Lesion of NPY Receptor-expressing Neurons in Perifornical Lateral Hypothalamus Attenuates Glucoprivic Feeding.

Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.

Neonatal inhibition of androgen activity alters the programming of body weight and orexinergic peptides differentially in male and female rats.

The involvement of androgens in the regulation of energy metabolism has been demonstrated. The main objective of the present research was to study the involvement of androgens in both the programming of energy metabolism and the regulatory peptides associated with feeding. For this purpose, androgen receptors and the main metabolic pathways of testosterone were inhibited during the first five days of postnatal life in male and female Wistar rats. Pups received a daily s.c. injection from the day of birth, postnatal day (P) 1, to P5 of Flutamide (a competitive inhibitor of androgen receptors), Letrozole (an aromatase inhibitor), Finasteride (a 5-alpha-reductase inhibitor) or vehicle. Body weight, food intake and fat pads were measured. Moreover, hypothalamic Agouti-related peptide (AgRP), neuropeptide Y (NPY), orexin, and proopiomelanocortin (POMC) were analyzed by quantitative real-time polymerase chain reaction assay. The inhibition of androgenic activity during the first five days of life produced a significant decrease in body weight in females at P90 but did not affect this parameter in males. Moreover, the inhibition of aromatase decreased hypothalamic AgRP mRNA levels in males while the inhibition of 5α-reductase decreased hypothalamic AgRP and orexin mRNA levels in female rats. Finally, food intake and visceral fat, but not subcutaneous fat, were affected in both males and females depending on which testosterone metabolic pathway was inhibited. Our results highlight the differential involvement of androgens in the programming of energy metabolism as well as the AgRP and orexin systems during development in male and female rats.

Selenium alleviates modafinil-induced neurobehavioral toxicity in rat via PI3K/Akt/mTOR/GSK3B signaling pathway and suppression of oxidative stress and apoptosis: in vivo and in silico study.

Nonmedical use of modafinil (MOD) led to increased rates of overdose toxicity, road accidents, addiction, withdrawal, suicide, and mental illnesses. The current study aims to determine the probable MOD brain toxicity and elucidate the possible role of selenium (Se) in ameliorating the neurotoxicity in rat models. Fifty-four male Albino rats were randomly assigned into nine groups. The groups were G1 (control negative), G2 (Se0.1), G3 (Se0.2), G4 (MOD300), G5 (MOD600), G6 (Se0.1 + MOD300), G7 (Se0.2 + MOD300), G8 (Se0.1 + MOD600), and G9 (Se0.2 + MOD600). After finishing the experiment, blood and brain tissue were harvested for biochemical and histological investigation. Neurobehavior parameters were assessed. Tissue neurotransmitter levels and oxidative stress markers were assessed. Gene expression of PI3K/Akt/mTOR-GSK3B, orexin, and orexin receptor2 was measured by qRT-PCR. Histological and immunohistochemistry assessments, as well as molecular docking, were carried out. MOD-induced neurobehavioral toxicity exhibited by behavioral and cognitive function impairments, which are associated with decreased antioxidant activities, increased MDA levels, and decreases in neurotransmitter levels. Brain levels of mRNA expression of PI3K, Akt, and mTOR were decreased, while GS3K, orexin, and orexin receptors were significantly elevated. These disturbances were confirmed by histopathological brain changes with increased silver and Bax immunostaining and decreased crystal violet levels. MOD induced neurotoxic effects in a dose-dependent manner. Compared with the MOD groups, SE coadministration significantly attenuates MOD-induced toxic changes. Docking study shows the protective role of Se as an apoptosis inhibitor and inflammation inhibitor. In conclusion, Se could be used as a biologically effective antioxidant compound to protect from MOD neurobehavioral toxicity in Wistar rats by reversing behavioral alterations, inflammation, apoptosis, and oxidative injury.

Spatial memory requires hypocretins to elevate medial entorhinal gamma oscillations.

