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Showing papers on "Hypothalamus published in 2022"


Journal ArticleDOI
28 Jan 2022-Neuron
TL;DR: In this paper , the authors identify the lateral hypothalamus (LH) as the most physiologically relevant input to LHb under stress and find that LH-LHb synaptic potentiation is determinant in stress-induced depression.

38 citations


Journal ArticleDOI
TL;DR: In this paper , the authors identify a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness induced by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid.
Abstract: During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger similar stereotyped symptoms such as fever, warmth-seeking, loss of appetite and fatigue1,2. Yet exactly how the nervous system alters body temperature and triggers sickness behaviours to coordinate responses to infection remains unknown. Here we identify a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness induced by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid. These neurons are crucial for generating a fever response and other sickness symptoms such as warmth-seeking and loss of appetite. Single-nucleus RNA-sequencing and multiplexed error-robust fluorescence in situ hybridization uncovered the identity and distribution of LPS-activated VMPO (VMPOLPS) neurons and non-neuronal cells. Gene expression and electrophysiological measurements implicate a paracrine mechanism in which the release of immune signals by non-neuronal cells during infection activates nearby VMPOLPS neurons. Finally, we show that VMPOLPS neurons exert a broad influence on the activity of brain areas associated with behavioural and homeostatic functions and are synaptically and functionally connected to circuit nodes controlling body temperature and appetite. Together, these results uncover VMPOLPS neurons as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection.

34 citations


Journal ArticleDOI
TL;DR: A review of the recent developments in the study of AgRP-, NPY- and POMC-producing neurons, specific to their role in controlling metabolism is presented in this paper .
Abstract: Obesity is a major health crisis affecting over a third of the global population. This multifactorial disease is regulated via interoceptive neural circuits in the brain, whose alteration results in excessive body weight. Certain central neuronal populations in the brain are recognised as crucial nodes in energy homeostasis; in particular, the hypothalamic arcuate nucleus (ARC) region contains two peptide microcircuits that control energy balance with antagonistic functions: agouti-related peptide/neuropeptide-Y (AgRP/NPY) signals hunger and stimulates food intake; and pro-opiomelanocortin (POMC) signals satiety and reduces food intake. These neuronal peptides levels react to energy status and integrate signals from peripheral ghrelin, leptin, and insulin to regulate feeding and energy expenditure. To manage obesity comprehensively, it is crucial to understand cellular and molecular mechanisms of information processing in ARC neurons, since these regulate energy homeostasis. Importantly, a specific strategy focusing on ARC circuits needs to be devised to assist in treating obese patients and maintaining weight loss with minimal or no side effects. The aim of this review is to elucidate the recent developments in the study of AgRP-, NPY- and POMC-producing neurons, specific to their role in controlling metabolism. The impact of ghrelin, leptin, and insulin signalling via action of these neurons is also surveyed, since they also impact energy balance through this route. Lastly, we present key proteins, targeted genes, compounds, drugs, and therapies that actively work via these neurons and could potentially be used as therapeutic targets for treating obesity conditions.

32 citations


Journal ArticleDOI
TL;DR: In this paper , a functional transneuronal circuit connecting the hypothalamus to β cells in mice was described, which is necessary for the β cell response to hypoglycemia.

