Melanin-concentrating Hormone Research Articles

Rapid Eye Movement Sleep Engages Melanin-Concentrating Hormone Neurons to Reduce Cocaine Seeking

BackgroundPersistent sleep disruptions following withdrawal from abused drugs may hold keys to battle drug relapse. It is posited that there may be sleep signatures that predict relapse propensity, identifying which may open new avenues for treating substance use disorders. MethodsWe trained male rats (approximately postnatal day 56) to self-administer cocaine. After long-term drug withdrawal (approximately postnatal day 100), we examined the correlations between the intensity of cocaine seeking and key sleep features. To test for causal relationships, we then used behavioral, chemogenetic, or optogenetic methods to selectively increase rapid eye movement sleep (REMS) and measured behavioral and electrophysiological outcomes to probe for cellular and circuit mechanisms underlying REMS-mediated regulation of cocaine seeking. ResultsA selective set of REMS features was preferentially associated with the intensity of cue-induced cocaine seeking after drug withdrawal. Moreover, selectively increasing REMS time and continuity by environmental warming attenuated a withdrawal time-dependent intensification of cocaine seeking, or incubation of cocaine craving, suggesting that REMS may benefit withdrawal. Warming increased the activity of lateral hypothalamic melanin-concentrating hormone (MCH) neurons selectively during prolonged REMS episodes and counteracted cocaine-induced synaptic accumulation of calcium-permeable AMPA receptors in the nucleus accumbens—a critical substrate for incubation. Finally, the warming effects were partly mimicked by chemogenetic or optogenetic stimulations of MCH neurons during sleep, or intra-accumbens infusions of MCH peptide during the rat’s inactive phase. ConclusionsREMS may encode individual vulnerability to relapse, and MCH neuron activities can be selectively targeted during REMS to reduce drug relapse.

Social Network Plasticity of Mice Parental Behavior.

Neural plasticity occurs during developmental stages and is essential for sexual differentiation of the brain and the ensuing sex-dependent behavioral changes in adults. Maternal behavior is primarily affected by sex-related differences in the brain; however, chronic social isolation even in mature male mice can induce maternal retrieving and crouching behavior when they are first exposed to pups. Social milieus influence the inherent behavior of adults and alter the molecular architecture in the brain, thereby allowing higher levels of associated gene expression and molecular activity. This review explores the possibility that although the development of neural circuits is closely associated with maternal behavior, the brain can still retain its neuroplasticity in adults from a neuromolecular perspective. In addition, neuronal machinery such as neurotransmitters and neuropeptides might influence sociobehavioral changes. This review also discusses that the neural circuits regulating behaviors such as parenting and infanticide (including neglect behavior), might be controlled by neural relay on melanin concentrating hormone (MCH)–oxytocin in the hypothalamus during the positive and negative mode of action in maternal behavior. Furthermore, MCH–oxytocin neural relay might contribute to the anxiolytic effect on maternal behavior, which is involved with reward circuits.

Molecular control of the development of hypothalamic neurons involved in metabolic regulation

The hypothalamus is a large brain region made of nuclei and areas involved in the control of behaviors and physiological regulations. Among them, the arcuate nucleus (ARH) and the lateral hypothalamic area (LHA) contain key neuronal populations expressing the pro-opiomelanocortin (POMC), the agouti-related peptide (AgRP), and the melanin-concentrating hormone (MCH), respectively, that are involved in goal-oriented behaviors (such as feeding behavior) and glucose homeostasis. These neuronal populations are generated from distinct parts of the germinative neuroepithelium during embryonic life, and acquire their cell fate under the influence of morphogen proteins, specific transcription factors, and epigenetic modulators. POMC and MCH neuronal development continues by sending long descending axonal projections before birth under the control of axon guidance molecules such as Netrin1 and Slit2. Later, during the postnatal period, POMC and AgRP neurons develop intra-hypothalamic projections notably to the paraventricular nucleus of the hypothalamus through the influence of other axon guidance cues such as the class3 Semaphorins. Other cellular processes, such as autophagy and primary cilia function, and hormonal cues also appear critical for the proper development of POMC neurons.

