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Frontiers in Physiology 2021Hyperactivity of the orexin system within the paraventricular nucleus (PVN) has been shown to contribute to increased sympathetic nerve activity (SNA) and blood pressure...
Hyperactivity of the orexin system within the paraventricular nucleus (PVN) has been shown to contribute to increased sympathetic nerve activity (SNA) and blood pressure (BP) in rodent animals. However, the underlying molecular mechanisms remain unclear. Here, we test the hypothesis that orexin system activation stimulates calcium/calmodulin-dependent kinase II (CaMKII) expression and activation, and stimulation of CaMKII expressing PVN neurons increases SNA and BP. Real-time PCR and/or western blot were carried out to test the effect of orexin-A administration on CaMKII expression in the PVN of normal Sprague Dawley (SD) rats and orexin receptor 1 (OX1R) expressing PC12 cells. Immunostaining was performed to assess OX1R cellular localization in the PVN of SD rats as well as orexin-A treatment on CaMKII activation in cultured hypothalamic neurons. In vivo sympathetic nerve recordings were employed to test the impact of optogenetic stimulation of CaMKII-expressing PVN neurons on the renal SNA (RSNA) and BP. The results showed that intracerebroventricular injection of orexin-A into the SD rat increases mRNA expression of CaMKII subunits in the PVN. In addition, Orexin-A treatment increases CaMKII expression and its phosphorylation in OX1R-expressing PC12 cells. Furthermore, Orexin-A treatment increases CaMKII activation in cultured hypothalamic neurons from neonatal SD rats. Finally, optogenetic excitation of PVN CaMKII-expressing neurons results in robust increases in RSNA and BP in SD rats. Our results suggest that increased orexin system activity activates CaMKII expression in cardiovascular relevant regions, and this may be relevant to the downstream cardiovascular effects of CaMKII.
PubMed: 34276418
DOI: 10.3389/fphys.2021.698185 -
The Journal of Neuroscience : the... May 2023To understand how sleep-wakefulness cycles are regulated, it is essential to disentangle structural and functional relationships between the preoptic area (POA) and...
To understand how sleep-wakefulness cycles are regulated, it is essential to disentangle structural and functional relationships between the preoptic area (POA) and lateral hypothalamic area (LHA), since these regions play important yet opposing roles in the sleep-wakefulness regulation. GABA- and galanin (GAL)-producing neurons in the ventrolateral preoptic nucleus (VLPO) of the POA (VLPO and VLPO neurons) are responsible for the maintenance of sleep, while the LHA contains orexin-producing neurons (orexin neurons) that are crucial for maintenance of wakefulness. Through the use of rabies virus-mediated neural tracing combined with hybridization (ISH) in male and female mice, we revealed that the vesicular GABA transporter ()- and galanin ()-expressing neurons in the VLPO directly synapse with orexin neurons in the LHA. A majority (56.3 ± 8.1%) of all VLPO input neurons connecting to orexin neurons were double-positive for and Using projection-specific rabies virus-mediated tracing in male and female and mice, we discovered that VLPO and VLPO neurons that send projections to the LHA received innervations from similarly distributed input neurons in many brain regions, with the POA and LHA being among the main upstream areas. Additionally, we found that acute optogenetic excitation of axons of VLPO neurons, but not VLPO neurons, in the LHA of male mice induced wakefulness. This study deciphers the connectivity between the VLPO and LHA, provides a large-scale map of upstream neuronal populations of VLPO→LHA neurons, and reveals a previously uncovered function of the VLPO→LHA pathway in the regulation of sleep and wakefulness. We identified neurons in the ventrolateral preoptic nucleus (VLPO) that are positive for vesicular GABA transporter () and/or galanin () and serve as presynaptic partners of orexin-producing neurons in the lateral hypothalamic area (LHA). We depicted monosynaptic input neurons of GABA- and galanin-producing neurons in the VLPO that send projections to the LHA throughout the entire brain. Their input neurons largely overlap, suggesting that they comprise a common neuronal population. However, acute excitatory optogenetic manipulation of the VLPO→LHA pathway, but not the VLPO→LHA pathway, evoked wakefulness. This study shows the connectivity of major components of the sleep/wake circuitry in the hypothalamus and unveils a previously unrecognized function of the VLPO→LHA pathway in sleep-wakefulness regulation. Furthermore, we suggest the existence of subpopulations of VLPO neurons that innervate LHA.