24 citations


Journal ArticleDOI
TL;DR: In this paper , the core components of the GnRH/luteinising hormone surge consist of an endocrine signal that initiates the process and a neural trigger that drives GnRH secretion during the surge.
Abstract: The concept that different systems control episodic and surge secretion of gonadotropin-releasing hormone (GnRH) was well established by the time that GnRH was identified and formed the framework for studies of the physiological roles of GnRH, and later kisspeptin. Here, we focus on recent studies identifying the neural mechanisms underlying these two modes of secretion, with an emphasis on their core components. There is now compelling data that kisspeptin neurons in the arcuate nucleus that also contain neurokinin B (NKB) and dynorphin (i.e., KNDy cells) and their projections to GnRH dendrons constitute the GnRH pulse generator in mice and rats. There is also strong evidence for a similar role for KNDy neurons in sheep and goats, and weaker data in monkeys and humans. However, whether KNDy neurons act on GnRH dendrons and/or GnRH soma and dendrites that are found in the mediobasal hypothalamus (MBH) of these species remains unclear. The core components of the GnRH/luteinising hormone surge consist of an endocrine signal that initiates the process and a neural trigger that drives GnRH secretion during the surge. In all spontaneous ovulators, the core endocrine signal is a rise in estradiol secretion from the maturing follicle(s), with the site of estrogen positive feedback being the rostral periventricular kisspeptin neurons in rodents and neurons in the MBH of sheep and primates. There is considerable species variations in the neural trigger, with three major classes. First, in reflex ovulators, this trigger is initiated by coitus and carried to the hypothalamus by neural or vascular pathways. Second, in rodents, there is a time of day signal that originates in the suprachiasmatic nucleus and activates rostral periventricular kisspeptin neurons and GnRH soma and dendrites. Finally, in sheep nitric oxide-producing neurons in the ventromedial nucleus, KNDy neurons and rostral kisspeptin neurons all appear to participate in driving GnRH release during the surge.

23 citations


Journal ArticleDOI
TL;DR: In this paper , an integrated reference atlas, HypoMap, is presented for the murine hypothalamus, consisting of 384,925 cells, with the ability to incorporate new additional experiments.
Abstract: Abstract The hypothalamus plays a key role in coordinating fundamental body functions. Despite recent progress in single-cell technologies, a unified catalog and molecular characterization of the heterogeneous cell types and, specifically, neuronal subtypes in this brain region are still lacking. Here, we present an integrated reference atlas, ‘HypoMap,’ of the murine hypothalamus, consisting of 384,925 cells, with the ability to incorporate new additional experiments. We validate HypoMap by comparing data collected from Smart-Seq+Fluidigm C1 and bulk RNA sequencing of selected neuronal cell types with different degrees of cellular heterogeneity. Finally, via HypoMap, we identify classes of neurons expressing glucagon-like peptide-1 receptor ( Glp1r ) and prepronociceptin ( Pnoc ), and validate them using single-molecule in situ hybridization. Collectively, HypoMap provides a unified framework for the systematic functional annotation of murine hypothalamic cell types, and it can serve as an important platform to unravel the functional organization of hypothalamic neurocircuits and to identify druggable targets for treating metabolic disorders.

19 citations


Journal ArticleDOI
TL;DR: In this paper , the effects of various stressors, such as restraint, nutritional/metabolic and social stress, on gonadotropin-inhibitory hormone (GnIH) expression and/or its neuronal activity leading to altered hypothalamic-pituitary-gonadal (HPG) action are discussed.

18 citations


Journal ArticleDOI
TL;DR: In this article, the effects of various stressors, such as restraint, nutritional/metabolic and social stress, on gonadotropin-inhibitory hormone (GnIH) expression and/or its neuronal activity leading to altered hypothalamic-pituitary-gonadal (HPG) action are discussed.

18 citations


Journal ArticleDOI
TL;DR: In this paper , the bed nucleus of the stria terminalis (BNST), a node that receives input encoding sex-specific olfactory cues from the medial amygdala, projects to hypothalamic nuclei that control mating and aggression.
Abstract: Mating and aggression are innate social behaviours that are controlled by subcortical circuits in the extended amygdala and hypothalamus1-4. The bed nucleus of the stria terminalis (BNSTpr) is a node that receives input encoding sex-specific olfactory cues from the medial amygdala5,6, and which in turn projects to hypothalamic nuclei that control mating7-9 (medial preoptic area (MPOA)) and aggression9-14 (ventromedial hypothalamus, ventrolateral subdivision (VMHvl)), respectively15. Previous studies have demonstrated that male aromatase-positive BNSTpr neurons are required for mounting and attack, and may identify conspecific sex according to their overall level of activity16. However, neural representations in BNSTpr, their function and their transformations in the hypothalamus have not been characterized. Here we performed calcium imaging17,18 of male BNSTprEsr1 neurons during social behaviours. We identify distinct populations of female- versus male-tuned neurons in BNSTpr, with the former outnumbering the latter by around two to one, similar to the medial amygdala and MPOA but opposite to VMHvl, in which male-tuned neurons predominate6,9,19. Chemogenetic silencing of BNSTprEsr1 neurons while imaging MPOAEsr1 or VMHvlEsr1 neurons in behaving animals showed, unexpectedly, that the male-dominant sex-tuning bias in VMHvl was inverted to female-dominant whereas a switch from sniff- to mount-selective neurons during mating was attenuated in MPOA. Our data also indicate that BNSTprEsr1 neurons are not essential for conspecific sex identification. Rather, they control the transition from appetitive to consummatory phases of male social behaviours by shaping sex- and behaviour-specific neural representations in the hypothalamus.

