Orexin Neurons Research Articles

Dual orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy.

Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unclear how orexin and MCH neurons interact to regulate sleep/wakefulness, we generated transgenic mice in which both orexin and MCH neurons could be ablated. Double-ablated mice exhibited increased wakefulness and decreased both rapid eye movement (REM) and non-REM (NREM) sleep. Double-ablated mice showed severe cataplexy compared with orexin neuron-ablated mice, suggesting that MCH neurons normally suppress cataplexy. Double-ablated mice also showed frequent sleep attacks with elevated spectral power in the delta and theta range, a unique state that we call 'delta-theta sleep'. Together, these results indicate a functional interaction between orexin and MCH neurons in vivo that suggests the synergistic involvement of these neuronal populations in the sleep/wakefulness cycle.

Deep brain stimulation of hypothalamus for narcolepsy-cataplexy in mice

BackgroundNarcolepsy type 1 (NT1, narcolepsy with cataplexy) is a disabling neurological disorder caused by loss of excitatory orexin neurons from the hypothalamus and is characterized by decreased motivation, sleep-wake fragmentation, intrusion of rapid-eye-movement sleep (REMS) during wake, and abrupt loss of muscle tone, called cataplexy, in response to sudden emotions. ObjectiveWe investigated whether subcortical stimulation, analogous to clinical deep brain stimulation (DBS), would ameliorate NT1 using a validated transgenic mouse model with postnatal orexin neuron degeneration. MethodsUsing implanted electrodes in freely behaving mice, the immediate and prolonged effects of DBS were determined upon behavior using continuous video-electroencephalogram-electromyogram (video/EEG/EMG) and locomotor activity, and neural activation in brain sections, using immunohistochemical labeling of the immediate early gene product c-Fos. ResultsBrief 10-s stimulation to the region of the lateral hypothalamus and zona incerta (LH/ZI) dose-responsively reversed established sleep and cataplexy episodes without negative sequelae. Continuous 3-h stimulation increased ambulation, improved sleep-wake consolidation, and ameliorated cataplexy. Brain c-Fos from mice sacrificed after 90 min of DBS revealed dose-responsive neural activation within wake-active nuclei of the basal forebrain, hypothalamus, thalamus, and ventral midbrain. ConclusionAcute and continuous LH/ZI DBS enhanced behavioral state control in a mouse model of NT1, supporting the feasibility of clinical DBS for NT1 and other sleep-wake disorders.

Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior in male mice.

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have various negative effects on patients, their families, and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, domination of subordinate social targets is reinforcing. Here, we show that in male mice, orexin neurons in the lateral hypothalamus activate a small population of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2). and activation of these GAD2 neurons promotes male–male aggression and conditioned place preference (CPP) for aggression-paired contexts. Moreover, LHb GAD2 neurons are inhibitory within the LHb and dampen the activity of the LHb as a whole. These results suggest that the orexin system is important for the regulation of inter-male aggressive behavior and provide the first functional evidence of a local inhibitory circuit within the LHb.

