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Autonomic Neuroscience : Basic &... Nov 2020Orexin (OX), which regulates sleep and wakefulness and feeding behaviors has 2 isoforms, orexin-A and -B (OXA and OXB). In this study, the distribution of OXA and OXB...
Orexin (OX), which regulates sleep and wakefulness and feeding behaviors has 2 isoforms, orexin-A and -B (OXA and OXB). In this study, the distribution of OXA and OXB was examined in the rat superior salivatory nucleus (SSN) using retrograde tracing and immunohistochemical and methods. OXA- and OXB-immunoreactive (-ir) nerve fibers were seen throughout the SSN. These nerve fibers surrounded SSN neurons retrogradely labeled with Fast blue (FB) from the corda-lingual nerve. FB-positive neurons had pericellular OXA- (47.5%) and OXB-ir (49.0%) nerve fibers. Immunohistochemistry for OX receptors also demonstrated the presence of OX1R and OX2R in FB-positive SSN neurons. The majority of FB-positive SSN neurons contained OX1R- (69.7%) or OX2R-immunoreactivity (57.8%). These neurons had small and medium-sized cell bodies. In addition, half of FB-positive SSN neurons which were immunoreactive for OX1R (47.0%) and OX2R (52.2%) had pericellular OXA- and OXB-ir nerve fibers, respectively. Co-expression of OX1R- and OX2R was common in FB-positive SSN neurons. The present study suggests a possibility that OXs regulate the activity of SSN neurons through OX receptors.
Topics: Animals; Autonomic Fibers, Preganglionic; Facial Nerve; Immunohistochemistry; Male; Orexin Receptors; Orexins; Rats; Rats, Wistar; Sublingual Gland; Submandibular Gland
PubMed: 32721850
DOI: 10.1016/j.autneu.2020.102712 -
Brain Research Bulletin Aug 2022Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal/startle, stress... (Review)
Review
Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal/startle, stress responses and insomnia. This review focuses on the importance of the orexin neural system as a novel mechanism related to the pathophysiology of PTSD. Orexinergic neurons originate in the lateral hypothalamus and project widely to key neurotransmitter systems, autonomic neurons, the hypothalamic-pituitary-adrenal (HPA) axis, and fear-related neural circuits. After trauma or stress, the basolateral amygdala (BLA) transmits sensory information to the central nucleus of the amygdala (CeA) and in turn to the hypothalamus and other subcortical and brainstem regions to promote fear and threat behaviors. Orexin receptors have a prominent role in this circuit as fear conditioned orexin receptor knockout mice show decreased fear expression while dual orexin receptor antagonists (DORAs) inhibit fear acquisition and expression. Orexin activation of an infralimbic-amygdala circuit impedes fear extinction while DORA treatments enhance it. Increased orexin signaling to the amygdalo-cortical-hippocampal circuit promotes avoidance behaviors. Orexin has an important role in activating sympathetic nervous system (SNS) activity and HPA axis stress responses. Blockade of orexin receptors reduces fear-conditioned startle responses. In PTSD models, individuals demonstrate sleep disturbances such as increased sleep latency and more transitions to wakefulness. Increased orexin activity impairs sleep by promoting wakefulness and reducing total sleep time while DORA treatments enhance sleep onset and maintenance. The orexinergic neural system provides important mechanisms for understanding multiple PTSD behaviors and provides new medication targets to treat this often persistent and debilitating illness.