18 citations


Journal ArticleDOI
TL;DR: The role of melatonin in leptin regulation has been investigated in this article, which showed that melatonin plays a vital role in hormonal regulation and energy metabolism, including leptin signalling and secretion, and the role of leptin resistance is due to excess leptin, a saturation of its transporters and deficiency in either the receptor level or signalling in the hypothalamus.

18 citations


Journal ArticleDOI
TL;DR: The role of melatonin in leptin regulation has been investigated in this article , which showed that melatonin plays a vital role in hormonal regulation and energy metabolism, including leptin signalling and secretion.

Journal ArticleDOI
TL;DR: A review of recent progress in understanding the mechanism of how the hypothalamus affects basal metabolism, modulates physical activity, and adapts to environmental temperature and food intake changes can be found in this paper .
Abstract: Abstract Energy expenditure and energy intake need to be balanced to maintain proper energy homeostasis. Energy homeostasis is tightly regulated by the central nervous system, and the hypothalamus is the primary center for the regulation of energy balance. The hypothalamus exerts its effect through both humoral and neuronal mechanisms, and each hypothalamic area has a distinct role in the regulation of energy expenditure. Recent studies have advanced the understanding of the molecular regulation of energy expenditure and thermogenesis in the hypothalamus with targeted manipulation techniques of the mouse genome and neuronal function. In this review, we elucidate recent progress in understanding the mechanism of how the hypothalamus affects basal metabolism, modulates physical activity, and adapts to environmental temperature and food intake changes.

Journal ArticleDOI
01 Jun 2022-Neuron
TL;DR: In this article , the authors established hypothalamic oxytocin neurons as the key regulators of the parental caregiving behaviors of male mice, and they used unbiased screening to identify excitatory neural connections originating from the lateral hypothalamus to the hypothalamic neurons to be drastically strengthened when male mice become fathers.

Journal ArticleDOI
31 May 2022-Science
TL;DR: A specific circuit allows animals to restore mental and body functions via sleeping, potentially providing a refined route for treating anxiety disorders.
Abstract: In mice, social defeat stress (SDS), an ethological model for psychosocial stress, induces sleep. Such sleep could enable resilience, but how stress promotes sleep is unclear. Activity-dependent tagging revealed a subset of ventral tegmental area γ-aminobutyric acid (GABA)–somatostatin (VTAVgat-Sst) cells that sense stress and drive non–rapid eye movement (NREM) and REM sleep through the lateral hypothalamus and also inhibit corticotropin-releasing factor (CRF) release in the paraventricular hypothalamus. Transient stress enhances the activity of VTAVgat-Sst cells for several hours, allowing them to exert their sleep effects persistently. Lesioning of VTAVgat-Sst cells abolished SDS-induced sleep; without it, anxiety and corticosterone concentrations remained increased after stress. Thus, a specific circuit allows animals to restore mental and body functions by sleeping, potentially providing a refined route for treating anxiety disorders. Description Sleep as a response to stress Stress-induced sleep has been hypothesized to dampen stress responses and to help mental processing of the stressful events. However, the mechanisms underlying these phenomena are not understood. Yu et al. discovered a specific circuit in the mouse midbrain dedicated to detecting stress and inducing restorative sleep (see the Perspective by Joëls and de Kloet). A subset of specialized neurons receive stress inputs and induce rapid eye movement (REM) and non-REM sleep through the lateral hypothalamus. Transient stress enhanced the activity of these neurons for several hours. Stress-induced sleep generated by this pathway alleviated stress levels and mitigated stress-induced anxiety, restoring mental and body functions. Sleep after stress can thus profoundly reduce the chronic stress response. —PRS In mice, social defeat stress has sleep-enhancing effects that protect against continuing stress and anxiety.