Whole-Brain Monosynaptic Afferents to Rostromedial Tegmental Nucleus Gamma-Aminobutyric Acid-Releasing Neurons in Mice.

Increasing evidence has revealed that the rostromedial tegmental area (RMTg) mediates many behaviors, including sleep and addiction. However, presynaptic patterns governing the activity of γ-aminobutyric acid-releasing (GABAergic) neurons, the main neuronal type in the RMTg, have not been defined. Here, we used cell-type-specific retrograde trans-synaptic rabies viruses to map and quantify the monosynaptic afferents to RMTg GABAergic neurons in mouse whole brains. We identified 71 ascending projection brain regions. Sixty-eight percent of the input neurons arise from the ipsilateral and 32% from the contralateral areas of the brain. The first three strongest projection regions were the ipsilateral lateral hypothalamus, zone incerta, and contralateral pontine reticular nucleus. Immunohistochemistry imaging showed that the input neurons in the dorsal raphe, laterodorsal tegmentum, and dorsal part of zone incerta were colocalized with serotoninergic, cholinergic, and neuronal nitric oxide synthetase-expressing neurons, respectively. However, in the lateral hypothalamus, a few input neurons innervating RMTg GABAergic neurons colocalized orexinergic neurons but lacked colocalization of melanin-concentrating hormone neurons. Our findings provide anatomical evidence to understand how RMTg GABAergic neurons integrate diverse information to exert varied functions.

Anxiolytic and antidepressant effects of melanin-concentrating hormone 1 receptor antagonist SNAP 94847

Background: Melatonin Concentrating Hormone (MCH) is a neuropeptide involved in the regulation of eating behavior, energy balance, mood, and the sleep/wake cycle.
 Aim: To study the effect of SNAP 94847, a selective melanin-concentrating hormone receptor type 1 (MCHR1) antagonist, on exploratory and emotional behavior in rats.
 Materials and methods: 38 male Wistar rats were used in the work. The selective MCHR1 antagonist SNAP 94847 was administered intranasally. The behavior of the animals was assessed in the tests: open field, elevated plus maze, Porsolt forced swimming, resident-intruder.
 Results: After intranasal administration SNAP 94847 there were an increase in the number of sniffs, the time of locomotion, and the number of squares crossed in open field test. In elevated plus maze test, after the administration of SNAP 94847, a decrease in the time spent by the animals in the closed arms of the maze was observed. In Porsolt forced swim test, the immobilization time decreased and the passive swimming time increased in experimental group.
 Conclusion: In animal tests, the antidepressant and anxiolytic effects of the selective MCHR1 antagonist SNAP 94847 have been shown.

The Efficacy and Psychoneuroimmunology Mechanism of Camouflage Combined With Psychotherapy in Vitiligo Treatment.

Background and ObjectivesThe efficacy of camouflage combined with psychotherapy and the underlying mechanisms are poorly understood in vitiligo management. This study aimed to investigate the joint efficacy and further explore psycho-neuro-endocrine-immune-skin interactions.Patients and MethodsIn a prospective, non-randomized and concurrent controlled trial, patients were divided into two groups. Quality of life (QOL) was evaluated using the Chinese version of the Vitiligo Life Quality Index (VLQI-C). Serum levels of neuropeptides and cytokines were detected by enzyme-linked immunosorbent assay.ResultsA total of 149 patients were included for final evaluation. After treatment for 4 weeks, total and subcategory quality of life scores in the intervention group were much lower than in the control group. Serum levels of neuropeptide-Y (NPY) and melanin-concentrating hormone (MCH) significantly decreased, and serum level of adrenocorticotropic hormone (ACTH) increased in both active and stable patients of the intervention group, but not in the control group. In addition, the serum levels of interferon-γ (IFN-γ), CXC chemokine ligand 10 (CXCL10), and interleukin-1β (IL-1β) decreased in both the active and stable patients of the intervention group and only in the active patients of the control group.ConclusionsThe combination of camouflage and psychotherapy provided a clinically meaningful improvement in quality of life and ameliorated the outcome by likely modulating the psycho-neuro-endocrine-immuno-skin system during vitiligo management.Clinical Trial Registrationwww.clinicaltrials.gov/ct2/show/NCT03540966, identifier: NCT03540966.

