (30 min) or more chronic (30 min/d for 7 d) restraint stress. We report here that after acute stress, prepubertal males exhibited a significantly prolonged hormonal stress response (e.g. ACTH and total and free corticosterone) compared with adults. In contrast, after chronic stress, prepubertal males exhibited a higher response immediately after the stressor, but a faster return to baseline, compared with adults. Additionally, we demonstrate that this differential stress reactivity is associated with differential neuronal activation in the paraventricular nucleus of the hypothalamus, as measured by FOS immunohistochemistry. Using triple-label immunofluorescence histochemistry, we found that a larger proportion of CRH, but not arginine vasopressin, cells are activated in the arginine vasopressin in response to both acute and chronic stress in prepubertal animals compared with adults. These data indicate that experience-dependent plasticity of the hypothalamic-pituitary-adrenal neuroendocrine axis is significantly influenced by pubertal maturation.

Repetitive Activation of Hypothalamic G Protein-Coupled Receptor 54 with Intravenous Pulses of Kisspeptin in the Juvenile Monkey (Macaca mulatta) Elicits a Sustained Train of Gonadotropin-Releasing Hormone Discharges

Abstract: The purpose of the present study was to further examine the hypothesis that activation of G protein-coupled receptor 54 (GPR54) signaling at the end of the juvenile phase of primate development is responsible for initiation of gonadarche and the onset of puberty. Accordingly, we determined whether repetitive iv administration of the GPR54 receptor agonist kisspeptin-10 (2 μg as a brief 1-min infusion once every hour for 48 h) to the juvenile male rhesus monkey would prematurely elicit sustained, pulsatile release of hypothalamic GnRH, the neuroendocrine trigger for gonadarche. GnRH release was monitored indirectly by measuring LH secretion from the in situ pituitary, the GnRH responsiveness of which had been heightened before the experiment with an intermittent iv infusion of synthetic GnRH. Agonadal animals (n = 4) were employed to eliminate any confounding and secondary effects of changing feedback signals from the testis. The first brief infusion of kisspeptin-10 evoked an LH discharge that mimicked th...

Connections of the lateral and medial divisions of the goldfish telencephalic pallium

Abstract: Biotinylated dextran amine and fluorescent carbocyanine dye (DiI) were used to examine connections of the lateral (Dl) and medial (Dm) divisions of the goldfish pallium. Besides numerous intrinsic telencephalic connections to Dl and Dm, major ascending projections to these pallial divisions arise in the preglomerular complex of the posterior tuberculum, rather than in the dorsal thalamus. The rostral subnucleus of the lateral preglomerular nucleus receives auditory input via the medial pretoral nucleus, lateral line input via the ventrolateral toral nucleus, and visual input via the optic tectum, and it projects to both Dl and Dm. The anterior preglomerular nucleus and caudal subnucleus of the lateral preglomerular nucleus receive auditory input via the central toral nucleus and project to Dm. This pallial division also receives chemosensory information via the medial preglomerular nucleus. The central posterior (CP) nucleus, which receives both auditory and visual inputs, also projects to Dm and is the only dorsal thalamic nucleus projecting to the pallium. Thus, both Dl and Dm clearly receive multisensory inputs. Major projections of CP and projections of all other dorsal thalamic nuclei are to the subpallium, however. Descending projections of Dl are primarily to the preoptic area and the caudal hypothalamus, whereas descending projections of Dm are more extensive and particularly heavy to the anterior tuber and nucleus diffusus of the hypothalamus. The topography and connections of Dl are remarkably similar to those of the hippocampus of tetrapods, whereas the topography and connections of Dm are similar to those of the amygdala.

Effects of early life stress on adult male aggression and hypothalamic vasopressin and serotonin.

Abstract: Early life stress in humans enhances the risk for psychopathologies, including excessive aggression and violence. In rodents, maternal separation is a potent early life stressor inducing long-lasting changes in emotional and neuroendocrine responsiveness to stress, associated with depression- and anxiety-like symptoms. However, effects of maternal separation on adult male aggression and underlying neurobiological mechanisms remain unknown. Therefore, we investigated the effects of maternal separation on adult intermale aggression in Wistar rats and on hypothalamic arginine vasopressin (AVP) mRNA expression, and AVP and serotonin (5-HT) immunoreactivity, as both AVP and 5-HT have been implicated in stress-coping and aggression. We showed that maternal separation induced depression-like behaviour (increased immobility) and higher adrenocorticotropin hormone responses to an acute stressor (forced swimming). Intermale aggression (lateral threat, offensive upright and keep down) was significantly higher in maternally separated rats compared with control rats. AVP mRNA expression and AVP immunoreactivity were higher in the hypothalamic paraventricular and supraoptic nuclei upon resident-intruder test exposure, whereas 5-HT immunoreactivity was decreased in the anterior hypothalamus of maternally separated rats. Moreover, 5-HT immunoreactivity in the anterior hypothalamus and supraoptic nucleus correlated negatively with aggression. These findings show that exposure to early life stress increases adult male aggression in an animal model of maternal separation. Furthermore, the maternal separation-induced changes in hypothalamic AVP and 5-HT systems may underlie these behavioural alterations.