Orexin Maintains Ventilation During a Critical Window of Postnatal Life

Orexinergic neurons in the lateral and perifornical hypothalamus project widely to respiratory regions of the brainstem. Also, orexin neurons are active in wakefulness and silent in sleep. In adult animals, chronic orexin deficiency reduces the respiratory response to CO2, but has no apparent effect on resting ventilation. The acute effects of orexin on breathing have not been described in adult or infant animals. This topic is important because narcoleptic patients have a higher incidence of sleep apnea, and there is pathological evidence of orexinergic dysfunction in Sudden Infant Death Syndrome (SIDS). SIDS is a leading cause of infant death that occurs in sleep, or in transitions between wakefulness and sleep. Most cases occur between 2–6 months of age (i.e. a “critical window” of development). There is evidence of respiratory defects associated with SIDS, including severe hypoventilation prior to death. We hypothesized that orexin receptor blockade would lead to acute hypoventilation in a vigilance state and age‐dependent manner. To test this hypothesis, we used whole‐body plethysmography to monitor the breathing of infant (postnatal days 7–8, 12–14, 17–19) and adult rats (~2 months old) treated with suvorexant, a selective orexin 1 and 2 receptor antagonist, via an intra‐abdominal catheter. In pups, we determined vigilance state using standard behavioral criteria, confirmed by video. In adults, vigilance state was determined with EMG and EEG, and by applying Fast Fourier Transform to the EEG and EMG signals. Pups were studied during the light period, and adults were tested during the transition from the dark to light period, when orexin levels peak. Rats cycled through quiet wakefulness (QW), quiet sleep (QS, or NREM in adults) and active sleep (AS, or REM in adults) for at least 1 hour, at which point suvorexant (5 mg/kg in 50% DMSO, for pups; 20 mg/kg in 100% DMSO, for adults) or vehicle alone was administered. Pups and adults were monitored for another 1 hr or 2 hr, respectively. We analyzed the effects of suvorexant on respiratory frequency (f), tidal volume (VT), and the ventilatory equivalent (VE/VO2) in QW, QS/NREM, and AS/REM. Separate groups of 2‐week‐old pups were used to test the effects of suvorexant on resting blood gases, and the ventilatory chemoreflex responses to 5% CO2 or hyperoxia (100% O2). In P12‐14 pups, suvorexant significantly reduced f in all states, VT only in QS, and VE/VO2 in QW and QS. These effects were absent at all other ages. Hypoventilation in P12‐14 pups was confirmed by blood gas analysis. Suvorexant appears to have no effect on ventilatory responses to CO2 or hyperoxia. These results suggest that orexin preserves eupneic breathing in QW and QS only during a critical window of neonatal life (P12‐14). Orexin stimulates breathing independently of the drive provided by the central or peripheral chemoreceptors. Defects in the orexin system may predispose an infant to SIDS during a critical window of development by increasing the risk of hypoventilation during periods of sleep, or transitions between sleep and wakefulness.Support or Funding InformationFunding: National Institute of Health (5R01HL136710‐02) to Kevin James Cummings

Disruption of estrogen regulation of orexin neurons: a novel mechanism in the pathophysiology of respiratory manifestations of panic disorder in females

Panic disorder (PD) is an anxiety disorder that affects ~5% of the population. A significant group of PD patients are characterised by excessive behavioral and physiological responses to CO2 inhalation. The prevalence of PD is 2 to 3 times more frequent in women yet, the origins of this sexual dimorphism are unknown; the fact that excessive responsiveness to CO2 inhalation peaks during the pre‐menstrual phase suggest a role of ovarian hormones. Early life stress is a significant risk factor for PD and there is growing evidence indicating that stress‐related increase in the function of orexin‐producing neurons (ORX) is key to PD. Based on data suggesting that 17b‐estradiol (E2) inhibits ORX, we tested the hypothesis that insufficient E2‐regulation of ORX neurons contributes to stress‐related respiratory manifestations of PD in females. Experiments were performed on adult female rats previously subjected to neonatal maternal separation (NMS; 3h/day postnatal days 3 to 12) or raised under standard conditions. In this model, NMS females show an excessive hyperventilatory response to CO2 by comparison with controls; this effect is greatest during the proestrus phase. Inactivation of ORX1 receptors by SB 33486 (15 mg/kg; ip) prevents this effect. Whole cell recordings (voltage clamp) were performed on GFP‐labeled ORX neurons by AAV microinjection. Excitatory post‐synaptic currents (EPSCs) converging onto ORX neurons were recorded under basal conditions and following E2 bath application (100nM; 10 min). Monitoring of the estrus cycle showed that in control females, EPSC frequency was inversely proportional to circulating E2 levels associated with each phase. This relationship was not observed in NMS females; EPSC frequency of NMS females was greater than controls during the proestrus phase. E2 application reduced EPSC frequency (but not amplitude); however, this effect was not affected by stress or the estrus cycle phase. We conclude that NMS disrupts E2‐mediated inhibition of ORX neurons. This is a novel mechanism in the pathophysiology of PD.Support or Funding InformationSupported by an operating grant from the Canadian Institutes of Health Research

Orexin in Respiratory and Autonomic Regulation, Health and Diseases.