Is paradoxical sleep setting up innate and acquired complex sensorimotor and adaptive behaviours?: A proposed function based on literature review.

We summarize here the progress in identifying the neuronal network as well as the function of paradoxical sleep and the gaps of knowledge that should be filled in priority. The core system generating paradoxical sleep localized in the brainstem is now well identified, and the next step is to clarify the role of the forebrain in particular that of the hypothalamus including the melanin-concentrating hormone neurons and of the basolateral amygdala. We discuss these two options, and also the discovery that cortical activation during paradoxical sleep is restricted to a few limbic cortices activated by the lateral supramammillary nucleus and the claustrum. Such activation nicely supports the findings recently obtained showing that neuronal reactivation occurs during paradoxical sleep in these structures, and induces both memory consolidation of important memory and forgetting of less relevant ones. The question that still remains to be answered is whether paradoxical sleep is playing more crucial roles in processing emotional and procedural than other types of memories. One attractive hypothesis is that paradoxical sleep is responsible for erasing negative emotional memories, and that this function is not properly functioning in depressed patients. On the other hand, the presence of a muscle atonia during paradoxical sleep is in favour of a role in procedural memory as new types of motor behaviours can be tried without harm during the state. In a way, it also fits with the proposed role of paradoxical sleep in setting up the sensorimotor system during development.

Melanin‐Concentrating Hormone (MCH) Decreases the Hypercapnic Ventilatory Response by Acting in the Lateral Hypothalamic Area (LHA)

MCH plays an inhibitory role in the central hypercapnic chemoreflex, but the mechanisms were unclear so far. In this study, we tested the hypothesis that MCH1‐R receptors activation in LHA and/or Locus coeruleus (LC) is involved in the modulation of hypercapnic ventilatory response during the sleep/wake cycle. To do this, we measured pulmonary ventilation (VE), body temperature, EEG and EMG of unanesthetized male Wistar rats before and after microinjection of the MCH agonist (MCH, 0.4 mM) into the LHA and LC, or the MCH1‐R antagonist (SNAP‐94847; 63 mM), into the LHA, in room air and in 7% CO2 during wakefulness and sleep, in the dark and light periods. MCH intra‐LHA decreased the CO2 ventilatory response by 27% during wakefulness (VE = 1923 ± 384; n = 7 versus 2645 ± 293 mL kg‐1 min‐1; n = 6; P < 0.0001) and 16% during sleep (VE = 1914 ± 228; n = 6 versus2273 ± 243 mL kg‐1 min‐1; n = 4; P < 0.005) in the light, but not in the dark period while SNAP‐94847 intra‐LHA caused an increased CO2 ventilatory response during wakefulness in the light period, compared with the control group (VE = 2547 ± 277; n = 6 versus 2106 ± 329 mL kg‐1 min‐1; n = 6; P < 0.05). In the LC, MCH caused no change in the hypercapnic ventilatory response of rats. Our results suggest that MCH via MCH1‐R in the LHA, but not in the LC, exerts an inhibitory modulation of the hypercapnic ventilatory response during the light‐inactive period in rats.

A low body-color regulating ability of spotted halibut Verasper variegatus: Evaluation of the roles of melanin-concentrating hormone and proopiomelanocortin systems

A low body-color regulating ability of spotted halibut Verasper variegatus: Evaluation of the roles of melanin-concentrating hormone and proopiomelanocortin systems

Roles of Neuropeptides in Sleep-Wake Regulation.