The hypocretin (Hcrt) (also known as orexin) neuropeptidic wakefulness-promoting system is implicated in the regulation of spatial memory, but its specific role and mechanisms remain poorly understood. In this study, we revealed the innervation of the medial entorhinal cortex (MEC) by Hcrt neurons in mice. Using the genetically encoded G-protein-coupled receptor activation-based Hcrt sensor, we observed a significant increase in Hcrt levels in the MEC during novel object-place exploration. We identified the function of Hcrt at presynaptic glutamatergic terminals, where it recruits fast-spiking parvalbumin-positive neurons and promotes gamma oscillations. Bidirectional manipulations of Hcrt neurons' projections from the lateral hypothalamus (LHHcrt) to MEC revealed the essential role of this pathway in regulating object-place memory encoding, but not recall, through the modulation of gamma oscillations. Our findings highlight the significance of the LHHcrt-MEC circuitry in supporting spatial memory and reveal a unique neural basis for the hypothalamic regulation of spatial memory.

Experimental sickness reduces hypocretin receptor 1 expression in the lateral hypothalamus and ventral tegmental area of female mice.

Recent studies have focused on how sickness behaviours, including lethargy, are coordinated in the brain in response to peripheral infections. Decreased hypocretin (orexin) signalling is associated with lethargy and previous research suggests that hypocretin signalling is downregulated during sickness. However, there are studies that find increases or no change in hypocretin signalling during sickness. It is further unknown whether hypocretin receptor expression changes during sickness. Using lipopolysaccharide (LPS) to induce sickness in female mice, we investigated how LPS-injection affects gene expression of hypocretin receptors and prepro-hypocretin as well as hypocretin-1 peptide concentrations in brain tissue. We found that hypocretin receptor 1 gene expression was downregulated during sickness in the lateral hypothalamus and ventral tegmental area, but not in the dorsal raphe nucleus or locus coeruleus. We found no changes in hypocretin receptor 2 expression. Using a gene expression calculation that accounts for primer efficiencies and multiple endogenous controls, we were unable to detect changes in prepro-hypocretin expression. Using radioimmunoassay, we found no change in hypocretin-1 peptide in rostral brain tissue. Our results indicate that hypocretin receptor expression can fluctuate during sickness, adding an additional level of complexity to understanding hypocretin signalling during sickness.

An anatomically distinct subpopulation of orexin neurons project from the lateral hypothalamus to the olfactory bulb.

Olfactory cues play a key role in natural behaviors such as finding food, finding mates, and avoiding predators. In principle, the ability of the olfactory system to carry out these perceptual functions would be facilitated by signaling related to an organism's physiological state. One candidate pathway includes a direct projection from the hypothalamus to the main olfactory bulb, the first stage of olfactory sensory processing. The pathway from the hypothalamus to the main olfactory bulb is thought to include neurons that express the neuropeptide orexin, although the proportion that is orexinergic remains unknown. A current model proposes that the orexin population is heterogeneous, yet it remains unknown whether the proportion that innervates the main olfactory bulb reflects a distinct subpopulation of the orexin population. Herein, we carried out combined retrograde tract tracing with immunohistochemistry for orexin-A in the mouse to define the proportion of hypothalamic input to the main olfactory bulb that is orexinergic and to determine what fraction of the orexin-A population innervates the bulb. The numbers and spatial positions of all retrogradely labeled neurons and all the orexin-A-expressing neurons were quantified in sequential sections through the hypothalamus. Retrogradely labeled neurons were found in the ipsilateral hypothalamus, of which 22% expressed orexin-A. The retrogradely labeled neurons that did and did not express orexin-A could be anatomically distinguished based on their spatial position and cell body area. Remarkably, only 7% of all the orexin-A neurons were retrogradely labeled, suggesting that only a small fraction of the orexin-A population directly innervate the main olfactory bulb. These neurons spatially overlapped with the orexin-A neurons that did not innervate the bulb, although the two cell populations were differentiated based on cell body area. Overall, these results support a model in which olfactory sensory processing is influenced by orexinergic feedback at the first synapse in the olfactory processing pathway.

