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Transcriptomic changes after orexin receptor antagonism in P301S/E4 mouse model of tauopathy

ABSTRACT: Our aim was to investigate whether increasing sleep via orexin receptor antagonism can modify tau-mediated neurodegeneration and neuroinflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE283736 | GEO | 2025/02/25

REPOSITORIES: GEO

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Orexin/Hypocretin Receptor 2 Signaling in MCH Neurons Regulates REM sleep and Insulin Sensitivity

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

Gene profiling within the orexin-producing neurons

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

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Global Analysis of Gene Expression Mediated By Orexin Receptor 1 Signaling in a Hypothalamic Cell Line

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.

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The in vitro influence of orexin B on the porcine myometrium on days 15 to 16 of gestation.

Project description:Orexin A (OXA) and orexin B (OXB) are hypothalamic-derived peptides that participate in the regulation of energy metabolism, food intake and reproductive function by influencing the hypothalamic-pituitary-ovarian axis. Orexins are also produced in the endometrium, myometrium and placenta, which suggests that they could act as a link between energy metabolism and the reproductive system. The aim of this study was to explore the influence of orexin B on global gene expression in the porcine myometrium during early gestation, on days 15 to 16 of pregnancy (implantation period).

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