Sleep and wakefulness are basic behavioral states that require coordination between several brain regions, and they involve multiple neurochemical systems, including neuropeptides. Neuropeptides are a group of peptides produced by neurons and neuroendocrine cells of the central nervous system. Like traditional neurotransmitters, neuropeptides can bind to specific surface receptors and subsequently regulate neuronal activities. For example, orexin is a crucial component for the maintenance of wakefulness and the suppression of rapid eye movement (REM) sleep. In addition to orexin, melanin-concentrating hormone, and galanin may promote REM sleep. These results suggest that neuropeptides play an important role in sleep–wake regulation. These neuropeptides can be divided into three categories according to their effects on sleep–wake behaviors in rodents and humans. (i) Galanin, melanin-concentrating hormone, and vasoactive intestinal polypeptide are sleep-promoting peptides. It is also noticeable that vasoactive intestinal polypeptide particularly increases REM sleep. (ii) Orexin and neuropeptide S have been shown to induce wakefulness. (iii) Neuropeptide Y and substance P may have a bidirectional function as they can produce both arousal and sleep-inducing effects. This review will introduce the distribution of various neuropeptides in the brain and summarize the roles of different neuropeptides in sleep–wake regulation. We aim to lay the foundation for future studies to uncover the mechanisms that underlie the initiation, maintenance, and end of sleep–wake states.

Short-term Fasting Induces Alternate Activation of Orexin and Melanin-concentrating Hormone Neurons in Rats

Orexin and melanin-concentrating hormone (MCH) neurons constitute the energy balance circuitry that coordinates the fasting response. Orexin neurons mediate food foraging at the expense of energy storage, while MCH neurons promote energy storage by reducing energy expenditure and increasing food intake. It is unknown if these cell groups undergo plastic changes as hunger and metabolic changes escalate over time during fasting. To address this, we performed in vitro electrophysiological recording on orexin and MCH neurons in the lateral hypothalamus and perifornical area from rats fasted for 12 or 24 h or fed ad-libitum. Orexin neurons showed a transient decrease in presynaptic glutamate release at 12 h. This turned to an increase at 24 h of fasting, while membrane potential depolarized and AMPA receptor conductance increased. In contrast, MCH neurons were transiently depolarized at 12 h fasting along with increased presynaptic glutamate release. These changes reversed at 24 h, while the number of AMPA receptors decreased. Our results indicate that MCH neurons are preferentially activated during the early phase of fasting (12 h), which would protect against weight loss. With a longer fast, orexin neurons become activated, which would promote arousal and exploratory activity required for foraging behaviors. This alternating activation of these cell groups may reflect a dynamic balance of energy conservation and foraging behaviors to optimize energy balance during ongoing fasting.

Identification and New Indication of Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonist Derived from Machine Learning and Transcriptome-Based Drug Repositioning Approaches.

Melanin-concentrating hormone receptor 1 (MCHR1) has been a target for appetite suppressants, which are helpful in treating obesity. However, it is challenging to develop an MCHR1 antagonist because its binding site is similar to that of the human Ether-à-go-go-Related Gene (hERG) channel, whose inhibition may cause cardiotoxicity. Most drugs developed as MCHR1 antagonists have failed in clinical development due to cardiotoxicity caused by hERG inhibition. Machine learning-based prediction models can overcome these difficulties and provide new opportunities for drug discovery. In this study, we identified KRX-104130 with potent MCHR1 antagonistic activity and no cardiotoxicity through virtual screening using two MCHR1 binding affinity prediction models and an hERG-induced cardiotoxicity prediction model. In addition, we explored other possibilities for expanding the new indications for KRX-104130 using a transcriptome-based drug repositioning approach. KRX-104130 increased the expression of low-density lipoprotein receptor (LDLR), which induced cholesterol reduction in the gene expression analysis. This was confirmed by comparison with gene expression in a nonalcoholic steatohepatitis (NASH) patient group. In a NASH mouse model, the administration of KRX-104130 showed a protective effect by reducing hepatic lipid accumulation, liver injury, and histopathological changes, indicating a promising prospect for the therapeutic effect of NASH as a new indication for MCHR1 antagonists.