Topics: Animals; Arousal; Extinction, Psychological; Fear; Hypothalamo-Hypophyseal System; Mice; Orexin Receptors; Orexins; Pituitary-Adrenal System; Sleep; Stress Disorders, Post-Traumatic
PubMed: 35618150
DOI: 10.1016/j.brainresbull.2022.05.006 -
Medicine Jun 2023Orexin, also known as hypocretin, is an excitatory neuropeptide secreted by the hypothalamus. Orexin is divided into orexin-A (OXA) and orexin-B (OXB), which are derived... (Review)
Review
Orexin, also known as hypocretin, is an excitatory neuropeptide secreted by the hypothalamus. Orexin is divided into orexin-A (OXA) and orexin-B (OXB), which are derived from a common precursor secreted by hypothalamic neurons. Orexin acts on orexin receptor-1 (OX1R) and orexin receptor-2 (OX2R). Orexin neurons, as well as receptors, are widely distributed in various regions of the brain as well as in the peripheral system and have a wider range of functions. This paper reviews the latest research results of orexin in the aspects of food intake, sleep, addiction, depression and anxiety. Because orexin has certain physiological functions in many systems, we further explored the possibility of orexin as a new target for the treatment of bulimia, anorexia nervosa, insomnia, lethargy, anxiety and depression. It is precisely because orexin has physiological functions in multiple systems that orexin, as a new target for the treatment of the above diseases, has potential contradictions. For example, it promotes the function of 1 system and may inhibit the function of another system. How to study a new drug, which can not only treat the diseases of this system, but also do not affect other system functions, is what we need to focus on.
Topics: Humans; Orexins; Orexin Receptors; Cognition; Brain; Anxiety
PubMed: 37390267
DOI: 10.1097/MD.0000000000034206 -
Trends in Endocrinology and Metabolism:... May 2023Orexin (OX)A and OXB are a pair of neuropeptides secreted by orexin-producing neurons in the lateral hypothalamus. The orexin system can regulate many physiological... (Review)
Review
Orexin (OX)A and OXB are a pair of neuropeptides secreted by orexin-producing neurons in the lateral hypothalamus. The orexin system can regulate many physiological processes through these two receptor pathways, such as feeding behavior, sleep/wake state, energy homeostasis, reward, and the coordination of emotion. Mammalian target of rapamycin (mTOR) can coordinate upstream signals with downstream effectors, thereby regulating fundamental cellular processes and also plays an essential role in the signaling network downstream of the orexin system. In turn, the orexin system can activate mTOR. Here, we review the association of the orexin system with the mTOR signaling pathway mainly by discussing that drugs in various diseases exert their effects on the orexin system, indirectly affecting the mTOR signaling pathway.
Topics: Humans; Animals; Orexins; Orexin Receptors; Neuropeptides; Signal Transduction; TOR Serine-Threonine Kinases; Mammals
PubMed: 36934048
DOI: 10.1016/j.tem.2023.02.008 -
ELife Jun 2019Uninterrupted arousal is important for survival during threatening situations. Activation of orexin/hypocretin neurons is implicated in sustained arousal. However,...
Uninterrupted arousal is important for survival during threatening situations. Activation of orexin/hypocretin neurons is implicated in sustained arousal. However, orexin neurons produce and release orexin as well as several co-transmitters including dynorphin and glutamate. To disambiguate orexin-dependent and -independent physiological functions of orexin neurons, we generated a novel Orexin-flippase (Flp) knock-in mouse line. Crossing with Flp-reporter or Cre-expressing mice showed gene expression exclusively in orexin neurons. Histological studies confirmed that orexin was knock-out in homozygous mice. Orexin neurons without orexin showed altered electrophysiological properties, as well as received decreased glutamatergic inputs. Selective chemogenetic activation revealed that both orexin and co-transmitters functioned to increase wakefulness, however, orexin was indispensable to promote sustained arousal. Surprisingly, such activation increased the total time spent in cataplexy. Taken together, orexin is essential to maintain basic membrane properties and input-output computation of orexin neurons, as well as to exert awake-sustaining aptitude of orexin neurons.
