Orexins

Stress is considered to be an important cause of disrupted sleep and insomnia. However, controlled and experimental studies in rodents indicate that effects of stress on sleep–wake regulation are complex and may strongly depend on the nature of the stressor. While most stressors are associated with at least a brief period of arousal and wakefulness, the subsequent amount and architecture of recovery sleep can vary dramatically across conditions even though classical markers of acute stress such as corticosterone are virtually the same. Sleep after stress appears to be highly influenced by situational variables including whether the stressor was controllable and/or predictable, whether the individual had the possibility to learn and adapt, and by the relative resilience and vulnerability of the individual experiencing stress. There are multiple brain regions and neurochemical systems linking stress and sleep, and the specific balance and interactions between these systems may ultimately determine the alterations in sleep–wake architecture. Factors that appear to play an important role in stress-induced wakefulness and sleep changes include various monominergic neurotransmitters, hypocretins, corticotro-pin releasing factor, and prolactin. In addition to the brain regions directly involved in stress responses such as the hypothalamus, the locus coeruleus, and the amygdala, differential effects of stressor controllability on behavior and sleep may be mediated by the medial prefrontal cortex. These various brain regions interact and influence each other and in turn affect the activity of sleep–wake controlling centers in the brain. Also, these regions likely play significant roles in memory processes and participate in the way stressful memories may affect arousal and sleep. Finally, stress-induced changes in sleep-architecture may affect sleep-related neuronal plasticity processes and thereby contribute to cognitive dysfunction and psychiatric disorders.

BACKGROUND AND PURPOSE:
Many studies have demonstrated a role of hypocretin 1 (orexin 1) receptors in home-cage food consumption in rodents. However, the role of these receptors in operant food self-administration or relapse to food seeking in animal models is unknown.

EXPERIMENTAL APPROACH:
In Experiment 1, we trained food-restricted rats (16-20 g per day) to lever press for high-fat (35%) pellets (3-6 h per day, every other day). We then tested the effect of the hypocretin 1 receptor antagonist SB 334867 (10, 20 mg kg(-1), i.p) on pellet self-administration. In Experiment 2, we trained rats to self-administer the food pellets, and following extinction of the food-reinforced responding, we tested the effect of hypocretin 1 (3 and 6 mug, i.c.v) on reinstatement of food-seeking and the effect of SB 334867 on this reinstatement. In Experiment 3, we tested the effect of SB 334867 on reinstatement induced by non-contingent pellet exposure (pellet-priming) or the pharmacological stressor yohimbine (2 mg kg(-1), i.p).

KEY RESULTS:
SB 334867 attenuated high-fat pellet self-administration. In contrast, SB 334867 had no effect on reinstatement of lever presses induced by hypocretin 1, pellet-priming or yohimbine.

CONCLUSIONS AND IMPLICATIONS:
These data indicate that during dieting, hypocretin 1 receptors contribute to operant high-fat pellet self-administration, but not to relapse to food seeking induced by acute re-exposure to the food itself or by the induction of a stress-like state.

There is an unmet need of pharmacological and non-pharmacological treatment options for migraine patients. Exercise can be used in the treatment of several pain conditions, including. However, what exact role exercise plays in migraine prevention is unclear. Here, we review the associations between physical exercise and migraine from an epidemiological, therapeutical and pathophysiological perspective. The review was based on a primary literature search on the PubMed using the search terms "migraine and exercise". Low levels of physical exercise and high frequency of migraine has been reported in several large population-based studies. In experimental studies exercise has been reported as a trigger factor for migraine as well as migraine prophylaxis. Possible mechanisms for how exercise may trigger migraine attacks, include acute release of neuropeptides such as calcitonin gene-related peptide or alternation of hypocretin or lactate metabolism. Mechanisms for migraine prev...

Sleep has been conserved throughout evolution; however, the molecular and neuronal mechanisms of sleep are largely unknown. The hypothalamic hypocretin/orexin (Hcrt) neurons regulate sleep\wake states, feeding, stress, and reward. To elucidate the mechanism that enables these various functions and to identify sleep regulators, we combined fluorescence cell sorting and RNA-seq inhcrt:EGFPzebrafish. Dozens of Hcrt-neuron–specific transcripts were identified and comprehensive high-resolution imaging revealed gene-specific localization in all or subsets of Hcrt neurons. Clusters of Hcrt-neuron–specific genes are predicted to be regulated by shared transcription factors. These findings show that Hcrt neurons are heterogeneous and that integrative molecular mechanisms orchestrate their diverse functions. The voltage-gated potassium channel Kcnh4a, which is expressed in all Hcrt neurons, was silenced by the CRISPR-mediated gene inactivation system. The mutantkcnh4a (kcnh4a-/-) larvae showe...

Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin(+) neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin(+) neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 a...

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORX...

Orexin neurons, and activation of orexin receptors, are generally thought to be sympathoexcitatory; however, the functional connectivity between orexin neurons and a likely sympathetic target, the hypothalamic spinally projecting neurons (SPNs) in the paraventricular nucleus of the hypothalamus (PVN) has not been established. To test the hypothesis that orexin neurons project directly to SPNs in the PVN, channelrhodopsin-2 (ChR2) was selectively expressed in orexin neurons to enable photoactivation of ChR2-expressing fibers while examining evoked postsynaptic currents in SPNs in rat hypothalamic slices. Selective photoactivation of orexin fibers elicited short-latency postsynaptic currents in all SPNs tested (n = 34). These light-triggered responses were heterogeneous, with a majority being excitatory glutamatergic responses (59%) and a minority of inhibitory GABAergic (35%) and mixed glutamatergic and GABAergic currents (6%). Both glutamatergic and GABAergic responses were present ...

The present study describes the nuclear organization of the cholinergic, catecholaminergic, serotonergic and orexinergic systems in the brains of the springhare and Beecroft’s scaly-tailed squirrel following immunohistochemical labelling. We aimed to investigate any differences in the nuclear organization of these neural systems when compared to previous data on other species of rodents, as these two rodent species have relatively large brains – 1.2 to 1.4 times larger than would be expected for mammals of their body mass and 1.7 – 1.9 times larger than would be expected for rodents of their body mass. A series of coronal sections were taken through two brains of each species and immunohistochemically labelled with antibodies against choline acetyltransferase, tyrosine hydroxylase, serotonin and orexin-A. Generally, the nuclear complement of these systems revealed extensive similarities between both species and to previously studied rodents. While no differences were observed in the nuclear complement of the serotonergic and orexinergic systems, some differences were observed in the nuclear complement of the cholinergic and catecholaminergic systems. These include the presence of cholinergic neurons in the cerebral cortex and nucleus of the trapezoid body in the springhare; while the Beecroft’s scaly-tailed squirrel exhibited cholinergic neurons in the pretectal area of the midbrain. For the catecholaminergic system it was observed that Beecroft’s scaly-tailed squirrel possessed immunoreactive neurons in the accessory olfactory bulb. Despite these four differences, most not previously observed in rodents, the remaining complement of cholinergic and catecholaminergic nuclei were identical to that observed in other rodents, including the presence of the rodent specific catecholaminergic rostral dorsal midline medullary (C3) nucleus in the medulla oblongata. Thus, even with a significant increase in relative brain size, the overall complement of nuclei forming these systems shows minimal changes in complexity within a specific mammalian order.

Several neurotransmitter systems and circulating factors regulate rapid eye movement (REM) sleep, non-REM (NREM) sleep, and wakefulness (W). The nuclei involved in the occurrence of W are located in the brainstem, hypothalamus, and the basal forebrain (BFB). These corresponding to the brainstem include the dorsal raphe nucleus (serotonergic neurons); locus coeruleus (noradrenergic neurons); ventral tegmental area, substantia nigra compacta, and ventral periaqueductal gray matter (dopaminergic neurons); and laterodorsal and pedunculopontine tegmental nuclei (cholinergic neurons). The structures found in the hypothalamus comprise the tuberomammillary nucleus (histaminergic neurons) and the posterior and lateral hypothalamus around the fornix (orexinergic neurons). The cholinergic neurons of the BFB are located mainly in the diagonal band of Broca, substantia innominata, and the medial septal area. The NREM sleep-inducing system comprises neurons located in the preoptic area, which contains Gamma-Aminobutyric Acid (GABA) and galanin, and cells containing melanin-concentrating hormone located in the lateral hypothalamus and incertohypothalamic area. The latter is also involved in the regulation of REM sleep. Somnogens, including adenosine (formed mainly by the breakdown of adenosine nucleotides), prostaglandin D2 (which is mainly present in the leptomeninges, choroid plexus, and oligodendrocytes), nitric oxide (synthesized predominantly from L-arginine), and cytokine promote also sleep, mainly NREM sleep. Melatonin is a hormone secreted during the night from the pineal gland and has a weak sleep-promoting effect in humans. The subcoeruleus nucleus has been proposed as the critical area for REM sleep regulation in the cat. Its equivalent in the rat is called the sublaterodorsal nucleus. The REM sleep generation region includes mainly glutamatergic and GABAergic neurons.
Sleep timing depends on two factors, sleep debt (process S; homeostasis) and circadian control (process C). When process S approaches the upper boundary, it triggers sleep. On the other hand, the markers of process C include melatonin and core body temperature

To evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence. Cross-sectional. Sleep laboratory. One hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and "subjective" hypersomnolence (sHS, n = 52). None. Polysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1. Sleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients...

Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10-4), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10-3), and B*35:01 (OR=...

The loss of specific neuronal phenotypes, as determined by immunohistochemistry, has become a powerful tool for identifying the nature and cause of neurological diseases. Here we show that the number of neurons identified and quantified using this method misses a substantial percentage of extant neurons in a phenotype specific manner. In mice, 24% more hypocretin/orexin (Hcrt) neurons are seen in the night compared to the day, and an additional 17% are seen after inhibiting microtubule polymerization with colchicine. We see no such difference between the number of MCH (melanin concentrating hormone) neurons in dark, light or colchicine conditions, despite MCH and Hcrt both being hypothalamic peptide transmitters. Although the size of Hcrt neurons did not differ between light and dark, the size of MCH neurons was increased by 15% in the light phase. The number of neurons containing histidine decarboxylase (HDC), the histamine synthesizing enzyme, was 34% greater in the dark than in t...

Neuropeptides orexin A and orexin B, which are exclusively produced by neurons in the lateral hypothalamic area, play an important role in the regulation of a wide range of behaviors and homeostatic processes, including regulation of sleep/wakefulness states and energy homeostasis. The orexin system has close anatomical and functional relationships with systems that regulate the autonomic nervous system, emotion, mood, the reward system, and sleep/wakefulness states. Recent pharmacological studies using selective antagonists have suggested that orexin receptor-1 (OX1R) is involved in physiological processes that regulate emotion, the reward system, and autonomic nervous system. Here, we examined Ox1r (-/-) mice with a comprehensive behavioral test battery to screen additional OX1R functions. Ox1r (-/-) mice showed increased anxiety-like behavior, altered depression-like behavior, slightly decreased spontaneous locomotor activity, reduced social interaction, increased startle respons...

Basic experiments support the impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Our aim was to assess the frequencies of smoking, alcohol and drug use, abuse and dependence in narcolepsy type 1 (NT1, hypocretin-deficient), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) (non-hypocretin-deficient conditions), in comparison to controls. We hypothesized that NT1 patients would be less vulnerable to drug abuse and addiction compared to other hypersomniac patients and controls from general population. We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 450 adult patients (median age 35 years; 41.3% men) with NT1 (n = 243), NT2 (n = 116), IH (n = 91), and 710 adult controls. All participants were evaluated for alcohol consumption, smoking habits, and substance (alcohol and illicit drug) abuse and dependence diagnosis during the past year using the Mini International Neuropsychiatric I...

Cardiac arrest (CA) affects >550,000 people annually in the United States whereas 80–90% of survivors suffer from a comatose state. Arousal from coma is critical for recovery, but mechanisms of arousal are undefined. Orexin-A, a hypothalamic excitatory neuropeptide, has been linked to arousal deficits in various brain injuries. We investigated the orexinergic system's role in recovery from CA-related neurological impairments, including arousal deficits. Using an asphyxial CA and resuscitation model in rats, we examine neurological recovery post-resuscitation in conjunction with changes in orexin-A levels in cerebrospinal fluid (CSF) and orexin-expressing neurons. We also conduct pharmacological inhibition of orexin post-resuscitation. We show that recovery from neurological deficits begins between 4 and 24 h post-resuscitation, with additional recovery by 72 h post-resuscitation. Orexin-A levels in the CSF are lowest during periods of poorest arousal post-resuscitation (4 h) and recover to control levels by 24 h. Immunostaining revealed that the number of orexin-A immunoreactive neurons declined at 4 h post-resuscitation, but increased to near normal levels by 24 h. There were no significant changes in the number of neurons expressing melanin-concentrating hormone, another neuropeptide localized in similar hypothalamus regions. Last, administration of the dual orexin receptor antagonist, suvorexant, during the initial 24 h post-resuscitation, led to sustained neurological deficits. The orexin pathway is critical during early phases of neurological recovery post-CA. Blocking this early action leads to persistent neurological deficits. This is of considerable clinical interest given that suvorexant recently received U.S. Food and Drug Administration approval for insomnia treatment.. Abstract text download from ncbi.nlm.nih.gov