Structural and molecular characterization of paraventricular thalamic glucokinase-expressing neuronal circuits in the mouse.

The thalamic paraventricular nucleus (PVT) is a structure highly interconnected with several nuclei ranging from forebrain to hypothalamus and brainstem. Numerous rodent studies have examined afferent and efferent connections of the PVT and their contribution to behavior, revealing its important role in the integration of arousal cues. However, the majority of these studies used a region‐oriented approach, without considering the neuronal subtype diversity of the nucleus. In the present study, we provide the anatomical and transcriptomic characterization of a subpopulation of PVT neurons molecularly defined by the expression of glucokinase (Gck). Combining a genetically modified mouse model with viral tracing approaches, we mapped both the anterograde and the retrograde projections of Gck‐positive neurons of the anterior PVT (GckaPVT). Our results demonstrated that GckaPVT neurons innervate several nuclei throughout the brain axis. The strongest connections are with forebrain areas associated with reward and stress and with hypothalamic structures involved in energy balance and feeding regulation. Furthermore, transcriptomic analysis of the Gck‐expressing neurons revealed that they are enriched in receptors for hypothalamic‐derived neuropeptides, adhesion molecules, and obesity and diabetes susceptibility transcription factors. Using retrograde labeling combined with immunohistochemistry and in situ hybridization, we identify that GckaPVT neurons receive direct inputs from well‐defined hypothalamic populations, including arginine‐vasopressin‐, melanin‐concentrating hormone‐, orexin‐, and proopiomelanocortin‐expressing neurons. This detailed anatomical and transcriptomic characterization of GckaPVT neurons provides a basis for functional studies of the integration of homeostatic and hedonic aspects of energy homeostasis, and for deciphering the potential role of these neurons in obesity and diabetes development.

Congenital idiopathic megaesophagus in the German shepherd dog is a sex-differentiated trait and is associated with an intronic variable number tandem repeat in Melanin-Concentrating Hormone Receptor 2.

Congenital idiopathic megaesophagus (CIM) is a gastrointestinal (GI) motility disorder of dogs in which reduced peristaltic activity and dilation of the esophagus prevent the normal transport of food into the stomach. Affected puppies regurgitate meals and water, fail to thrive, and experience complications such as aspiration pneumonia that may necessitate euthanasia. The German shepherd dog (GSD) has the highest disease incidence, indicative of a genetic predisposition. Here, we discover that male GSDs are twice as likely to be affected as females and show that the sex bias is independent of body size. We propose that female endogenous factors (e.g., estrogen) are protective via their role in promoting relaxation of the sphincter between the esophagus and stomach, facilitating food passage. A genome-wide association study for CIM revealed an association on canine chromosome 12 (P-val = 3.12x10-13), with the lead SNPs located upstream or within Melanin-Concentrating Hormone Receptor 2 (MCHR2), a compelling positional candidate gene having a role in appetite, weight, and GI motility. Within the first intron of MCHR2, we identified a 33 bp variable number tandem repeat (VNTR) containing a consensus binding sequence for the T-box family of transcription factors. Across dogs and wolves, the major allele includes two copies of the repeat, whereas the predominant alleles in GSDs have one or three copies. The single-copy allele is strongly associated with CIM (P-val = 1.32x10-17), with homozygosity for this allele posing the most significant risk. Our findings suggest that the number of T-box protein binding motifs may correlate with MCHR2 expression and that an imbalance of melanin-concentrating hormone plays a role in CIM. We describe herein the first genetic factors identified in CIM: sex and a major locus on chromosome 12, which together predict disease state in the GSD with greater than 75% accuracy.