Journal ArticleDOI
TL;DR: In this paper , the authors demonstrate that liraglutide is shuttled to target cells in the mouse hypothalamus by specialized ependymoglial cells called tanycytes, bypassing the blood-brain barrier.

Journal ArticleDOI
TL;DR: In this paper , a review focused on hypothalamic mechanisms that underlie the disturbance of hypothalamic-pituitary-ovarian (HPO) axis during obesity with an attempt to promote future studies and/or novel therapeutic strategies for ovulatory disorders in obesity.
Abstract: Obese female mice models demonstrate that obesity-causing ovulatory disorders are mainly for neuroendocrine dysfunction of hypothalamic–pituitary–ovarian (HPO) axis. Hypothalamus is the center of energy homeostasis and reproduction. The proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) and agouti-related peptide (AgRP)/neuropeptide Y (NPY) neurons in arcuate nucleus (ARC) regulating energy metabolism interplay with gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus. Kisspeptin neurons act as a mediator between energy metabolism and the reproductive system. Leptin acts on kisspeptin neurons indirectly through POMC/CART and AgRP/NPY neurons to affect energy metabolism and GnRH release. The nitric oxide (NO) signaling pathway is involved in reproduction and energy balance. The kisspeptin–receptor of kisspeptin (Kiss1r) pathway activated by estradiol stimulates the phosphorylation of neuronal NO synthase (nNOS) protein and switches surge-mode release of GnRH and promotes ovulation. Leptin resistance in hypothalamus caused by diet-induced obesity (DIO) hampers the treatment of obesity with leptin. Hypothalamic inflammation induced by high-fat diet (HFD) is regarded as a potential pathophysiological mechanism of obesity and dysfunction of the HPO axis. Ovulatory disorders are the most common clinical feature exhibited among obese women. Initiation of ovulation physiologically requires a surge of gonadotropin-releasing hormone (GnRH) released from GnRH neurons located in the hypothalamus. These GnRH neurons receive metabolic signals from circulation and vicinal neurons to regulate GnRH release. Leptin acts indirectly on GnRH via adjacent leptin receptor (LEPR)-expressing neurons such as proopiomelanocortin (POMC), neuropeptide Y (NPY)/agouti-related peptide (AgRP), and neuronal nitric oxide (NO) synthase (nNOS) neurons to affect GnRH neuronal activities. Additionally, hypothalamic inflammation also affects ovulation independent of obesity. Therefore, this review focuses on hypothalamic mechanisms that underlie the disturbance of hypothalamic–pituitary–ovarian (HPO) axis during obesity with an attempt to promote future studies and/or novel therapeutic strategies for ovulatory disorders in obesity. Ovulatory disorders are the most common clinical feature exhibited among obese women. Initiation of ovulation physiologically requires a surge of gonadotropin-releasing hormone (GnRH) released from GnRH neurons located in the hypothalamus. These GnRH neurons receive metabolic signals from circulation and vicinal neurons to regulate GnRH release. Leptin acts indirectly on GnRH via adjacent leptin receptor (LEPR)-expressing neurons such as proopiomelanocortin (POMC), neuropeptide Y (NPY)/agouti-related peptide (AgRP), and neuronal nitric oxide (NO) synthase (nNOS) neurons to affect GnRH neuronal activities. Additionally, hypothalamic inflammation also affects ovulation independent of obesity. Therefore, this review focuses on hypothalamic mechanisms that underlie the disturbance of hypothalamic–pituitary–ovarian (HPO) axis during obesity with an attempt to promote future studies and/or novel therapeutic strategies for ovulatory disorders in obesity. separates cerebrospinal fluid in the central nervous system from circulating blood, prevents the harmful substance to invade brain, and maintains the normal function of the nervous system. It is formed by microvascular endothelial cells, astrocyte end-feet, and pericytes. is a condition in which energy intake exceeds energy expenditure. The high-energy diets include high-fat, high-sucrose, and high-calorie diet. is a plant compound with antioxidant, anti-inflammatory, and antiallergenic properties. is an area located in the central lower part of the brain, adjacent to the third ventricle. It consists of interconnecting neurons controlling caloric intake, energy expenditure, and reproduction. Thus, it is the center of controlling energy homeostasis and reproductive function. is a complete and coordinated neuroendocrine system controlling female reproduction. The HPO axis includes hypothalamic gonadotropin-releasing hormone neurons, pituitary gland, ovaries, and their secreting hormones. is a master switch of innate immunity and inflammation. IKKβ is a kinase that inhibits nuclear factor kappa B and can be activated by inflammatory factors and growth factors. NF-κB is a protein compound. Phosphorylated IKKβ leads to NF-κB activated from an inhibited state, which controls the expression of immune and inflammatory genes. Moreover, IKKβ/NF-κB mediates overnutrition and the dysfunctions of hypothalamic signaling, leading to obesity. is the reproductive cycle of primates and humans. a condition in which the ovary is unable to ovulate during the estrous cycle, mostly due to dysfunction of the hypothalamus or pituitary. as a site in the hypothalamus, is the leak part of the BBB, which is located in the supraoptic recess of the third ventricle wall place. It is highly permeable to macromolecular substances. Harmful molecules in the circulation can enter the brain from OVLT.