The lateral hypothalamus (LH) orexinergic neurons project to numerous brain regions implicated in pain perception, including the CA1 part of the hippocampal formation. Moreover, the roles of orexin receptors (OXRs) in the CA1 in anti-analgesic consequences of the LH chemical stimulation by carbachol, muscarinic receptor agonist, in acute pain have not been clarified. The current research showed OXRs antagonist administration's effect in the CA1 on analgesia elicited by the LH chemical stimulation in a tail-flick test as an acute model of pain. The control groups, including vehicle-control groups, were given intra-LH administration of saline (0.5 μL), following intra-CA1 infusion of DMSO (12 %; 0.5 μL), and carbachol-control groups were treated with carbachol (250 nM/0.5 μL saline) into the LH following DMSO in the CA1. Treated groups received SB334867 (1, 3, 10, and 30 nM/0.5 μL DMSO) or TCS OX2 29 (0.1, 1, 10, and 20 nM/0.5 μL DMSO) as OX1R or OX2R antagonist, respectively, in the CA1 prior intra-LH administration of carbachol. After all injections, all rats underwent the tail-flick test over a 60min time. Infusion of SB334867 or TCS OX2 29 in the CA1 impaired the analgesic consequences following chemical stimulation of the LH in acute pain. Meanwhile suppressive impact of the OX1R or OX2R antagonist on the analgesic impact of LH chemical stimulation was approximately identical. The current investigation provided a new document about the critical involvement of hippocampal orexinergic system in the modulatory role of the LH-CA1 path in pain perception.

Kleine-Levin syndrome (KLS) is a rare disorder of relapsing sleepiness. The hypothesis was that the syndrome is related to a change in the vigilance peptide orexin A. From 2002 to 2013, 57 patients with relapsing hypersomnolence were clinically assessed in a referral academic center in Beijing, China, and 44 (28 males and 16 females; mean age 18.3 ± 8.9 y (mean ± standard deviation, range 9-57 y) were determined to have clinical and behavioral criteria consistent with KLS. Cerebrospinal fluid orexin A levels and diurnal blood pressure were measured in relapse versus remission in a subgroup of patients. Presenting symptoms included relapsing or remitting excessive sleepiness-associated parallel complaints of cognitive changes (82%), eating disorders (84%); depression (45%); irritability (36%); hypersexuality (18%); and compulsions (11%). Episodes were 8.2+/-3.3 days in duration. In relapse, diurnal values for blood pressure and heart rate were lower (P< 0.001). In a subgroup (n = ...

Orexins or hypocretins are neurotransmitters produced by a small population of neurons in the lateral hypothalamus. This family of peptides modulates sleep‑wake cycle, arousal and feeding behaviors; however, the mechanisms regulating their expression remain to be fully elucidated. There is an interest in defining the key molecular elements in orexin regulation, as these may serve to identify targets for generating novel therapies for sleep disorders, obesity and addiction. Our previous studies showed that the expression of orexin was decreased in mice carrying null‑mutations of the transcription factor early B‑cell factor 2 (ebf2) and that the promoter region of the prepro‑orexin (Hcrt) gene contained two putative ebf‑binding sites, termed olf‑1 sites. In the present study, a minimal promoter region of the murine Hcrt gene was identified, which was able to drive the expression of a luciferase reporter gene in the human 293 cell line. Deletion of the olf1‑site proximal to the transcr...

BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system. Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (-16.1±1.6 and -11.0±1.1 mm Hg, respectively;P<0.001 compared with vehicle). However, when...

Type 1 narcolepsy is caused by deficiency of hypothalamic orexin/hypocretin. An autoimmune basis is suspected, but no specific antibodies, either causative or as biomarkers, have been identified. However, the AS03 adjuvanted split virion H1N1 (H1N1-AS03) vaccine, created to protect against the 2009 Pandemic, has been implicated as a trigger of narcolepsy particularly in children. Sera and CSFs from 13 H1N1-AS03-vaccinated patients (12 children, 1 young adult) with type 1 narcolepsy were tested for autoantibodies to known neuronal antigens including the N-methyl-D-aspartate receptor (NMDAR) and contactin-associated protein 2 (CASPR2), both associated with encephalopathies that include disordered sleep, to rodent brain tissue including the lateral hypothalamus, and to live hippocampal neurons in culture. When sufficient sample was available, CSF levels of melanin-concentrating hormone (MCH) were measured. Sera from 44 H1N1-ASO3-vaccinated children without narcolepsy were also examined...

