Orexin/Hypocretin Receptor 2 Signaling in MCH Neurons Regulates REM sleep and Insulin Sensitivity
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PROVIDER: PRJNA1182770 | ENA |
REPOSITORIES: ENA
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Project description:Orexin/hypocretin receptor type 2 (Ox2R), which is widely expressed in the brain, receives orexin signals and modulates sleep and metabolism. Ox2R selective agonists are currently under clinical trials for narcolepsy treatment. Nevertheless, it remains unclear whether Ox2R exerts an inhibitory effect via Gi proteins in addition to an excitatory effect via Gq proteins. Here, we focused on Ox2R expression and function in MCH neurons, which have opposite roles to orexin neurons in sleep and metabolism regulation. Ox2R-expressing MCH neurons showed heterogeneity of RNA expression, and orexin B application in brain slices induced both excitatory and inhibitory responses in distinct MCH neuron populations. Ox2R inactivation in MCH neurons reduced transitions from NREM to REM sleep and impaired insulin sensitivity with hyperphagia. In conclusion, Ox2R mediates excitatory and inhibitory responses in MCH neuron subpopulations in vivo, which might regulate sleep and metabolism.
2024-11-19 | GSE281229 | GEO
Project description:In Alzheimer’s disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment. Hippocampal hyperactivity and decreased sleep quality are associated with early AD, but their basis is poorly understood. We find that homeostatic mechanisms transiently counteract increased excitatory drive of hippocampal CA1 neurons in AppNL-G-F mice, but fail to stabilize it at control levels. Spatial transcriptomics (ST) analysis identifies the Pmch gene encoding Melanin-Concentrating Hormone (MCH) as part of the adaptive response in AppNL-G-F mice. Hypothalamic MCH peptide is produced in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission and modulates firing rate homeostasis in hippocampal neurons. Moreover, MCH reverses the increased excitatory drive of CA1 neurons in AppNL-G-F mice. Consistent with our finding that a reduced fraction of MCH-neurons is active in AppNL-G-F mice, these animals spend less time in rapid eye movement (REM) sleep. In addition, MCH-axons projecting to CA1 become progressively impaired in both AppNL-G-F mice and AD patients. Our findings identify the MCH-system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampal-dependent functions.
2023-09-07 | GSE225181 | GEO
Project description:The perioculomotor (pIII) region of the midbrain was postulated as a sleep-regulating center in the 1890s but largely neglected in subsequent studies. Using activity-dependent labeling and gene-expression profiling, we identified pIII neurons that promote non-REM (NREM) sleep.
2019-05-01 | GSE124681 | GEO
Project description:Imprinted genes are highly expressed in the hypothalamus, however whether specific imprinted genes affect hypothalamic neuromodulators and their functions is unknown. It has been suggested that Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by lack of paternal expression at the chromosome 15q11-q13, characterised with a hypothalamic insufficiency. Here we investigate the role of paternally expressed Snord116 gene within the context of sleep and metabolic abnormalities of PWS, and we report a novel role of this imprinted gene in the function and organisation of the two main neuromodulatory systems of the lateral hypothalamus (LH), namely the orexin (OX) and the melanin concentrating hormone (MCH). We observe that the dynamic between neuronal discharge in the LH and sleep-wake states of mice carrying the paternal deletion of the Snord116 (PWScrm+/p-) is compromised. This abnormal state-dependent neuronal activity is paralleled by a significant reduction of OX neurons in LH of mutants. Therefore, we propose that unbalance between OX- and MCH- expressing neurons in the LH of mutants reflects in a series of deficits manifested in the PWS, such as dysregulation of rapid eye movement (REM) sleep, food intake and temperature control.