Orexin neurons, located in the hypothalamus, produce orexin-A and orexin-B neuropeptides and send widespread projections throughout the central nervous system, including many nuclei that are critically involved in sleep-wake, cardiorespiratory, and autonomic regulation. Significant progress has been made to better understand the roles of orexins in the control of breathing and autonomic functions since the discovery of orexins in 1998. Orexin neurons are CO2 /pH chemosensitive and blockade of orexin receptors with orexin receptor antagonists can significantly attenuate ventilatory response to hypercapnia or CO2 chemoreflex. Animal models with orexin abnormalities, for example, too little or too much, have all been reported to have significant alterations in breathing, central chemoreception (hypercapnic chemoreflex), blood pressure, thermoregulation, and cardiorespiratory responses to stress. More recent studies further show that abnormalities of the orexin system are linked to many neurological disorders in addition to narcolepsy, for example, sleep disorders, neurodegenerative disorders, neurogenic hypertension, and sudden infant death syndrome. These new findings have significantly advanced the knowledge in understanding the underlying mechanism of orexin-associated health and diseases while providing a new pathway for possible treatments. In this article, we will discuss some of the progresses in basic research and in health and diseases. © 2020 American Physiological Society. Compr Physiol 10:345-363, 2020.

Mechanisms of Memory Impairment Induced by Orexin-A via Orexin 1 and Orexin 2 Receptors in Post-traumatic Stress Disorder Rats

Post-traumatic stress disorder (PTSD) patients exhibit abnormal learning and memory. Axons from orexin neurons in the lateral hypothalamus innervate the hippocampus, modulating learning and memory via the orexin 1 and 2 receptors (OX1R and OX2R). However, the role of the orexin system in the learning and memory dysfunction observed in PTSD is unknown. This was investigated in the present study using PTSD animal model-single prolonged stress (SPS) rats. Spatial learning and memory in the rats were evaluated with the Morris water maze (MWM) test; changes in body weight and food intake were recorded to assess changes in appetite; and the expression of orexin-A and its receptors in the hypothalamus and hippocampus was examined and quantified by immunohistochemistry, western blotting and real-time PCR. The results showed that spatial memory was impaired and food intake was decreased in SPS rats; this was accompanied by downregulation of orexin-A in the hypothalamus and upregulation of OX1R and OX2R in the hippocampus and of OX1R in the hypothalamus. Intracerebroventricular administration of orexin-A improved spatial memory and enhanced appetite in SPS rats and partly reversed the increases in OX1R and OX2R levels in the hippocampus and hypothalamus. These results suggest that the orexin system plays a critical role in the memory and appetite dysfunction observed in PTSD.

The Lateral Hypothalamus: An Uncharted Territory for Processing Peripheral Neurogenic Inflammation.

The roles of the hypothalamus and particularly the lateral hypothalamus (LH) in the regulation of inflammation and pain have been widely studied. The LH consists of a parasympathetic area that has connections with all the major parts of the brain. It controls the autonomic nervous system (ANS), regulates feeding behavior and wakeful cycles, and is a part of the reward system. In addition, it contains different types of neurons, most importantly the orexin neurons. These neurons, though few in number, perform critical functions such as inhibiting pain transmission and interfering with the reward system, feeding behavior and the hypothalamic pituitary axis (HPA). Recent evidence has identified a new role for orexin neurons in the modulation of pain transmission associated with several inflammatory diseases, including rheumatoid arthritis and ulcerative colitis. Here, we review recent findings on the various physiological functions of the LH with special emphasis on the orexin/receptor system and its role in mediating inflammatory pain.

Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin.

Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic-clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2 ) in low-risk and high-risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high-risk KO mice. Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. Intermittent bradycardia was more prevalent in high-risk KO mice, an effect that may be the result of increased parasympathetic drive. High-risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild-type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea-apnea. Blocking orexin receptors prevented the methacholine (MCh)-induced increase in breathing frequency in KO mice and reduced MCh-induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high-risk KO mice increased longevity. High-risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.

Significant Quantitative Differences in Orexin Neuronal Activation After Pain Assessments in an Animal Model of Sickle Cell Disease.

