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Translational profiling of hypocretin neurons identifies Lhx9 as necessary for normal development of the hypocretinergic system.

ABSTRACT: The immense molecular diversity of neurons challenges our ability to deconvolve the relationship between the genetic and the cellular underpinnings of neuropsychiatric disorders. Hypocretin (orexin) containing neurons of the lateral hypothalamus are clearly essential for the normal regulation of sleep and wake behaviors, and have been implicated in feeding, anxiety, depression and reward. However, little is known about the molecular phenotypes of these cells, or the mechanism of their specification. We have generated a Hcrt bacTRAP line for comprehensive translational profiling of these neurons in vivo. From this profile, we have identified 188 transcripts, as enriched in these neurons, in additions to thousands more moderately enriched or nominally expressed. We validated many of these at the RNA and protein level, including the transcription factor Lhx9. Lhx9 protein is found in a subset of these neurons, and ablation of these gene results in a 30% loss of Hcrt neuron number, and a profound hypersomnolence in mice. This data suggests that Lhx9 may be important for specification of some Hcrt neurons, and the subsets of these neurons may contribute to discrete sleep phenotypes.

ORGANISM(S): Mus musculus

PROVIDER: GSE38668 | GEO | 2013/03/22

SECONDARY ACCESSION(S): PRJNA168457

REPOSITORIES: GEO

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Translational profiling of hypocretin neurons identifies Lhx9 as necessary for normal development of the hypocretinergic system.

Project description:The immense molecular diversity of neurons challenges our ability to deconvolve the relationship between the genetic and the cellular underpinnings of neuropsychiatric disorders. Hypocretin (orexin) containing neurons of the lateral hypothalamus are clearly essential for the normal regulation of sleep and wake behaviors, and have been implicated in feeding, anxiety, depression and reward. However, little is known about the molecular phenotypes of these cells, or the mechanism of their specification. We have generated a Hcrt bacTRAP line for comprehensive translational profiling of these neurons in vivo. From this profile, we have identified 188 transcripts, as enriched in these neurons, in additions to thousands more moderately enriched or nominally expressed. We validated many of these at the RNA and protein level, including the transcription factor Lhx9. Lhx9 protein is found in a subset of these neurons, and ablation of these gene results in a 30% loss of Hcrt neuron number, and a profound hypersomnolence in mice. This data suggests that Lhx9 may be important for specification of some Hcrt neurons, and the subsets of these neurons may contribute to discrete sleep phenotypes. Four independent TRAP replicates were collected, and total RNA from both the immunoprecipitate(IP) and unbound(total) fractions were seperately amplified and hybridized. Unbound fractions are provided to serve as total RNA controls for the tissue. Biological replicates are GCRMA normalized within groups. Following averaging of replicates, we recommend further global normalization between groups, using affymetrix biotinylated controls, to correct for any broad biases in scanning and hybridization. Finally for many analyses, we also recommend filtering to remove those probesets with low IP/Total fold change values from each cell type(see PMID:20962086). Researchers can contact us for spreadsheets where these additional steps have been completed.

2013-03-22 | E-GEOD-38668 | biostudies-arrayexpress

Transcriptome analysis of different brain areas in Hcrt gene and Hcrt cell ablated mice

Project description:Hypocretin (HCRT) and melanin concentrating hormone (MCH) are brain neuropeptides regulating a wide range of functions including sleep and metabolism. Loss of function of HCRT causes the sleep disorder narcolepsy. We found that loss of HCRT neurons in Hcrt-ataxin-3 mice results in a specific 50% decrease in another orexigenic neuropeptide QRFP that might explain the metabolic syndrome in narcolepsy.

2019-09-01 | GSE126345 | GEO

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

Molecular codes defining lateral hypothalamic sleep regulating neurons

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

Hypocretin-specific CD4+ T cells in narcolepsy patients and controls: in vivo clonal expansion and phenotypes

Project description:Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found the associations of narcolepsy with human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor α (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. However, DQ6+ individuals generate DQ6-HCRT tetramer+/TRAJ24+ TCRs. Without a proof that an HCRT-reactive cell expressing such TCRs has expanded in vivo, T cell-mediated autoimmunity in narcolepsy remains speculative. Here, we isolated DQ6-HCRT tetramer+/CD4+ T cells (low frequency, <0.04%) from DQ6+ individuals with/without narcolepsy. Within 74 informative TRAJ24+ TCRαβ from 8/12 patients and 11/12 controls, we identified a conserved family of clonotypes shared by 2 patients and 2 controls using identical α/β genes. TRAJ24-G allele+ clonotypes only expanded in the two patients, whereas a TRAJ24-C allele+ clonotype expanded in a control. A representative tetramer+/G-allele+ TCR showed signaling reactivity to the physiologically modified form of the epitope HCRT87-97. Clonally expanded G-allele+ T cells also exhibited an unconventional effector phenotype. In vivo expansion of HCRT-reactive TRAJ24-G allele+ cells provides critical evidence for an autoimmune contribution to narcolepsy development.

2019-10-15 | GSE135852 | GEO

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

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

| PRJNA1182770 | ENA

Molecular and Cellular Mechanisms for Differential Effects of Chronic Social Isolation Stress in Males and Females

Project description:Chronic social isolation stress during adolescence induces susceptibility for neuropsychiatric disorders. Here we show that 5-week post-weaning isolation stress induces sex-specific behavioral abnormalities and neuronal activity changes in the prefrontal cortex (PFC), basal lateral amygdala (BLA), and ventral tegmental area (VTA). Chemogenetic manipulation, optogenetic recording, and in vivo calcium imaging identify that the PFC to BLA pathway is causally linked to heightened aggression in stressed males, and the PFC to VTA pathway is causally linked to social withdrawal in stressed females. Isolation stress induces genome-wide transcriptional alterations in a region-specific manner. Particularly, the upregulated genes in BLA of stressed males are under the control of activated transcription factor CREB, and CREB inhibition in BLA normalizes gene expression and reverses aggressive behaviors. On the other hand, neuropeptide Hcrt (Hypocretin/Orexin) is among the top-ranking downregulated genes in VTA of stressed females, and Orexin-A treatment rescues social withdrawal. These results have revealed molecular mechanisms and potential therapeutic targets for stress-related mental illness.

2022-03-22 | GSE198725 | 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

2010-02-24 | E-GEOD-17617 | biostudies-arrayexpress

Gene profiling within the orexin-producing neurons

2010-02-15 | GSE17617 | GEO

Sleep Deprivation and Recovery Sleep for 7 Regions of Mouse Brain.

Project description:Analysis of the effects of sleep deprivation, recovery sleep, and three time-of-day controls on seven brain regions laser microdissected from mouse brain. The regions include the locus coeruleus, suprachiasmatic nucleus, hypocretin area, tuberomammillary nucleus, orbital cortex, posteromedial cortical amygdala, and entorhinal cortex.

2010-08-17 | GSE23628 | GEO

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