2020-05-25 | GSE139524 | GEO
Project description:Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). The best biological marker of narcolepsy is orexin deficiency with dramatic loss in hypothalamic orexin-producing neurons. Together with a tight HLA and T-cell receptor alpha(5) association, narcolepsy is believed to be autoimmune although all attempts to prove it have failed.To characterize orexin specific peptides we produced a transgenic mouse model to access to the orexin neurons transcription profile. We generated BAC-based transgenic mice by replacing the orexin coding sequence by a flag-tagged poly(A) binding protein (Pabp1) cDNA sequence. The basis of this construct is to take advantage of the ability of Pabp1 to bind to the poly(A) tails of mRNAs in vivo. Thus mRNAs from orexin cells are expected to be enriched by cross-linking them to the flag-tagged PABP and then co-immunoprecipitating this complex with a specific anti-flag monoclonal antibody. Keywords: cell type comparison
2010-02-15 | GSE17617 | GEO
Project description:Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). The best biological marker of narcolepsy is orexin deficiency with dramatic loss in hypothalamic orexin-producing neurons. Together with a tight HLA and T-cell receptor alpha(5) association, narcolepsy is believed to be autoimmune although all attempts to prove it have failed.To characterize orexin specific peptides we produced a transgenic mouse model to access to the orexin neurons transcription profile. We generated BAC-based transgenic mice by replacing the orexin coding sequence by a flag-tagged poly(A) binding protein (Pabp1) cDNA sequence. The basis of this construct is to take advantage of the ability of Pabp1 to bind to the poly(A) tails of mRNAs in vivo. Thus mRNAs from orexin cells are expected to be enriched by cross-linking them to the flag-tagged PABP and then co-immunoprecipitating this complex with a specific anti-flag monoclonal antibody. Keywords: cell type comparison Comparison between immunoprecipitated (IP) mRNA (n=9) and whole brain (WB) RNA (n=9) from BAC-based transgenic mice
2010-02-24 | E-GEOD-17617 | biostudies-arrayexpress
Project description:Hypothalamic hypocretin (HCRT) and melanin concentrating hormone (MCH) have multiple functions including sleep and metabolism. How these neuropeptides are produced and involved in divers functions remain unknown. We developed methods to sort and purify HCRT and MCH neurons from mouse hypothalamus. RNA-sequencing revealed key factors of fate determination for HCRT (Peg3, Ahr1, Six6, Nr2f2 and Prrx1) and MCH (Lmx1, Gbx2 and Peg3) neurons. Amongst these, loss of Peg3 in mice significantly reduces HCRT and MCH cell numbers while knock-down of Peg3 ortholog in zebrafish completely abolishes their expression resulting in a two fold increase in sleep. The transcriptome results were used to produce HCRT and MCH neurons from induced pluripotent stem cells (iPSCs) and ascorbic acid was found necessary for HCRT and BMP7 for MCH cell differentiation. Our results provide a platform to understand the development and expression of HCRT and MCH and their multiple functions in health and disease.
2019-09-01 | GSE126330 | GEO
Project description:An Excitatory Circuit in Perioculomotor Midbrain for Non-REM Sleep Control
| PRJNA513052 | ENA
Project description:The orexins/hypocretins and their cognate G-protein coupled receptors have been widely studied due to their associations with various behaviors and cellular processes. However, the detailed downstream signaling cascades that mediate these effects are not completely understood. We report the generation of a neuronal model cell line that stably expresses orexin receptor 1 and an RNA-Seq analysis of changes in gene expression seen upon receptor activation. Upon treatment with orexin, several related families of related transcription factors are transcriptionally regulated, including the early growth response genes (Egr), the Kruppel-like factors (Klf), and the Nr4a subgroup of nuclear hormone receptors. Furthermore, the transcriptional effects observed showed a degree of similarity with data from in vivo sleep deprivation microarray studies, supporting the physiological relevance of the data set. These results provide new insight into the molecular signaling events that occur during orexin receptor 1 signaling and support a role for orexin signaling in the stimulation of wakefulness during sleep deprivation studies.
2018-02-13 | GSE99690 | GEO