Role of orexin in pathogenesis of neurodegenerative parkinsonisms.

INTRODUCTION: The pathogenesis of parkinsonisms is not fully understood. Among possible factors which may influence the course of neurodegenerative diseases, endocrine abnormalities may be interpreted as having been underevaluated. STATE OF THE ART: Growing interest is associated with the role of neuropeptides such as orexin. Orexin is a neuropeptide produced by orexigenic neurons in the lateral parts of the hypothalamus and is linked with excitement, wakefulness and appetite. An extended analysis of this neuropeptide might answer whether changes in the metabolism of orexin is more likely to be a cause or a consequence of neurodegeneration. CLINICAL SIGNIFICANCE: Orexin is a neuropeptide produced by orexigenic neurons in the lateral parts of the hypothalamus and is linked with excitement, wakefulness and appetite. The aim of this study was to discuss the role of this factor and its abnormalities in the pathogenesis and course of parkinsonian syndrome. FUTURE DIRECTIONS: Understanding the role of orexin in these diseases may be interpreted as an important feature in evolving therapeutical methods. Further evaluation based on larger groups of patients is required.

Anandamide improves food intake and orexinergic neuronal activity in the chronic sleep deprivation induction model in rats by modulating the expression of the CB1 receptor in the lateral hypothalamus.

Sleep deprivation alters orexinergic neuronal activity in the lateral hypothalamus (LH), which is the main regulator of sleep-wake, arousal, appetite, and energy regulation processes. Cannabinoid receptor (CBR) expression in this area is involved in modulating the function of orexin neurons. In this study, we investigated the effects of endocannabinoid anandamide (AEA) administration on improving food intake and appetite by modulating the activity of orexin neurons and CB1R expression after chronic sleep deprivation. Adult male Wistar rats (200-250 g) were randomly divided into three groups: control + vehicle (Control), chronic sleep deprivation + vehicle (SD), and chronic sleep deprivation +20 mg/kg AEA (SD + A). For SD induction, the rats were kept in a sleep deprivation device for 18 h (7 a.m. to 1 a.m.) daily for 21 days. Weight gain, food intake, the electrical power of orexin neurons, CB1R mRNA expression in hypothalamus, CB1R protein expression in the LH, TNF-α, IL-6, IL-4 levels and antioxidant activity in hypothalamus were measured after SD induction. Our results showed that AEA administration significantly improved food intake (p < 0.01), Electrical activity of orexin neurons (p < 0.05), CB1R expression in the hypothalamus (p < 0.05), and IL-4 levels (p < 0.05). AEA also reduced mRNA expression of OX1R and OX2R (p < 0.01 and p < 0.05 respectively), also IL-6 and TNF-α (p < 0.01) and MDA level (p < 0.05) in hypothalamic tissue. As a consequence, AEA modulates orexinergic system function and improves food intake by regulating the expression of the CB1 receptor in the LH in sleep deprived rats.

Core body temperature varies according to the time of exercise without affecting orexin-A production in the dorsal hypothalamus in male rats.

Physical exercise differentially increases body temperature according to the time of day, which shows the importance of circadian rhythm in thermal regulation. Given its contribution in central pathways involved in thermoregulation, orexin A could play a role in the regulation of core body temperature during and after exercise. To test this hypothesis, we assessed the effect of exercise, performed at two times of day, on core temperature and on the amount of orexin A in the production zone, i.e., the dorsal hypothalamus. Forty-nine male Wistar rats underwent forced treadmill exercise during the HG phase and HL phase of core temperature. Basal core temperature was recorded continuously for 48 h by implanted telemetric sensors in 11 rats. Regulation of core temperature during exercise (20 min) and after each exercise (60 min) was modeled with a modified logistic-type function. During HG exercise, core temperature curve reached a significantly higher maximum (asymptote: +0.70 ± 0.10 °C) and took longer to attain the strongest inclination of the core temperature regulation curve (Xmid: 3.46 ± 0.72 min). After HG exercise, time of recovery was significantly longer than after HL exercise. In male rats, thermoregulatory response to acute physical exercise was influenced by the time of day. There was no effect of either physical activity or time of day on the level of orexin A in the dorsal hypothalamus. Our results suggest that orexin A in the dorsal hypothalamus is not involved in the effects of physical exercise on thermoregulation.

Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy.

Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.

Cellular Localization of Orexin 1 Receptor in Human Hypothalamus and Morphological Analysis of Neurons Expressing the Receptor.

The orexin system is related to food behavior, energy balance, wakefulness and the reward system. It consists of the neuropeptides orexin A and B, and their receptors, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R). OX1R has selective affinity for orexin A, and is implicated in multiple functions, such as reward, emotions, and autonomic regulation. This study provides information about the OX1R distribution in human hypothalamus. The human hypothalamus, despite its small size, demonstrates a remarkable complexity in terms of cell populations and cellular morphology. Numerous studies have focused on various neurotransmitters and neuropeptides in the hypothalamus, both in animals and humans, however, there is limited experimental data on the morphological characteristics of neurons. The immunohistochemical analysis of the human hypothalamus revealed that OX1R is mainly found in the lateral hypothalamic area, the lateral preoptic nucleus, the supraoptic nucleus, the dorsomedial nucleus, the ventromedial nucleus, and the paraventricular nucleus. The rest of the hypothalamic nuclei do not express the receptor, except for a very low number of neurons in the mammillary bodies. After identifying the nuclei and neuronal groups that were immunopositive for OX1R, a morphological and morphometric analysis of those neurons was conducted using the Golgi method. The analysis revealed that the neurons in the lateral hypothalamic area were uniform in terms of their morphological characteristics, often forming small groups of three to four neurons. A high proportion of neurons in this area (over 80%) expressed the OX1R, with particularly high expression in the lateral tuberal nucleus (over 95% of neurons). These results were analyzed, and shown to represent, at the cellular level, the distribution of OX1R, and we discuss the regulatory role of orexin A in the intra-hypothalamic areas, such as its special role in the plasticity of neurons, as well as in neuronal networks of the human hypothalamus.

Effects of light therapy on sleep/wakefulness, daily rhythms, and the central orexin system in a diurnal rodent model of seasonal affective disorder.

BACKGROUND: Bright light therapy (BLT) is the first-line treatment for seasonal affective disorder. However, the neural mechanisms underlying BLT are unclear. To begin filling this gap, the present study examined the impact of BLT on sleep/wakefulness, daily rhythms, and the wakefulness-promoting orexin/hypocretin system in a diurnal rodent, Nile grass rats (Arvicanthis niloticus). METHODS: Male and female grass rats were housed under a 12:12 h light/dark cycle with dim light (50 lx) during the day. The experimental group received daily 1-h early morning BLT (full-spectrum white light, 10,000 lx), while the control group received narrowband red light for 4 weeks. Sleep/wakefulness and in-cage locomotor activity were monitored, followed by examination of hypothalamic prepro-orexin and orexin receptors OX1R and OX2R expression in corticolimbic brain regions. RESULTS: The BLT group had higher wakefulness during light treatment, better nighttime sleep quality, and improved daily rhythm entrainment compared to controls. The impact of BLT on the orexin system was sex- and brain region-specific, with males showing higher OX1R and OX2R in the CA1, while females showed higher prepro-orexin but lower OX1R and OX2R in the BLA, compared to same-sex controls. LIMITATIONS: The present study focused on the orexin system in a limited number of brain regions at a single time point. Sex wasn't a statistical factor, as male and female cohorts were run independently. CONCLUSIONS: The diurnal grass rats show similar behavioral responses to BLT as humans, thus could be a good model for further elucidating the neural mechanisms underlying the therapeutic effects of BLT.

Changes in sensorimotor cortex oscillatory activity by orexin-A in the ventrolateral preoptic area of the hypothalamus reflect increased muscle tone.