Topics: Action Potentials; Animals; Arousal; Behavior, Animal; Mice; Neurons; Orexins; Wakefulness
PubMed: 31159922
DOI: 10.7554/eLife.44927 -
Biological Psychiatry Dec 2022In 2014, we proposed that orexin signaling transformed motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a... (Review)
Review
In 2014, we proposed that orexin signaling transformed motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a threat, a process we referred to as motivational activation. Advancements in animal models since then have permitted higher-resolution measurements of motivational states; in particular, the behavioral economics approach for studying drug demand characterizes conditions that lead to the enhanced motivation that underlies addiction. This motivational plasticity is paralleled by persistently increased orexin expression in a topographically specific manner-a finding confirmed across species, including in humans. Normalization of orexin levels also reduces drug motivation in addiction models. These new advancements lead us to update our proposed framework for the orexin function. We now propose that the capacity of orexin neurons to exhibit dynamic shifts in peptide production contributes to their role in adaptive motivational regulation and that this is achieved via a pool of reserve orexin neurons. This reserve is normally bidirectionally recruited to permit motivational plasticity that promotes flexible, adaptive behavior. In pathological states such as addiction, however, we propose that the orexin system loses capacity to adaptively adjust peptide production, resulting in focused hypermotivation for drug, driven by aberrantly and persistently high expression in the orexin reserve pool. This mechanistic framework has implications for the understanding and treatment of several psychiatric disorders beyond addiction, particularly those characterized by motivational dysfunction.
Topics: Animals; Humans; Orexins; Neuropeptides; Intracellular Signaling Peptides and Proteins; Behavior, Addictive; Motivation; Orexin Receptors
PubMed: 36328706
DOI: 10.1016/j.biopsych.2022.06.027 -
Brain Research Mar 2020Orexin neurons (Orx; also referred to as hypocretin) are found exclusively in the hypothalamus, and release the neuropeptides orexin A and orexin B (also referred to as...
Orexin neurons (Orx; also referred to as hypocretin) are found exclusively in the hypothalamus, and release the neuropeptides orexin A and orexin B (also referred to as hypocretin 1 and 2) throughout the CNS. With its widespread targets, the orexin system is involved in a number of functions including, but not limited to stress, reward, wakefulness, and food seeking. Our laboratory has previously proposed that the dorsomedial hypothalamus (DMH) and perifornical (PFA) orexin neurons function in stress and arousal whereas those in lateral hypothalamus (LH) participate in reward processes (Harris and Aston-Jones, 2006). In the current study, we compared Fos activation in orexin neurons located in medial hypothalamus (DMH and PFA) to those in LH during a Go/No-Go task for a highly palatable food reward, a task that would likely activate regions for arousal/attention as well as reward. The Go/No-Go paradigm is a useful behavioral tool to measure behavioral inhibition, impulsivity, learning, and reaction time. Our results revealed increased activation of medial hypothalamic orexin neurons correlated with greater accuracy on the Go/No-Go task. No correlation was found between Go/No-Go accuracy and activation of lateral hypothalamic orexin neurons. This study supports a functional dichotomy of medial vs lateral orexin neurons, and indicates a role for medial orexin neurons in behavioral performance that requires response inhibition.
Topics: Animals; Behavior, Animal; Hypothalamus, Middle; Inhibition, Psychological; Male; Neurons; Orexins; Rats, Sprague-Dawley; Reaction Time; Reward
PubMed: 30176242
DOI: 10.1016/j.brainres.2018.08.031 -
Frontiers of Neurology and Neuroscience 2021Orexin receptors (OXRs) are promiscuous G-protein-coupled receptors that signal via several G-proteins and, putatively, via other proteins. On which basis the signal... (Review)
Review
Orexin receptors (OXRs) are promiscuous G-protein-coupled receptors that signal via several G-proteins and, putatively, via other proteins. On which basis the signal pathways are selected and orchestrated is largely unknown. We also have an insufficient understanding of the kind of signaling that is important for specific types of cellular responses. OXRs are able to form complexes with several other G-protein-coupled receptors in vitro, and one possibility is that the complexing partners regulate the use of certain signal transducers. In the central nervous system neurons, the main acute downstream responses of OXR activation are the inhibition of K+ channels and the activation of the Na+/Ca2+ exchanger and non-selective cation channels of unknown identity. The exact nature of the intracellular signal chain between the OXRs and these downstream targets is yet to be elucidated, but the Gq-phospholipase C (PLC) protein kinase C pathway - which is a significant signaling pathway for OXRs in recombinant cells - may be one of the players in neurons. The Gq-PLC pathway may also, under certain circumstances, take the route to diacylglycerol lipase, which leads to the production of the potent endocannabinoid (eCB), 2-arachidonoyl glycerol, and thereby connects orexins with eCB signaling. In addition, OXRs have been studied in the context of neurodegeneration and cancer cell death. Overall, OXR signaling is complex, and it can change depending on the cell type and environment.