Journal ArticleDOI
TL;DR: In this article , the authors used high-resolution 3D mapping methods to describe the 3D distribution, monosynaptic input and long-range output of Oxt neurons, and their relationship with Oxt receptor (Oxtr) expression across the entire mouse brain.
Abstract: Oxytocin (Oxt) neurons regulate diverse physiological responses via direct connections with different neural circuits. However, the lack of comprehensive input-output wiring diagrams of Oxt neurons and their quantitative relationship with Oxt receptor (Oxtr) expression presents challenges to understanding circuit-specific Oxt functions. Here, we establish a whole-brain distribution and anatomic connectivity map of Oxt neurons, and their relationship with Oxtr expression using high-resolution 3D mapping methods in adult male and female mice. We use a flatmap to describe Oxt neuronal expression in four hypothalamic domains including under-characterized Oxt neurons in the tuberal nucleus (TU). Oxt neurons in the paraventricular hypothalamus (PVH) broadly project to nine functional circuits that control cognition, brain state, and somatic visceral response. In contrast, Oxt neurons in the supraoptic (SO) and accessory (AN) nuclei have limited central projection to a small subset of the nine circuits. Surprisingly, quantitative comparison between Oxt output and Oxtr expression showed no significant correlation across the whole brain, suggesting abundant indirect Oxt signaling in Oxtr-expressing areas. Unlike output, Oxt neurons in both the PVH and SO receive similar monosynaptic inputs from a subset of the nine circuits mainly in the thalamic, hypothalamic, and cerebral nuclei areas. Our results suggest that PVH-Oxt neurons serve as a central modulator to integrate external and internal information via largely reciprocal connection with the nine circuits while the SO-Oxt neurons act mainly as unidirectional Oxt hormonal output. In summary, our Oxt wiring diagram provides anatomic insights about distinct behavioral functions of Oxt signaling in the brain.SIGNIFICANCE STATEMENT Oxytocin (Oxt) neurons regulate diverse physiological functions from prosocial behavior to pain sensation via central projection in the brain. Thus, understanding detailed anatomic connectivity of Oxt neurons can provide insight on circuit-specific roles of Oxt signaling in regulating different physiological functions. Here, we use high-resolution mapping methods to describe the 3D distribution, monosynaptic input and long-range output of Oxt neurons, and their relationship with Oxt receptor (Oxtr) expression across the entire mouse brain. We found Oxt connections with nine functional circuits controlling cognition, brain state, and somatic visceral response. Furthermore, we identified a quantitatively unmatched Oxt-Oxtr relationship, suggesting broad indirect Oxt signaling. Together, our comprehensive Oxt wiring diagram advances our understanding of circuit-specific roles of Oxt neurons.