Determination of the Interaction and Pharmacological Modulation of MCHR1 Signaling by the C-Terminus of MRAP2 Protein

Melanin concentrating hormone (MCH), an orexigenic neuropeptide, is primarily secreted by the hypothalamus and acts on its receptor, the melanin-concentrating hormone receptor 1 (MCHR1), to regulate appetite and energy homeostasis. The Melanocortin Receptor Accessory Protein 2 (MRAP2), a small single transmembrane protein broadly expressed in multiple tissues, has been defined as a vital endocrine modulator of five melanocortin receptors (MC1R–MC5R) and several other GPCRs in the regulation of central neuronal activities and peripheral energy balance. Here, we demonstrated the interaction between MRAP2 and MCHR1 by immunoprecipitation and bimolecular fluorescent assay and found that MRAP2 could inhibit MCHR1 signaling in vitro. A series of functional truncations of different regions further identified that the C-terminal domains of MRAP2 protein were required for the pharmacological modulation of intracellular Ca2+ coupled cascades and membrane transport. These findings elucidated the broad regulatory profile of MRAP2 protein in the central nervous system and may provide implications for the modulation of central MCHR1 function in vivo.

Characterization of Hypothalamic MCH Neuron Development in a 3D Differentiation System of Mouse Embryonic Stem Cells.

Hypothalamic melanin-concentrating hormone (MCH) neurons are important regulators of multiple physiological processes, such as sleep, feeding, and memory. Despite the increasing interest in their neuronal functions, the molecular mechanism underlying MCH neuron development remains poorly understood. We report that a three-dimensional culture of mouse embryonic stem cells (mESCs) can generate hypothalamic-like tissues containing MCH-positive neurons, which reproduce morphologic maturation, neuronal connectivity, and neuropeptide/neurotransmitter phenotype of native MCH neurons. Using this in vitro system, we demonstrate that Hedgehog (Hh) signaling serves to produce major neurochemical subtypes of MCH neurons characterized by the presence or absence of cocaine- and amphetamine-regulated transcript (CART). Without exogenous Hh signals, mESCs initially differentiated into dorsal hypothalamic/prethalamic progenitors and finally into MCH+CART+ neurons through a specific intermediate progenitor state. Conversely, activation of the Hh pathway specified ventral hypothalamic progenitors that generate both MCH+CART− and MCH+CART+ neurons. These results suggest that in vivo MCH neurons may originate from multiple cell lineages that arise through early dorsoventral patterning of the hypothalamus. Additionally, we found that Hh signaling supports the differentiation of mESCs into orexin/hypocretin neurons, a well-defined cell group intermingled with MCH neurons in the lateral hypothalamic area (LHA). The present study highlights and improves the utility of mESC culture in the analysis of the developmental programs of specific hypothalamic cell types.

Crosstalk between Melanin Concentrating Hormone and Endocrine Factors: Implications for Obesity.

Melanin-concentrating hormone (MCH) is a 19aa cyclic peptide exclusively expressed in the lateral hypothalamic area, which is an area of the brain involved in a large number of physiological functions and vital processes such as nutrient sensing, food intake, sleep-wake arousal, memory formation, and reproduction. However, the role of the lateral hypothalamic area in metabolic regulation stands out as the most relevant function. MCH regulates energy balance and glucose homeostasis by controlling food intake and peripheral lipid metabolism, energy expenditure, locomotor activity and brown adipose tissue thermogenesis. However, the MCH control of energy balance is a complex mechanism that involves the interaction of several neuroendocrine systems. The aim of the present work is to describe the current knowledge of the crosstalk of MCH with different endocrine factors. We also provide our view about the possible use of melanin-concentrating hormone receptor antagonists for the treatment of metabolic complications. In light of the data provided here and based on its actions and function, we believe that the MCH system emerges as an important target for the treatment of obesity and its comorbidities.

Effects of cluster headache preventatives on mouse hypothalamic transcriptional homeostasis.