Sickle cell disease is a hemoglobinopathy that causes sickling of red blood cells, resulting in vessel blockage, stroke, anemia, inflammation, and extreme pain. The development and treatment of pain, in particular, neuropathic pain in sickle cell disease patients is poorly understood and impedes our progress toward the development of novel therapies to treat pain associated with sickle cell disease. The orexin/hypocretin system offers a novel approach to treat chronic pain and hyperalgesia. These neuropeptides are synthesized in three regions: perifornical area (PFA), lateral hypothalamus (LH), and dorsomedial hypothalamus (DMH). Data suggest that orexin–A neuropeptide has an analgesic effect on inflammatory pain and may affect mechanisms underlying the maintenance of neuropathic pain. The purpose of this study was to determine whether there are neuronal activation differences in the orexin system as a result of neuropathic pain testing in a mouse model of sickle cell disease. Female transgenic sickle mice that express exclusively (99%) human sickle hemoglobin (HbSS-BERK) and age-/gender-matched controls (HbAA-BERK mice; n = 10/group, 20–30 g) expressing normal human hemoglobin A were habituated to each test protocol and environment before collecting baseline measurements and testing. Four measures were used to assess pain-related behaviors: thermal/heat hyperalgesia, cold hyperalgesia, mechanical hyperalgesia, and deep-tissue hyperalgesia. Hypothalamic brain sections from HbAA-BERK and HbSS-BERK mice were processed to visualize orexin and c-Fos immunoreactivity and quantified. The percentage of double labeled neurons in the PFA was significantly higher than the percentage of double labeled neurons in the LH orexin field of HbAA-BERK mice (*p < 0.05). The percentages of double labeled neurons in PFA and DMH orexin fields are significantly higher than those neurons in the LH of HbSS-BERK mice (*p < 0.05). These data suggest that DMH orexin neurons were preferentially recruited during neuropathic pain testing and a more diverse distribution of orexin neurons may be required to produce analgesia in response to pain in the HbSS-BERK mice. Identifying specific orexin neuronal populations that are integral in neuropathic pain processing will allow us to elucidate mechanisms that provide a more selective, targeted approach in treating of neuropathic pain in sickle cell disease.

Centrifugal projections to the main olfactory bulb revealed by transsynaptic retrograde tracing in mice.

A wide range of evidence indicates that olfactory perception is strongly involved in food intake. However, the polysynaptic circuitry linking the brain areas involved in feeding behavior to the olfactory regions is not well known. The aim of this article was to examine such circuits. Thus, we described, using hodological tools such as transsynaptic viruses (PRV152) transported in a retrograde manner, the long-distance indirect projections (two to three synapses) onto the main olfactory bulb (MOB). The ß-subunit of the cholera toxin which is a monosynaptic retrograde tracer was used as a control to be able to differentiate between direct and indirect projections. Our tracing experiments showed that the arcuate nucleus of the hypothalamus, as a major site for regulation of food intake, sends only very indirect projections onto the MOB. Indirect projections to MOB also originate from the solitary nucleus which is involved in energy homeostasis. Other indirect projections have been evidenced in areas of the reward circuit such as VTA and accumbens nucleus. In contrast, direct projections to the MOB arise from melanin-concentrating hormone and orexin neurons in the lateral hypothalamus. Functional significances of these projections are discussed in relation to the role of food odors in feeding and reward-related behavior.

Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder

Converging evidence indicates that orexins (ORXs), the regulatory neuropeptides, are implicated in anxiety- and depression-related behaviors via the modulation of neuroendocrine, serotonergic, and noradrenergic systems. This study evaluated the role of the orexinergic system in stress-associated physiological responses in a controlled prospective animal model. The pattern and time course of activation of hypothalamic ORX neurons in response to predator-scent stress (PSS) were examined using c-Fos as a marker for neuronal activity. The relationship between the behavioral response pattern 7 days post-exposure and expressions of ORXs was evaluated. We also investigated the effects of intracerebroventricular microinfusion of ORX-A or almorexant (ORX-A/B receptor antagonist) on behavioral responses 7 days following PSS exposure. Hypothalamic levels of ORX-A, neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF) were assessed. Compared with rats whose behaviors were extremely disrupted (post-traumatic stress disorder [PTSD]-phenotype), those whose behaviors were minimally selectively disrupted displayed significantly upregulated ORX-A and ORX-B levels in the hypothalamic nuclei. Intracerebroventricular microinfusion of ORX-A before PSS reduced the prevalence of the PTSD phenotype compared with that of artificial cerebrospinal fluid or almorexant, and rats treated with almorexant displayed a higher prevalence of the PTSD phenotype than did untreated rats. Activated ORX neurons led to upregulated expressions of BDNF and NPY, which might provide an additional regulatory mechanism for the modulation of adaptive stress responses. The study indicates that the activated ORX system might promote adaptive responses to PSS probably via stimulation of BDNF and NPY secretion, and early intervention with ORX-A reduces the prevalence of the PTSD phenotype and increases the prevalence of adaptive phenotypes. The findings provide some insights into the mechanisms underlying the involvement of the ORX system in stress-related disorders.