Topics: Humans; Orexin Receptors; Orexins; Signal Transduction
PubMed: 34052812
DOI: 10.1159/000514962 -
Neuroscience Jun 2020Palatable taste can stimulate appetite in the absence of hunger, and individual differences in hedonic eating may be critical to overeating. Women are more prone to...
Palatable taste can stimulate appetite in the absence of hunger, and individual differences in hedonic eating may be critical to overeating. Women are more prone to obesity and binge eating than men, which warrants comparisons of hedonic versus physiological consumption and the underlying neural substrates in both sexes. The current study examined palatable (high-sugar) food consumption in male and female rats under physiological hunger and satiety, and the role of the neuropeptide orexin/hypocretin (ORX). Across multiple tests, females consistently consumed similar amounts of palatable food regardless of whether they were hungry or sated prior to testing. In contrast, males typically adjusted their consumption according to their hunger/satiety state. This difference was specific to palatable food consumption, as both sexes ate standard chow according to their hunger state. ORX is important in food motivation and reward behaviors. Thus, to begin to determine the neuronal mechanisms of hedonic eating, we examined activation and signaling of ORX neurons. We systematically characterized Fos induction patterns of ORX neurons across the entire rostrocaudal extent of the lateral hypothalamus and found that they were activated by food and by fasting in both sexes. Then, we showed that systemic blockade of ORX receptor 1 signaling with SB-334867 decreased palatable food consumption in hungry and sated rats of both sexes. These results demonstrate sex differences in hedonic eating; increased susceptibility in females to overeat palatable food regardless of hunger state, and that ORX is a critical neuropeptide mechanism of hedonic eating in both sexes.
Topics: Animals; Bulimia; Eating; Female; Hunger; Male; Motivation; Orexins; Rats; Sex Characteristics
PubMed: 32283183
DOI: 10.1016/j.neuroscience.2020.04.008 -
Journal of Ovarian Research May 2023Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder without definitive treatments. Orexin and Substance-P (SP) neuropeptides can affect the ovarian...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder without definitive treatments. Orexin and Substance-P (SP) neuropeptides can affect the ovarian steroidogenesis. Moreover, there are limited studies about the role of these neuropeptides in PCOS. We aimed here to clarify the effects of orexins and SP in PCOS as well as any possible interactions between them.
METHODS
For this purpose, the animals (n = five rats per group) received intraperitoneally a single dose of SB-334,867-A (orexin-1 receptor antagonist; OX1Ra), JNJ-10,397,049 (orexin-2 receptor antagonist; OX2Ra), and CP-96,345 (neurokinin-1 receptor antagonist; NK1Ra), alone or in combination with each other after two months of PCOS induction. The blocking of orexin and SP receptors was studied in terms of ovarian histology, hormonal changes, and gene expression of ovarian steroidogenic enzymes.
RESULTS
The antagonists' treatment did not significantly affect the formation of ovarian cysts. In the PCOS groups, the co-administration of OX1Ra and OX2Ra as well as their simultaneous injections with NK1Ra significantly reversed testosterone levels and Cyp19a1 gene expression when compared to the PCOS control group. There were no significant interactions between the PCOS groups that received NK1Ra together with one or both OX1R- and OX2R-antagonists.
CONCLUSION
The blocking of the orexin receptors modulates abnormal ovarian steroidogenesis in the PCOS model of rats. This suggests that the binding of orexin-A and -B to their receptors reduces Cyp19a1 gene expression while increasing testosterone levels.
Topics: Animals; Female; Humans; Rats; Neuropeptides; Orexins; Polycystic Ovary Syndrome; Rats, Wistar; Substance P; Testosterone
PubMed: 37147728
DOI: 10.1186/s13048-023-01168-4