To investigate how cluster headache preventatives verapamil, lithium and prednisone affect expression of hypothalamic genes involved in chronobiology. C57Bl/6 mice were exposed to daily, oral treatment with verapamil, lithium, prednisone or amitriptyline (as negative control), and transcripts of multiple genes quantified in the anterior, lateral and posterior hypothalamus. Verapamil, lithium or prednisone did not affect expression of clock genes of the anterior hypothalamus (Clock, Bmal1, Cry1/2 and Per1/2). Prednisone altered expression of hypothalamic neuropeptides melanin-concentrating hormone and histidine decarboxylase within the lateral and posterior hypothalamus, respectively. The three preventatives did not affect expression of the neurohypophyseal hormones oxytocin and arginine-vasopressin in the posterior hypothalamus. Conversely, amitriptyline reduced mRNA levels of Clock, oxytocin and arginine-vasopressin. Data suggest that cluster headache preventatives act upstream or downstream from the hypothalamus. Our findings provide new insights on hypothalamic homeostasis during cluster headache prophylaxis, as well as neurochemistry underlying cluster headache treatment.

Fibroblast growth factor 2: Role in prenatal alcohol-induced stimulation of hypothalamic peptide neurons

Prenatal alcohol exposure (PAE) increases alcohol consumption and risk for alcohol use disorder. This phenomenon in rodents is suggested to involve a stimulatory effect of PAE, in female more than male offspring, on neurogenesis and density of neurons expressing neuropeptides in lateral hypothalamus (LH), including melanin-concentrating hormone (MCH), known to promote alcohol intake. With evidence suggesting a role for fibroblast growth factor 2 (FGF2) and its receptor FGFR1 in stimulating neurogenesis and alcohol drinking, we investigated here whether the FGF2-FGFR1 system is involved in the PAE-induced increase in MCH neurons, in postnatal offspring of pregnant rats given ethanol orally (embryonic day 10–15) at a low-moderate (2 g/kg/day) or high (5 g/kg/day) dose. Our results demonstrate that PAE at the low-moderate but not high dose stimulates FGF2 and FGFR1 gene expression and increases the density of MCH neurons co-expressing FGF2, only in females, but FGFR1 in both sexes. PAE induces this effect in the dorsal but not ventral area of the LH. Further analysis of FGF2 and FGFR1 transcripts within individual MCH neurons reveals an intracellular, sex-dependent effect, with PAE increasing FGF2 transcripts positively related to FGFR1 in the nucleus as well as cytoplasm of females but transcripts only in the cytoplasm of males. Peripheral injection of FGF2 itself (80 μg/kg, s.c.) in pregnant rats mimics these effects of PAE. Together, these results support the involvement of the FGF2-FGFR1 system in mediating the PAE-induced, sex dependent increase in density of MCH neurons, possibly contributing to increased alcohol consumption in the offspring.

Sleep and Body Temperature

Mammals and birds seek a warm environment prior to sleep, which triggers vasodilatation and body cooling. Ambient temperatures outside the thermoneutral zone suppress sleep, particularly rapid eye movement (REM) sleep. We discuss the neurocircuit interactions associated with thermal and sleep regulation that occur primarily in the hypothalamic areas. An increase in ambient temperature stimulates the median preoptic/medial preoptic area of the hypothalamus, decreases body temperature, and increases non-REM sleep. Similarly, optical stimulation of the ventrolateral preoptic nucleus, which contains galanin (VLPOGAL), results in body cooling and non-REM sleep. A decrease in VLPOGAL disrupts sleep in elderly individuals and may also be associated with reduced decline in core body temperature during sleep. However, stimulation of neurons that synthesize melanin-concentrating hormone in the lateral hypothalamus decreases body temperature and induces REM sleep. We also discussed the acute effect of light on sleep induction and decreased body temperature, implicated with gamma-aminobutyric acid-ergic neurons in the preoptic area. Further investigation is needed to determine the mechanisms that induce physiological responses in diurnal and nocturnal species. These studies will contribute to a better understanding of the association between sleep and thermoregulation.