Targeted recombination in active populations as a new mouse genetic model to study sleep-active neuronal populations: Demonstration that Lhx6+ neurons in the ventral zona incerta are activated during paradoxical sleep hypersomnia.

The cFos immunostaining allowed the identification of multiple populations of neurons involved in the generation of paradoxical sleep. We adopted the transgenic (targeted recombination in active populations) mouse model, which following injection of tamoxifen, allows expression of Cre-dependent reporter constructs (i.e., mCherry) in neurons expressing cFos during waking or paradoxical sleep hypersomnia following automatic paradoxical sleep deprivation. Three groups of mice were subjected to two periods of waking, one period of waking and one of paradoxical sleep hypersomnia, or two periods of paradoxical sleep hypersomnia. A high percentage of double-labelled neurons was observed in the lateral hypothalamic area and zona incerta of two periods of waking and two periods of paradoxical sleep hypersomnia in mice, but not in those of one period of waking and one of paradoxical sleep hypersomnia in animals. Melanin-concentrating hormone neurons in the lateral hypothalamic area and Lhx6+ cells in the zona incerta constituted 5.7±1.5% and 8.8±2.3% of all mCherry+ cells and 20.6±4.8% and 24.6±5.9% of all cFos+ neurons in two periods of paradoxical sleep hypersomnia in animals. In addition, melanin-concentrating hormone cells as well as Lhx6+ neurons rarely expressed mCherry (or cFos) in the waking condition, in contrast to orexin neurons, which constituted approximately 30% of mCherry+ and cFos+ neurons. Our results validate the TRAP methodology and open the way to use it for identifying the neurons activated during waking and paradoxical sleep hypersomnia. Furthermore, they indicate for the first time that Lhx6+ neurons in the zona incerta, like melanin-concentrating hormone cells in the lateral hypothalamic area, are activated during paradoxical sleep hypersomnia but not during waking. These results indicate that Lhx6+ neurons might play a role in the control of paradoxical sleep, like the melanin-concentrating hormone cells.

Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia

BackgroundStress-induced analgesia (SIA) is an evolutionarily conserved phenomenon during stress. Neuropeptide S (NPS), orexins, substance P, glutamate and endocannabinoids are known to be involved in stress and/or SIA, however their causal links remain unclear. Here, we reveal an unprecedented sequential cascade involving these mediators in the lateral hypothalamus (LH) and ventrolateral periaqueductal gray (vlPAG) using a restraint stress-induced SIA model.MethodsMale C57BL/6 mice of 8–12 week-old were subjected to intra-cerebroventricular (i.c.v.) and/or intra-vlPAG (i.pag.) microinjection of NPS, orexin-A or substance P alone or in combination with selective antagonists of NPS receptors (NPSRs), OX1 receptors (OX1Rs), NK1 receptors (NK1Rs), mGlu5 receptors (mGlu5Rs) and CB1 receptors (CB1Rs), respectively. Antinociceptive effects of these mediators were evaluated via the hot-plate test. SIA in mice was induced by a 30-min restraint stress. NPS levels in the LH and substance P levels in vlPAG homogenates were compared in restrained and unrestrained mice.ResultsNPS (i.c.v., but not i.pag.) induced antinociception. This effect was prevented by i.c.v. blockade of NPSRs. Substance P (i.pag.) and orexin-A (i.pag.) also induced antinociception. Substance P (i.pag.)-induced antinociception was prevented by i.pag. Blockade of NK1Rs, mGlu5Rs or CB1Rs. Orexin-A (i.pag.)-induced antinociception has been shown previously to be prevented by i.pag. blockade of OX1Rs or CB1Rs, and here was prevented by NK1R or mGlu5R antagonist (i.pag.). NPS (i.c.v.)-induced antinociception was prevented by i.pag. blockade of OX1Rs, NK1Rs, mGlu5Rs or CB1Rs. SIA has been previously shown to be prevented by i.pag. blockade of OX1Rs or CB1Rs. Here, we found that SIA was also prevented by i.c.v. blockade of NPSRs or i.pag. blockade of NK1Rs or mGlu5Rs. Restrained mice had higher levels of NPS in the LH and substance P in the vlPAG than unrestrained mice.ConclusionsThese results suggest that, during stress, NPS is released and activates LH orexin neurons via NPSRs, releasing orexins in the vlPAG. Orexins then activate OX1Rs on substance P-containing neurons in the vlPAG to release substance P that subsequently. Activates NK1Rs on glutamatergic neurons to release glutamate. Glutamate then activates perisynaptic mGlu5Rs to initiate the endocannabinoid retrograde inhibition of GABAergic transmission in the vlPAG, leading to analgesia.