Though overlapping in distribution through the hypothalamus, orexin (Orx) and melanin-concentrating hormone (MCH) neurons play opposite roles in the regulation of sleep-wake states. Orx neurons discharge during waking, whereas MCH neurons discharge during sleep. In the present study, we examined in mice whether GABAA and GABAB receptors (Rs) are present on Orx and MCH neurons and might undergo differential changes as a function of their different activities following sleep deprivation (SD) and sleep recovery (SR). Applying quantitative stereological image analysis to dual-immunofluorescent stained sections, we determined that the proportion of Orx neurons positively immunostained for GABAARs was significantly higher following SD (∼48%) compared with sleep control (SC; ∼24%) and SR (∼27%), and that the luminance of the GABAARs was significantly greater. In contrast, the average proportion of the MCH neurons immunostained for GABAARs was insignificantly lower following SD (∼43%) compa...

Evidence of impaired function of orexin neurons has been found in individuals with cardiorespiratory disorders such as obstructive sleep apnea (OSA) and sudden infant death syndrome (SIDS), but the mechanisms responsible are unknown. Individuals with OSA and SIDS experience repetitive breathing cessations and/or rebreathing of expired air, resulting in hypoxia/hypercapnia (H/H). In this study we examined the responses of fluorescently identified rat orexin neurons in the lateral hypothalamus to acute H/H to test if and how these neurons alter their activity and function during this challenge. Experiments were conducted in an in-vitro slice preparation using voltage-clamp and current-clamp configurations. H/H (10 min) induced hyperpolarization accompanied by rapid depression and finally cessation of firing activity in orexin neurons. Hypoxia alone had similar but less potent effects. H/H did not alter the frequency of inhibitory glycinergic postsynaptic currents. The frequency of GAB...

Nicotine is known to affect the metabolism of glucose; however, the underlying mechanism remains unclear. Therefore, we herein investigated whether nicotine promoted the central regulation of glucose metabolism, which is closely linked to the circadian system. The oral intake of nicotine in drinking water, which mainly occurred during the nighttime active period, enhanced daily hypothalamic prepro-orexin gene expression and reduced hyperglycemia in type 2 diabetic db/db mice without affecting body weight, body fat content and serum levels of insulin. Nicotine administered at the active period appears to be responsible for the effect on blood glucose, because nighttime but not daytime injections of nicotine lowered blood glucose levels in db/db mice. The chronic oral treatment with nicotine suppressed the mRNA levels of glucose-6-phosphatase, the rate-limiting enzyme of gluconeogenesis, in the liver of db/db and wild-type control mice. In the pyruvate tolerance test to evaluate hepat...

While the neural control of glucoregulatory responses to insulin-induced hypoglycemia is beginning to be elucidated, brain sites responsible for behavioral responses to hypoglycemia are relatively poorly understood. To help elucidate central control mechanisms associated with hypoglycemia unawareness, we first evaluated the effect of recurrent hypoglycemia on a simple behavioral measure, the robust feeding response to hypoglycemia, in rats. First, food intake was significantly, and similarly, increased above baseline saline-induced intake (1.1 ± 0.2 g; n = 8) in rats experiencing a first (4.4 ± 0.3; n = 8) or third daily episode of recurrent insulin-induced hypoglycemia (IIH, 3.7 ± 0.3 g; n = 9; P < 0.05). Because food intake was not impaired as a result of prior IIH, we next developed an alternative animal model of hypoglycemia-induced behavioral arousal using a conditioned place preference (CPP) model. We found that hypoglycemia severely blunted previously acquired CPP in rats ...

GnRH neurons integrate internal and external cues to control sexual maturation and fertility. Homeostasis of energy balance and food intake correlates strongly with the status of reproduction. Neuropeptides secreted by the hypothalamus involved in modulating energy balance and feeding may play additional roles in the regulation of reproduction. Hypocretin (also known as orexin) is one such peptide, primarily controlling sleep/wakefulness, food intake, and reward processing. There is a growing body of evidence indicating that hypocretin/orexin (Hcrt) modulates reproduction through interacting with the hypothalamo-pituitary gonadal axis in mammals. To explore potential morphological and functional interactions between the GnRH and Hcrt neuronal systems we employed a variety of experimental approaches including confocal imaging, immunohistochemistry, and electrophysiology in transgenic zebrafish in which fluorescent proteins are genetically expressed in GnRH3 and Hcrt neurons. Our imag...

Orexins are peptide neurotransmitters which are produced in the lateral and posterior part of the hypothalamus in the brain. There are two Orexin receptors which has been identified till date viz. Orexin 1 (OX  1) and Orexin 2 (OX 2 receptor).