Journal ArticleDOI
TL;DR: In this article , it was shown that brain-derived neurotrophic factor (BDNF) signaling within the ventromedial hypothalamus (VMH) modulates neuronal activity in response to changes in energy status.
Abstract: Brain-derived neurotrophic factor (BDNF) is essential for maintaining energy and glucose balance within the central nervous system. Because the study of its metabolic actions has been limited to effects in neuronal cells, its role in other cell types within the brain remains poorly understood. Here we show that astrocytic BDNF signaling within the ventromedial hypothalamus (VMH) modulates neuronal activity in response to changes in energy status. This occurs via the truncated TrkB.T1 receptor. Accordingly, either fasting or central BDNF depletion enhances astrocytic synaptic glutamate clearance, thereby decreasing neuronal activity in mice. Notably, selective depletion of TrkB.T1 in VMH astrocytes blunts the effects of energy status on excitatory transmission, as well as on responses to leptin, glucose and lipids. These effects are driven by increased astrocytic invasion of excitatory synapses, enhanced glutamate reuptake and decreased neuronal activity. We thus identify BDNF/TrkB.T1 signaling in VMH astrocytes as an essential mechanism that participates in energy and glucose homeostasis. Ameroso et al. reveal a role for astrocytic brain-derived neurotrophic factor in the hypothalamus for regulating whole body energy homeostasis by means of TrkB.T1 receptor signaling.

Journal ArticleDOI
14 Mar 2022-Stresses
TL;DR: A student’s emotional state of mind is essential and may cause hyperactivation of the HPA axis during stress encountered during testing, exacerbating cortisol levels and nervous responsiveness.
Abstract: Test anxiety may be a contributing factor to low-performing examination scores among students. There can be numerous physiological responses in the body that lead to test anxiety. One is the body’s response to stress, which activates the brain to release hormones that stimulate central and peripheral nervous responses. The hypothalamus–pituitary–adrenal (HPA) axis is a known responder during stress, causing an elevation of cortisol in the blood, a glucocorticoid (GC) hormone that affects sympathetic nervous responses. Stressors during testing include the method of information delivered, prior knowledge of the subject material, emotional state, or how accurately the student can retain knowledge. A student’s emotional state of mind is essential and may cause hyperactivation of the HPA axis during stress encountered during testing, exacerbating cortisol levels and nervous responsiveness. This review discusses the potential involvement of the HPA stress axis on an individual’s performance during testing and assessment.

Journal ArticleDOI
TL;DR: There are significant differences in OT levels and distribution of OTRs in men from women, particularly in the reproduction, and the reduction of OT secretion accounts for many menopausal symptoms and diseases.
Abstract: Oxytocin (OT) is a nonapeptide mainly produced in the supraoptic and paraventricular nuclei. OT in the brain and blood has extensive functions in both mental and physical activities. These functions are mediated by OT receptors (OTRs) that are distributed in a broad spectrum of tissues with dramatic sexual dimorphism. In both sexes, OT generally facilitates social cognition and behaviors, facilitates parental behavior and sexual activity and inhibits feeding and pain perception. However, there are significant differences in OT levels and distribution of OTRs in men from women. Thus, many OT functions in men are different from women, particularly in the reproduction. In men, the reproductive functions are relatively simple. In women, the reproductive functions involve menstrual cycle, pregnancy, parturition, lactation, and menopause. These functions make OT regulation of women’s health and disease a unique topic of physiological and pathological studies. In menstruation, pre-ovulatory increase in OT secretion in the hypothalamus and the ovary can promote the secretion of gonadotropin-releasing hormone and facilitate ovulation. During pregnancy, increased OT synthesis and preterm release endow OT system the ability to promote maternal behavior and lactation. In parturition, cervix expansion-elicited pulse OT secretion and uterine OT release accelerate the expelling of fetus and reduce postpartum hemorrhage. During lactation, intermittent pulsatile OT secretion is necessary for the milk-ejection reflex and maternal behavior. Disorders in OT secretion can account for maternal depression and hypogalactia. In menopause, the reduction of OT secretion accounts for many menopausal symptoms and diseases. These issues are reviewed in this work.