Local administration of the orexin receptor antagonist MK-4305, but not orexin-A, into the nucleus accumbens increases accumbal dopamine efflux in freely moving rats

The nucleus accumbens (NAc), a major terminal area of mesolimbic dopaminergic projections, receives inputs from orexin neurons. Behavioural studies suggest that accumbal orexin receptors (-Rs) play modulatory roles in the regulation of accumbal dopaminergic activity-dependent locomotion in rats (Kotani et al., 2008). We studied the effects of intra-accumbal application of orexin-R ligands on accumbal dopamine (DA) efflux in freely moving rats, using in vivo microdialysis, to analyse the roles of orexin-Rs in regulating accumbal dopaminergic neural activity. Orexin-R ligands were applied into NAc though a microinjection needle attached with a dialysis probe. The OX1- and OX2-R agonist orexin-A failed to alter DA levels in NAc. However, the OX1- and OX2-R antagonist MK-4305 induced a dose-related increase in DA levels. This MK-4305-induced increase in accumbal DA levels was suppressed by infusion of TTX through the probe and was inhibited by local co-administration of orexin-A. These results suggest that intra-accumbal application of MK-4305 could enhance accumbal DA efflux by antagonism of OX1- and/or OX2-Rs. The present study also indicates that accumbal OX1- and/or OX2-Rs could play inhibitory roles in the regulation of accumbal dopaminergic neural activity.

Roles of orexin neurons in motivated behaviors in rats

Roles of orexin neurons in motivated behaviors in rats

Targeting Orexin Neurons for Treatment of Obesity is It Feasible in Human Being-A Systematic Review

Obesity is increasing at epidemic proportions both in children and adults posing a big public health problem among children as well as adults. With parallel increase in comorbidities like type2 diabetes mellitus (T2DM), metabolic syndrome (MetS) a need arises for developing medical therapies that can maintain long term weight loss. Earlier we have tried to consider multiple options like utilization of drug combinations like Qsymia, Contravene, Liraglutide, thylakoids, probiotics, Combination of glucagon like peptides1 (GLP1) with glucagon etc but nothing has proved to be as efficacious as BS in long term maintenance of weight loss. Earlier we had reviewed the cellular changes related to orexin A and B changes that are isoforms of neuropeptides that get liberated from the lateral hypothalamus (LH). Here we further review the pathophysiology of orexin neurons with regard to their role in neuroinflammation in the central nervous system (CNS) via microglial cell changes and role in spontaneous physical activity (SPA) and sleep physiology commonly termed sleep-wake promoting neuropeptides along with role in reward circuitry and how targeting them might be of help in treating obesity. Possibility is that subtle increases in SPA have been found to improve energy expenditure (EE) and that has been utilized in some workplaces where treadmill like chairs are utilized, restless people who keep sitting and standing do burn calories thus promoting carparks at distance places, no elevators have been thought as some ways by which lethargic individuals refuse to follow exercise might get helped by modulating orexin neurons besides correcting sleep problems coexisting with obesity

Neurophysiology and Treatment of Disorders of Consciousness Induced by Traumatic Brain Injury: Orexin Signaling as a Potential Therapeutic Target.