Orexin-A (OXA) is a hypothalamic neuropeptide implicated in the regulation of wakefulness, appetite, reward processing, muscle tone, motor activity, and other physiological processes. The broad range of systems affected stems from the widespread projections of orexin neurons toward multiple brain regions regulating numerous physiological processes. Orexin neurons integrate nutritional, energetic, and behavioral cues and modulate the functions of target structures. Orexin promotes spontaneous physical activity (SPA), and we recently showed that orexin injected into the ventrolateral preoptic area (VLPO) of the hypothalamus increases behavioral arousal and SPA in rats. However, the specific mechanisms underlying the role of orexin in physical activity are unknown. Here we tested the hypothesis that OXA injected into the VLPO alters the oscillatory activity in the electroencephalogram (EEG) to reflect an increased excitability of the sensorimotor cortex, which may explain the associated increase in SPA. The results showed that OXA increased wakefulness following injections into the VLPO. In addition, OXA altered the power spectrum of the EEG during the awake state by decreasing the power of 5-19 Hz oscillations and increasing the power of >35 Hz oscillations, which are markers of increased sensorimotor excitability. Consistently, we found that OXA induced greater muscle activity. Furthermore, we found a similar change in power spectrum during slow-wave sleep, which suggests that OXA altered the EEG activity in a fundamental way, even in the absence of physical activity. These results support the idea that OXA increases the excitability of the sensorimotor system, which may explain the corresponding increase in awake time, muscle tone, and SPA.

Sensitivity of Hypocretin System to Chronic Alcohol Exposure: A Human and Animal Study.

Human heroin addicts and mice administered morphine for a 2 week period show a greatly increased number of hypothalamic hypocretin (Hcrt or orexin) producing neurons with a concomitant reduction in Hcrt cell size. Male rats addicted to cocaine similarly show an increased number of detectable Hcrt neurons. These findings led us to hypothesize that humans with alcohol use disorder (AUD) would show similar changes. We now report that humans with AUD have a decreased number and size of detectable Hcrt neurons. In addition, the intermingled melanin concentrating hormone (MCH) neurons are reduced in size. We saw no change in the size and number of tuberomammillary histamine neurons in AUD. Within the Hcrt/MCH neuronal field we found that microglia cell size was increased in AUD brains. In contrast, male rats with 2 week alcohol exposure, sufficient to elicit withdrawal symptoms, show no change in the number or size of Hcrt, MCH and histamine neurons, and no change in the size of microglia. The present study indicates major differences between the response of Hcrt neurons to opioids and that to alcohol in human subjects with a history of substance abuse.

Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity.

OBJECTIVE: Orexin-A (OX-A) is a neuropeptide produced selectively by neurons of the lateral hypothalamus. It exerts powerful control over brain function and physiology by regulating energy homeostasis and complex behaviors linked to arousal. Under conditions of chronic or acute brain leptin signaling deficiency, such as in obesity or short-term food deprivation, respectively, OX-A neurons become hyperactive and promote hyperarousal and food seeking. However, this leptin-dependent mechanism is still mostly unexplored. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) is known to be implicated in food consumption by promoting hyperphagia and obesity, and we and others demonstrated that OX-A is a strong inducer of 2-AG biosynthesis. Here, we investigated the hypothesis that, under acute (6 h fasting in wt mice) or chronic (in ob/ob mice) hypothalamic leptin signaling reduction, OX-A-induced enhancement of 2-AG levels leads to the production of the 2-AG-derived 2-arachidonoyl-sn-glycerol-3-phosphate (2-AGP), a bioactive lipid belonging to the class of lysophosphatidic acids (LPAs), which then regulates hypothalamic synaptic plasticity by disassembling α-MSH anorexigenic inputs via GSK-3ß-mediated Tau phosphorylation, ultimately affecting food intake. METHODS: We combined cell-type-specific morphological (CLEM and confocal microscopy), biochemical, pharmacological, and electrophysiological techniques to dissect the leptin- and OX-A/2-AGP-mediated molecular pathways regulating GSK-3ß-controlled pT231-Tau production at POMC neurons of obese ob/ob and wild-type (wt) lean littermate mice and in an in vitro model of POMC neurons such as mHypoN41 neurons (N41). RESULTS: 2-AGP is overproduced in the hypothalamus of obese leptin-deficient, or lean 6 h food-deprived mice, and promotes food intake by reducing α-MSH-expressing synaptic inputs to OX-A neurons via lysophosphatidic acid type-1 receptor (LPA1-R) activation, and pT231-Tau accumulation in α-MSH projections. This effect is due to the activation of the Pyk2-mediated pTyr216-GSK3ß pathway and contributes to further elevating OX-A release in obesity. Accordingly, we found a strong correlation between OX-A and 2-AGP levels in the serum of obese mice and of human subjects. CONCLUSIONS: Hypothalamic feeding pathways are endowed with 2-AGP-mediated synaptic plasticity according to their inherent functional activities and the necessity to adapt to changes in the nutritional status. These findings reveal a new molecular pathway involved in energy homeostasis regulation, which could be targeted to treat obesity and related disturbances.