Projections from bed nuclei of the stria terminalis, anteromedial area: cerebral hemisphere integration of neuroendocrine, autonomic, and behavioral aspects of energy balance.

Abstract: The anteromedial area of the bed nuclei of the stria terminalis (BSTam) is the relatively undifferentiated region of the anterior medial (anteromedial) group of the bed nuclei of the stria terminalis (BSTamg), which also includes the more distinct dorsomedial, magnocellular, and ventral nuclei. The overall pattern of axonal projections from the rat BSTam was analyzed with the PHAL anterograde pathway tracing method. Brain areas receiving relatively moderate to strong inputs from the BSTam fall into five general categories: neuroendocrine system (regions containing pools of magnocellular oxytocin neurons, and parvicellular corticotropin-releasing hormone, thyrotropin-releasing hormone, somatostatin, and dopamine neurons); central autonomic control network (central amygdalar nucleus, descending paraventricular nucleus, and ventrolateral periaqueductal gray); hypothalamic visceromotor pattern generator network (5 of 6 known components); behavior control column (descending paraventricular nucleus and associated arcuate nucleus; ventral tegmental area and associated nucleus accumbens and substantia innominata); and behavioral state control (supramammillary and tuberomammillary nuclei). The BSTam projects lightly to thalamocortical feedback loops (via the medial-midline-intralaminar thalamus). Its pattern of axonal projections, combined with its pattern of neural inputs (the most varied of all BST cell groups), suggest that the BSTam is part of a striatopallidal differentiation involved in coordinating neuroendocrine, autonomic, and behavioral or somatic responses associated with maintaining energy balance homeostasis.

Opposing Crosstalk between Leptin and Glucocorticoids Rapidly Modulates Synaptic Excitation via Endocannabinoid Release

Abstract: The hypothalamic paraventricular nucleus (PVN) integrates preautonomic and neuroendocrine control of energy homeostasis, fluid balance, and the stress response. We recently demonstrated that glucocorticoids act via a membrane receptor to rapidly cause endocannabinoid-mediated suppression of synaptic excitation in PVN neurosecretory neurons. Leptin, a major signal of nutritional state, suppresses CB(1) cannabinoid receptor-dependent hyperphagia (increased appetite) in fasting animals by reducing hypothalamic levels of endocannabinoids. Here we show that glucocorticoids stimulate endocannabinoid biosynthesis and release via a Galpha(s)-cAMP-protein kinase A-dependent mechanism and that leptin blocks glucocorticoid-induced endocannabinoid biosynthesis and suppression of excitation in the PVN via a phosphodiesterase-3B-mediated reduction in intracellular cAMP levels. We demonstrate this rapid hormonal interaction in both PVN magnocellular and parvocellular neurosecretory cells. Leptin blockade of the glucocorticoid-induced, endocannabinoid-mediated suppression of excitation was absent in leptin receptor-deficient obese Zucker rats. Our findings reveal a novel hormonal crosstalk that rapidly modulates synaptic excitation via endocannabinoid release in the hypothalamus and that provides a nutritional state-sensitive mechanism to integrate the neuroendocrine regulation of energy homeostasis, fluid balance, and the stress response.

Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2

Abstract: Prokineticins, multifunctional secreted proteins, activate two endogenous G protein-coupled receptors PKR1 and PKR2. From in situ analysis of the mouse brain, we discovered that PKR2 is predominantly expressed in the olfactory bulb (OB). To examine the role of PKR2 in the OB, we created PKR1- and PKR2-gene-disrupted mice (Pkr1−/− and Pkr2−/−, respectively). Phenotypic analysis indicated that not Pkr1−/−but Pkr2−/−mice exhibited hypoplasia of the OB. This abnormality was observed in the early developmental stages of fetal OB in the Pkr2−/− mice. In addition, the Pkr2−/− mice showed severe atrophy of the reproductive system, including the testis, ovary, uterus, vagina, and mammary gland. In the Pkr2−/− mice, the plasma levels of testosterone and follicle-stimulating hormone were decreased, and the mRNA transcription levels of gonadotropin-releasing hormone in the hypothalamus and luteinizing hormone and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that gonadotropin-releasing hormone neurons were absent in the hypothalamus in the Pkr2−/− mice. The phenotype of the Pkr2−/− mice showed similarity to the clinical features of Kallmann syndrome, a human disease characterized by association of hypogonadotropic hypogonadism and anosmia. Our current findings demonstrated that physiological activation of PKR2 is essential for normal development of the OB and sexual maturation.

Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: Morphologic evidence of interrelated function within the arcuate nucleus.