Journal ArticleDOI
TL;DR: This work defined a population of glucose-sensing GLP-1R neurons in the dorsomedial hypothalamic nucleus (DMH), by which endogenous GLp-1 decreases glucose levels via the cross-talk between the hypothalamus and pancreas and illustrated the sufficiency and necessity of DMHGLP- 1R in glucose regulation.
Abstract: Glucagon-like peptide-1 (GLP-1) regulates energy homeostasis via activation of the GLP-1 receptors (GLP-1Rs) in the central nervous system. However, the mechanism by which the central GLP-1 signal controls blood glucose levels, especially in different nutrient states, remains unclear. Here, we defined a population of glucose-sensing GLP-1R neurons in the dorsomedial hypothalamic nucleus (DMH), by which endogenous GLP-1 decreases glucose levels via the cross-talk between the hypothalamus and pancreas. Specifically, we illustrated the sufficiency and necessity of DMHGLP-1R in glucose regulation. The activation of the DMHGLP-1R neurons is mediated by a cAMP-PKA–dependent inhibition of a delayed rectifier potassium current. We also dissected a descending control of DMHGLP-1R –dorsal motor nucleus of the vagus nerve (DMV)–pancreas activity that can regulate glucose levels by increasing insulin release. Thus, our results illustrate how central GLP-1 action in the DMH can induce a nutrient state–dependent reduction in blood glucose level.

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TL;DR: In this paper , the role of anteroventral periventricular (AVPV) and preoptic nucleus (POA) kisspeptin neurons in the anterior hypothalamus is investigated.

Journal ArticleDOI
TL;DR: In this paper , a single-nuclei RNA sequencing of 40,064 hypothalamic nuclei from young and aged female mice was performed to identify cell type-specific signatures of aging in neuronal subtypes.
Abstract: Abstract Alterations in metabolism, sleep patterns, body composition and hormone status are all key features of aging. While the hypothalamus is a well-conserved brain region that controls these homeostatic and survival-related behaviors, little is known about the intrinsic features of hypothalamic aging. Here, we perform single-nuclei RNA sequencing of 40,064 hypothalamic nuclei from young and aged female mice. We identify cell type-specific signatures of aging in neuronal subtypes as well as astrocytes and microglia. We uncover changes in cell types critical for metabolic regulation and body composition and in an area of the hypothalamus linked to cognition. Our analysis also reveals an unexpected female-specific feature of hypothalamic aging: the master regulator of X inactivation, Xist , is elevated with age, particularly in hypothalamic neurons. Moreover, using machine learning, we show that levels of X chromosome genes and Xist itself, can accurately predict cellular age. This study identifies critical cell-specific changes of the aging hypothalamus in mammals and uncovers a potential marker of neuronal aging in females.

Journal ArticleDOI
TL;DR: This paper used single-cell RNA sequencing (RNA-seq) and hybridization chain reaction (HCR) to profile multiple stages of early hypothalamic development in the chick and identified selective markers for major subdivisions of the developing chick hypothalamus and candidate regulators of hypothalamic induction, regionalization, and neurogenesis.