The hypothalamic neuropeptide, QRFP, regulates high fat diet intake in female Long-Evans rats following ovariectomy.

Obesity rates in women continue to increase throughout the lifespan and obesity-related comorbidities are prevalent in women in estrogen deficiency. The hypothalamic neuropeptide, QRFP, is an orexigenic peptide that increases the intake of high fat diet (HFD) in female rats and is overexpressed following ovariectomy (OVX). Therefore, the goal of the current series of experiments was to elucidate the effect of QRFP on HFD intake following OVX and determine if QRFP-26 administration in ovariectomized females altered expression of prepro-neuropeptide Y (NPY), agouti-related peptide (AgRP) and proopiomelanocortin (POMC) mRNA in the mediobasal hypothalamus (MBH) and prepro-orexin in the lateral hypothalamus (LH). The intake of HFD was measured following acute administration of QRFP-26 prior to or following estradiol benzoate (EB) treatment in ovariectomized females. When administered prior to EB treatment, QRFP-26 increased HFD intake. EB treatment attenuated the effects of QRFP-26 on HFD intake. Sub-chronic, continuous administration of QRFP-26 increased HFD intake and weight gain following OVX. Subchronic, continuous administration of QRFP siRNA into the 3rd ventricle via osmotic pump decreased prepro-QRFP mRNA levels in the MBH by ∼75%, decreased HFD intake and decreased weight gain following OVX. QRFP-26administration did not alter the expression of prepro-NPY, AgRP or POMC mRNA in the MBH, but decreased prepro-orexin mRNA in the LH of ovariectomized females. Overall, results from these studies support the orexigenic neuropeptide, QRFP, as an important mediator of the ingestion of highly palatable foods and subsequent weight gain in females during estrogen deficiency.

The orphan G protein-coupled receptor, GPR139, is expressed in the hypothalamus and is involved in the regulation of body mass, blood glucose, and insulin.

GPR139 is an orphan G-protein-coupled receptor that is expressed in restricted areas of the nervous system, including the hypothalamus. In this study, we hypothesized that GPR139 could be involved in the regulation of energy balance and metabolism. In the first part of the study, we confirmed that GPR139 is expressed in the hypothalamus and particularly in proopiomelanocortin and agouti-related peptide neurons of the mediobasal hypothalamus. Using a lentivirus with a short-hairpin RNA, we inhibited the expression of GPR139 bilaterally in the mediobasal hypothalamus of mice. The intervention promoted a 40% reduction in the hypothalamic expression of GPR139, which was accompanied by an increase in body mass, a reduction in fasting blood glucose levels, and an increase in insulin levels. In the hypothalamus, inhibition of GPR139 was accompanied by a reduction in the expression of orexin. As previous studies using a pharmacological antagonist of orexin showed a beneficial impact on type 2 diabetes and glucose metabolism, we propose that the inhibition of hypothalamic GPR139 could be acting indirectly through the orexin system to control systemic glucose and insulin. In conclusion, this study advances the characterization of GPR139 in the hypothalamus, demonstrating its involvement in the regulation of body mass, blood insulin, and glycemia.