Abstract: Considerable evidence suggests that dynorphin and neurokinin B (NKB) neurons in the hypothalamic arcuate nucleus participate in the sex-steroid regulation of reproduction. In the present study, we used dual-label immunofluorescence to explore the distribution of prodynorphin and proNKB immunoreactivity in the rat hypothalamus. Additionally, we investigated whether arcuate prodynorphin-ir (immunoreactive) neurons expressed the neurokinin 3 receptor (NK3R) or nuclear estrogen receptor-alpha (ERalpha). We found that the majority of prodynorphin-ir neurons in the rat arcuate nucleus expressed proNKB, whereas nearly all (99%) of the proNKB neurons were immunoreactive for prodynorphin. The arcuate nucleus was the only site in the hypothalamus where neuronal somata coexpressing prodynorphin and proNKB-immunoreactivity were identified. A dense plexus of double-labeled prodynorphin/proNKB-ir fibers was found within the arcuate nucleus extending to the median eminence and throughout the periventricular zone of the hypothalamus. Prodynorphin/proNKB fibers were also identified in the paraventricular nucleus, anterior hypothalamic area, medial preoptic area, median preoptic nucleus, anteroventral periventricular nucleus, and bed nucleus of the stria terminalis in a distribution consistent with previously described arcuate nucleus projections. Interestingly, the majority of prodynorphin-ir neurons in the arcuate nucleus expressed NK3R, and nearly 100% of the prodynorphin-ir neurons contained nuclear ERalpha. Our results suggest that there is a close functional relationship between dynorphin and NKB peptides within the arcuate nucleus of the rat, which may include an autofeedback loop mediated through NK3R. The diverse hypothalamic projections of fibers expressing both prodynorphin and proNKB provide evidence that these neurons may participate in a variety of homeostatic and neuroendocrine processes.

Differential effects of acute and chronic social defeat stress on hypothalamic-pituitary-adrenal axis function and hippocampal serotonin release in mice.

Abstract: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) stress axis and disturbances in serotonin (5-HT) neurotransmission have been implicated in the pathogenesis of depressive disorder. Repeated social defeat of male NMRI mice has been shown to induce increases in core body temperature and corticosterone, indicative of a state of chronic stress in subordinate animals. The present study further characterised the HPA axis response to social defeat stress, and also examined hippocampal extracellular 5-HT release during the stress. Exposure to an acute social defeat elicits increases in plasma adrenocorticotrophic hormone and corticosterone levels, peaking at 15 and 30 min, respectively, and enhances corticotrophin-releasing factor (CRF) mRNA, but not arginine vasopressin (AVP) mRNA within the medial parvocellular division of the hypothalamic paraventricular nucleus. A concomitant increase in hippocampal corticosterone and 5-HT levels is observed. By contrast, although chronic social defeat is associated with greatly elevated corticosterone levels, the predominant drive appears to be via parvocellular AVP rather than CRF. Furthermore, subordinate animals allowed to recover for 9 days after chronic social defeat display an increase in immobility in the forced swimming model of depression, indicating that animals previously exposed to the homotypic defeat stress are sensitised to the behavioural effects of a novel stressor. These results demonstrate that social defeat induces prolonged activation of the HPA axis and alterations in 5-HT neurotransmission that could be of relevance to some of the pathological abnormalities observed in clinical depression.

Expression of Hypothalamic KiSS-1 System and Rescue of Defective Gonadotropic Responses by Kisspeptin in Streptozotocin-Induced Diabetic Male Rats

Abstract: Hypogonadotropism is a common feature of uncontrolled diabetes, for which the ultimate mechanism remains to be elucidated. Kisspeptins, ligands of G protein-coupled receptor 54 (GPR54) encoded by the KiSS-1 gene, have recently emerged as major gatekeepers of the gonadotropic axis. Alteration in the hypothalamic KiSS-1 system has been reported in adverse metabolic conditions linked to suppressed gonadotropins, such as undernutrition. However, its potential contribution to defective gonadotropin secretion in diabetes has not been evaluated. We report herein analyses of luteinizing hormone (LH) responses to kisspeptin and hypothalamic expression of the KiSS-1 gene in streptozotocin (STZ)-induced diabetic male rats. In addition, functional studies involving kisspeptin replacement or continuous administration of leptin and insulin to diabetic male rats are presented. Kisspeptin administration evoked robust LH and testosterone bursts and enhanced postgonadectomy LH concentrations, despite prevailing attenuation of gonadotropic axis in diabetic animals. In addition, hypothalamic KiSS-1 mRNA levels were unambiguously decreased in diabetic male rats, and the postorchidectomy rise in KiSS-1 mRNA was severely blunted. Repeated administration of kisspeptin to diabetic rats evoked persistent LH and testosterone responses and partially rescued prostate and testis weights. In addition, central infusion of leptin, but not insulin, was sufficient to normalize hypothalamic KiSS-1 mRNA levels, as well as LH and testosterone concentrations. In summary, we provide evidence for altered expression of the hypothalamic KiSS-1 system in a model of uncontrolled diabetes. This observation, together with the ability of exogenous kisspeptin to rescue defective LH responses in diabetic rats, unravel the physiopathological implication, and potential therapeutic intervention, of the KiSS-1 system in altered gonadotropin secretion of type 1 diabetes.