Journal ArticleDOI
TL;DR: Both neuroendocrine and autonomic PVN roles in BP and BPV regulation are addressed, with a focus on the autonomic part of the PVN.
Abstract: The paraventricular nucleus (PVN) is a highly organized structure of the hypothalamus that has a key role in regulating cardiovascular and osmotic homeostasis. Functionally, the PVN is divided into autonomic and neuroendocrine (neurosecretory) compartments, both equally important for maintaining blood pressure (BP) and body fluids in the physiological range. Neurosecretory magnocellular neurons (MCNs) of the PVN are the main source of the hormones vasopressin (VP), responsible for water conservation and hydromineral balance, and oxytocin (OT), involved in parturition and milk ejection during lactation. Further, neurosecretory parvocellular neurons (PCNs) take part in modulation of the hypothalamic–pituitary–adrenal axis and stress responses. Additionally, the PVN takes central place in autonomic adjustment of BP to environmental challenges and contributes to its variability (BPV), underpinning the PVN as an autonomic master controller of cardiovascular function. Autonomic PCNs of the PVN modulate sympathetic outflow toward heart, blood vessels and kidneys. These pre-autonomic neurons send projections to the vasomotor nucleus of rostral ventrolateral medulla and to intermediolateral column of the spinal cord, where postganglionic fibers toward target organs arise. Also, PVN PCNs synapse with NTS neurons which are the end-point of baroreceptor primary afferents, thus, enabling the PVN to modify the function of baroreflex. Neuroendocrine and autonomic parts of the PVN are segregated morphologically but they work in concert when the organism is exposed to environmental challenges via somatodendritically released VP and OT by MCNs. The purpose of this overview is to address both neuroendocrine and autonomic PVN roles in BP and BPV regulation.

Journal ArticleDOI
TL;DR: In this article , the role of the specific molecules expressed by these hypothalamic neurons in the regulation of innate behaviors that are essential to survival is highlighted, highlighting the challenges associated with targeting these pathways for weight loss therapy.

Journal ArticleDOI
TL;DR: In this paper , the responses between male and female C57BL/6 mice to multiple metabolic challenges to understand the importance of sex in the control of energy homeostasis was compared.
Abstract: The present study aims to compare the responses between male and female C57BL/6 mice to multiple metabolic challenges to understand the importance of sex in the control of energy homeostasis.Male and female C57BL/6 mice were subjected to nutritional and hormonal challenges, such as food restriction and refeeding, diet-induced obesity, feeding response to ghrelin and leptin, ghrelin-induced growth hormone secretion, and central responsiveness to ghrelin and leptin. The hypothalamic expression of transcripts that control energy homeostasis was also evaluated.Male mice lost more weight and lean body mass in response to food restriction, compared to females. During refeeding, males accumulated more body fat and exhibited lower energy expenditure and glycemia, as compared to females. Additionally, female mice exhibited a higher protection against diet-induced obesity and related metabolic imbalances in comparison to males. Low dose ghrelin injection elicited higher food intake and growth hormone secretion in male mice, whereas the acute anorexigenic effect of leptin was more robust in females. However, the sex differences in the feeding responses to ghrelin and leptin were not explained by variations in the central responsiveness to these hormones nor by differences in the fiber density from arcuate nucleus neurons. Female, but not male, mice exhibited compensatory increases in hypothalamic Pomc mRNA levels in response to diet-induced obesity.Our findings revealed several sexually differentiated responses to metabolic challenges in C57BL/6 mice, highlighting the importance of taking into account sex differences in metabolic studies.

Journal ArticleDOI
TL;DR: In this paper , the authors discuss the fundamentals and individual differences in the non-visual effects of light and propose a set of actions to improve their evidence database to be more diverse: understanding systematic bias in the evidence base, dedicated efforts to recruit more diverse participants, routine deposition and sharing of data, and development of data standards and reporting guidelines.

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TL;DR: A review of the evolutionary history, localisation, and significance of the Kiss-KissR gene in reproduction and reproductive behaviours in mammalian and non-mammalian vertebrates is presented in this paper.

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TL;DR: A review of the evolutionary history, localisation, and significance of the Kiss-KissR gene in reproduction and reproductive behaviours in mammalian and non-mammalian vertebrates is presented in this paper .