Traumatic brain injury (TBI) can cause disorders of consciousness (DOC) by impairing the neuronal circuits of the ascending reticular activating system (ARAS) structures, including the hypothalamus, which are responsible for the maintenance of the wakefulness and awareness. However, the effectiveness of drugs targeting ARAS activation is still inadequate, and novel therapeutic modalities are urgently needed. The goal of this work is to describe the neural loops of wakefulness, and explain how these elements participate in DOC, with emphasis on the identification of potential new therapeutic options for DOC induced by TBI. Hypothalamus has been identified as a sleep/wake center, and its anterior and posterior regions have diverse roles in the regulation of the sleep/wake function. In particular, the posterior hypothalamus (PH) possesses several types of neurons, including the orexin neurons in the lateral hypothalamus (LH) with widespread projections to other wakefulness-related regions of the brain. Orexins have been known to affect feeding and appetite, and recently their profound effect on sleep disorders and DOC has been identified. Orexin antagonists are used for the treatment of insomnia, and orexin agonists can be used for narcolepsy. Additionally, several studies demonstrated that the agonists of orexin might be effective in the treatment of DOC, providing novel therapeutic opportunities in this field. The hypothalamic-centered orexin has been adopted as the point of entry into the system of consciousness control, and modulators of orexin signaling opened several therapeutic opportunities for the treatment of DOC.

PRESERVED NUMBER OF OREXIN NEURONS IN POSTMORTEM HYPOTHALAMIC TISSUE OF CHRONIC ALCOHOLICS

The hypothalamic orexin system is critically involved in addiction, including chronic alcohol abuse. Microinjection of orexin into the lateral hypothalamus increases alcohol intake in rats, while reduced immunoreactivity of orexin neurons is associated with decreased alcohol drinking. Recently, the numbers of orexin neurons were found to be increased in opiate addiction in humans [4] and cocaine addiction in rats [2], but the integrity of orexin neurons has not yet been studied in human alcoholics. We examined the hypothalamus of 9 patients of chronic alcoholism and 10 subjects without a history of alcoholism or any other neurological or psychiatric disorder. We performed immunohistochemistry for orexin A, followed by stereological quantification. The hypothalamic tissue of chronic alcoholics exhibited a slightly increased number (9%) of orexin-containing neurons compared to the control group (123’087 ± 18’536 and 110’431 ± 14’439, p = 0.11). Mean Gundersen’s coefficient of error was 0.06 ± 0.01. The number of orexin neurons was similar in chronic alcoholics and control subjects without a history of alcoholism. Further examination of alcohol-induced hypothalamic damage is needed to understand, whether a neuroplastic increase in orexin neurons counterbalances a concurrent alcohol-toxic damage to these neurons.

Dual orexin receptor antagonist induces changes in core body temperature in rats after exercise

Hypothalamic orexin neurons are involved in various physiological functions, including thermoregulation. The orexinergic system has been considered as a potent mediator of the exercise response. The present study describes how the antagonization of the orexinergic system by a dual orexin receptor antagonist (DORA) modifies the thermoregulatory process during exercise. Core Body Temperature (CBT) and Spontaneous Locomotor Activity (SLA) of 12 male Wistar rats were recorded after either oral administration of DORA (30 mg/kg or 60 mg/kg) or placebo solution, both at rest and in exercise conditions with treadmill running. DORA ingestion decreased SLA for 8 hours (p < 0.001) and CBT for 4 hours (p < 0.01). CBT (°C) response was independent of SLA. The CBT level decreased from the beginning to the end of exercise when orexin receptors were antagonized, with a dose-dependent response (39.09 ± 0.36 and 38.88 ± 0.28 for 30 and 60 mg/kg; p < 0.001) compared to placebo (39.29 ± 0.31; p < 0.001). CBT increased during exercise was also blunted after DORA administration, but without dose effects of DORA. In conclusion, our results favor the role of orexin in the thermoregulation under stress related to exercise conditions.