Topics: Mice; Male; Female; Animals; Preoptic Area; Hypothalamic Area, Lateral; Orexins; Galanin; Neurons; Wakefulness; Sleep; gamma-Aminobutyric Acid
PubMed: 37117013
DOI: 10.1523/JNEUROSCI.1913-22.2023 -
Molecules (Basel, Switzerland) Apr 2023Twenty-five years have passed since the discovery of the orexin system, during which time we have learned more and more about it. A number of studies have been conducted... (Review)
Review
Twenty-five years have passed since the discovery of the orexin system, during which time we have learned more and more about it. A number of studies have been conducted showing the role of the orexin system in insomnia, as well as its potential use in the treatment of obesity and depression. In this review, we present the role of the orexin system in the development of depressive illness and show the characteristics of seltorexant, a potential drug for the treatment of depression. This review describes the structure and synthesis of the compound as well as its pharmacodynamics and pharmacokinetics. Pre-clinical and clinical studies are also described, including side effects. There is evidence that the use of seltorexant is considered safe, with no clear or major clinically significant side effects, which makes it a promising candidate for the treatment of depression and anxiety disorders.
Topics: Humans; Orexins; Depression; Orexin Receptor Antagonists; Anxiety Disorders; Anxiety
PubMed: 37110810
DOI: 10.3390/molecules28083575 -
Brain Circulation 2020Orexin is a neuropeptide secreted from lateral hypothalamus and pre-frontal cortex concerned in the wakefulness and excitement. This study aimed to review the possible... (Review)
Review
Orexin is a neuropeptide secreted from lateral hypothalamus and pre-frontal cortex concerned in the wakefulness and excitement. This study aimed to review the possible neurobiological effect of orexin. A diversity of search strategies was adopted and assumed which included electronic database searches of Medline and PubMed using MeSH terms, keywords, and title words during the search. Orexin plays a vital role in activation of learning, memory acquisition, and consolidation through activation of monoaminergic system, which affect cognitive flexibility and cognitive function. Orexin stimulates adrenocorticotropin and corticosteroid secretions via activation of central corticotropin-releasing hormone. Cerebrospinal fluid (CSF) and serum orexin serum levels are reduced in depression, schizophrenia, and narcolepsy. However, high orexin serum levels are revealed in drug addictions. Regarding neurodegenerative brain diseases, CSF and serum orexin serum levels are reduced Parkinson disease, Alzheimer dementia, Huntington's disease, amyotrphic lateral sclerosis, and multiple sclerosis. Orexin antagonist leads to significant reduction of sympathetic over-activity during withdrawal syndrome. As well, orexin antagonist improves sleep pattern. Orexinergic system is involved in the different psychiatric and neurological disorders; therefore, targeting of this system could be possible novel pathway in the management of these disorders. In addition, measurement of CSF and serum orexin levels might predict the relapse and withdrawal of addict patients.
PubMed: 33033776
DOI: 10.4103/bc.bc_42_19 -
Brain Research Mar 2020Hypothalmic orexin/hypocretin (Orx) neurons in the lateral and dorsomedial perifornical region (LH-DMH/PeF) innervate broadly throughout the brain, and receive similar... (Review)
Review
Hypothalmic orexin/hypocretin (Orx) neurons in the lateral and dorsomedial perifornical region (LH-DMH/PeF) innervate broadly throughout the brain, and receive similar inputs. This wide distribution, as well as two Orx peptides (Orx and Orx) and two Orx receptors (Orx and Orx) allow for functionally related but distinctive behavioral outcomes, that include arousal, sleep-wake regulation, food seeking, metabolism, feeding, reward, addiction, and learning. These are all motivational functions, and tie the orexin systems to anxiety and depression as well. We present evidence, that for affective behavior, Orx and Orx receptors appear to have opposing functions. The majority of research on anxiety- and depression-related outcomes has focused on Orx receptors, which appear to have primarily anxiogenic and pro-depressive actions. Although there is significant research suggesting contrary findings, the primary potential for pharmacotherapies linked to the Orx receptor is via antagonists to block anxious and depressive behavior. Dual orexin receptor antagonists have been approved for treatment of sleep disorders, and are likely candidates for adaptation for affect disorder treatments. However, we present evidence here that demonstrates the Orx receptors are anxiolytic and antidepressive. Using a new experimental pre-clinical model of anxious and depressive behavior stimulated by social stress and decision-making that produces two stable behavioral phenotypes, Escape/Resilient and Stay/Susceptible, we tested the effects of intracerebroventricular injections of Orx agonist and antagonist drugs. Over ten behavioral measures, we have demonstrated that Orx agonists promote resilience, as well as anxiolytic and antidepressive behavior. In contrast, Orx antagonists or knockdown kindle anxious and pro-depressive behavior plus increase susceptibility. The results suggest that the Orx receptor may be a useful target for pharmacotherapies to treat anxiety and depression.
Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Brain; Conditioning, Classical; Decision Making; Depression; Fear; Humans; Orexin Receptor Antagonists; Orexin Receptors; Stress, Psychological
PubMed: 30590027
DOI: 10.1016/j.brainres.2018.12.036 -
Frontiers in Endocrinology 2023Premenstrual syndrome (PMS) occurs recurrently during the luteal phase of a woman's menstrual cycle and disappears after menstruation ends. It is characterized by... (Review)
Review
Premenstrual syndrome (PMS) occurs recurrently during the luteal phase of a woman's menstrual cycle and disappears after menstruation ends. It is characterized by abnormal changes in both the body and mood, and in certain cases, severe disruptions in daily life and even suicidal tendencies. Current drugs for treating PMS, such as selective serotonin reuptake inhibitors, do not yield satisfactory results. Orexin, a neuropeptide produced in the lateral hypothalamus, is garnering attention in the treatment of neurological disorders and is believed to modulate the symptoms of PMS. This paper reviews the advancements in research on sleep disturbances, mood changes, and cognitive impairment caused by PMS, and suggests potential pathways for orexin to address these symptoms. Furthermore, it delves into the role of orexin in the molecular mechanisms underlying PMS. Orexin regulates steroid hormones, and the cyclic fluctuations of estrogen and progesterone play a crucial role in the pathogenesis of PMS. Additionally, orexin also modulates the gamma-aminobutyric acid (GABA) system and the inflammatory response involved in coordinating the mechanism of PMS. Unraveling the role of orexin in the pathogenesis of PMS will not only aid in understanding the etiology of PMS but also hold implications for orexin as a novel target for treating PMS.
Topics: Female; Humans; Orexins; Premenstrual Syndrome; Menstrual Cycle; Luteal Phase; Estrogens
PubMed: 38292774
DOI: 10.3389/fendo.2023.1266806 -
Acta Neuropathologica Jun 2023Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with...
Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1 mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.
Topics: Male; Mice; Animals; Amyotrophic Lateral Sclerosis; Superoxide Dismutase-1; Neuropeptides; Orexins; Eating; Weight Loss
PubMed: 37058170
DOI: 10.1007/s00401-023-02569-x -
ELife Apr 2020Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate...
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.
Topics: Animals; Cataplexy; Hypothalamic Hormones; Melanins; Mice; Mice, Transgenic; Neurons; Orexins; Pituitary Hormones; Sleep; Wakefulness
PubMed: 32314734
DOI: 10.7554/eLife.54275 -
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 -
International Journal of Molecular... Feb 2024Ever since the discovery of the brain's orexin/hypocretin system, most research was directed toward unveiling its contribution to the normal functioning of individuals.... (Review)
Review
Ever since the discovery of the brain's orexin/hypocretin system, most research was directed toward unveiling its contribution to the normal functioning of individuals. The investigation of reward-seeking behaviors then gained a lot of attention once the distribution of orexinergic neurons was revealed. Here, we discuss findings on the involvement of orexins in social interaction, a natural reward type. While some studies have succeeded in defining the relationship between orexin and social interaction, the controversy regarding its nature (direct or inverse relation) raises questions about what aspects have been overlooked until now. Upon examining the literature, we identified a research gap concerning conditions influencing the impact of orexins on social behavior expression. In this review, we introduce a number of factors (e.g., stress, orexin's source) that must be considered while studying the role of orexins in social interaction. Furthermore, we refer to published research to investigate the stage at which orexins affect social interaction and we highlight the nucleus accumbens (NAc) shell's role in social interaction and other rewarding behaviors. Finally, the underlying orexin molecular pathway influencing social motivation in particular illnesses is proposed. We conclude that orexin's impact on social interaction is multifactorial and depends on specific conditions available at a time.
Topics: Humans; Orexins; Neuropeptides; Motivation; Social Interaction; Nucleus Accumbens
PubMed: 38473854
DOI: 10.3390/ijms25052609