Dorsoventral Arrangement of Lateral Hypothalamus Populations in the Mouse Hypothalamus: a Prosomeric Genoarchitectonic Analysis.

The lateral hypothalamus (LH) has a heterogeneous cytoarchitectonic organization that has not been elucidated in detail. In this work, we analyzed within the framework of the prosomeric model the differential expression pattern of 59 molecular markers along the ventrodorsal dimension of the medial forebrain bundle in the mouse, considering basal and alar plate subregions of the LH. We found five basal (LH1-LH5) and four alar (LH6-LH9) molecularly distinct sectors of the LH with neuronal cell groups that correlate in topography with previously postulated alar and basal hypothalamic progenitor domains. Most peptidergic populations were restricted to one of these LH sectors though some may have dispersed into a neighboring sector. For instance, histaminergic Hdc-positive neurons were mostly contained within the basal LH3, Nts (neurotensin)- and Tac2 (tachykinin 2)-expressing cells lie strictly within LH4, Hcrt (hypocretin/orexin)-positive and Pmch (pro-melanin-concentrating hormone)-positive neurons appeared within separate LH5 subdivisions, Pnoc (prepronociceptin)-expressing cells were mainly restricted to LH6, and Sst (somatostatin)-positive cells were identified within the LH7 sector. The alar LH9 sector, a component of the Foxg1-positive telencephalo-opto-hypothalamic border region, selectively contained Satb2-expressing cells. Published studies of rodent LH subdivisions have not described the observed pattern. Our genoarchitectonic map should aid in systematic approaches to elucidate LH connectivity and function.

The opposite roles of orexin neurons in pain and itch neural processing.

Pain and itch are antagonistically regulated sensations; pain suppresses itch, and inhibition of pain enhances itch. Understanding the central neural circuit of antagonistic regulation between pain and itch is required to develop new therapeutics better to manage these two feelings in a clinical situation. However, evidence of the neural mechanism underlying the pain-itch interaction in the central nervous system (CNS) is still insufficient. To pave the way for this research area, our laboratory has focused on orexin (ORX) producing neurons in the hypothalamus, which is known as a master switch that induces various defense responses when animals face a stressful environment. This review article summarized the previous evidence and our latest findings to argue the neural regulation between pain and itch and the bidirectional roles of ORX neurons in processing these two sensations. i.e., pain relief and itch exacerbation. Further, we discussed the possible neural circuit mechanism for the opposite controlling of pain and itch by ORX neurons. Focusing on the roles of ORX neurons would provide a new perspective to understand the antagonistic regulation of pain and itch in CNS.

Acupuncture Interventions for Alzheimer's Disease and Vascular Cognitive Disorders: A Review of Mechanisms.

Cognitive impairment (CI) related to Alzheimer's disease (AD) and vascular cognitive disorders (VCDs) has become a key problem worldwide. Importantly, CI is a neuropsychiatric abnormality mainly characterized by learning and memory impairments. The hippocampus is an important brain region controlling learning and memory. Recent studies have highlighted the effects of acupuncture on memory deficits in AD and VCDs. By reviewing the literature published on this topic in the past five years, the present study intends to summarize the effects of acupuncture on memory impairment in AD and VCDs. Focusing on hippocampal synaptic plasticity, we reviewed the mechanisms underlying the effects of acupuncture on memory impairments through regulation of synaptic proteins, AD characteristic proteins, intestinal microbiota, neuroinflammation, microRNA expression, orexin system, energy metabolism, etc., suggesting that hippocampal synaptic plasticity may be the common as well as the core link underlying the above mechanisms. We also discussed the potential strategies to improve the effect of acupuncture. Additionally, the effects of acupuncture on synaptic plasticity through the regulation of vascular-glia-neuron unit were further discussed.