Single-Cell Transcriptomics of hypothalamic CRH-expressing neurons informs mechanisms by which Early-Life Adversity sculpts stress-responses enduringly
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PROVIDER: PRJNA728123 | ENA |
REPOSITORIES: ENA
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Project description:Mental and cognitive health, as well as vulnerability to neuropsychiatric disorders, involve the interplay of genes with the environment during sensitive developmental periods. Genetic and environmental factors contribute to the development and maturation of neurons, synapses, and the resulting brain circuits. Within the hypothalamus, early-life experiences cause changes in the number of excitatory synapses onto corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN). Further, such synaptic changes suffice to induce enduring epigenomic changes within these cells, influencing programs of gene expression. However, the epigenetic mechanisms by which early-life experiences orchestrate transcriptional programs within individual CRH-expressing neurons, with enduring functional consequences, remain unknown. We utilize animal models of an impoverished environment and unpredictable maternal care (in a limited bedding and nesting [LBN] paradigm), which provokes major alterations in cognitive and emotional outcomes. We are focused on the change in gene expression profiles of stress-sensitive CRH-neurons in the PVN following early-life adversity (ELA). Because of the known heterogeneity of CRH-expressing neuronal populations, we are using single-cell RNA sequencing (RNA-seq) to determine differential gene expression associated with early-life adversity and establish the upstream mechanisms and downstream consequences. We found that CRH-expressing populations of neurons in the PVN can be clustered by both their gene expression profiles as well as by their neurotransmitter phenotype. ELA significantly modified gene expression programs in some neuronal clusters more than others, reducing programs of neuronal development and differentiation and enhancing gene families involved in responses to stress and inflammation. The use of single-cell transcriptomics revealed that ELA impacts gene expression profiles in a cell-type specific manner, with distinctive influence on the different clusters and subpopulations of CRH neurons.
2022-05-06 | GSE174085 | GEO
Project description:The molecular mechanism regulating phasic corticotropin-releasing hormone (CRH) release from parvocellular neurons (PVN) remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single-cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH-releasing neuron population reliant on secretagogin’s Ca2+ sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone.
2014-11-20 | GSE63093 | GEO
Project description:The molecular mechanism regulating phasic corticotropin-releasing hormone (CRH) release from parvocellular neurons (PVN) remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single-cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH-releasing neuron population reliant on secretagoginM-bM-^@M-^Ys Ca2+ sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone. single cells from the PVN region juvenile (21-28 days) mice were dissected and subject to whole transcriptome analysis
2014-11-20 | E-GEOD-63093 | biostudies-arrayexpress
Project description:Here we translationally profiled the transcriptome of Crh-expressing neurons (Crh neurons) within the CeA following fear conditioning (FC) and fear extinction (EXT) in mice using translating ribosome affinity purification (TRAP) followed by RNA sequencing. A tone alone group (TA) was used as a control group.
2020-09-05 | GSE157021 | GEO
Project description:Recent genome-wide association studies (GWAS) identified Dusp8, a dual-specificity phosphatase targeting MAP kinases, as type 2 diabetes risk gene. Here, we unravel Dusp8 as gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male but not female Dusp8 loss-of-function mice, either with global or CRH neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic–pituitary–adrenal (HPA) axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of male Dusp8 KO mice, respectively. This sex-specific and rheostatic role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity and systemic glucose tolerance was consistent with fMRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. In summary, our findings suggest GWAS-identified gene Dusp8 as novel hypothalamic factor that plays a functional role in the etiology of type 2 diabetes.
2020-08-17 | PXD019451 | Pride
Project description:We generated a single nuclei RNA-seq (snRNA-seq) dataset derived from the postnatal hypothalamus of CRH-IRESCre (CRH-Cre) mice using a retrograde Connect-seq approach.
2023-08-19 | GSE240765 | GEO
Project description:Early life adversity has been linked to altered reproductive development in humans, including changes in the timing of pubertal onset and sexual activity. One common form of early life adversity is having limited access to resources. This form of early life adversity can be modeled in rodents using the limited bedding and nesting model (LBN), in which rat dams and pups are placed in a low resource environment from postnatal day (PND) 2 through 9. Our laboratory has previously shown that male rats raised in LBN conditions have elevated levels of plasma estradiol compared to control males. Female rats, on the other hand, show no effect of LBN on plasma hormone levels, pubertal timing, or estrous cycle duration in adulthood. Here, we find that LBN males also show changes in adult reproductive behaviors. LBN males acquired the suite of reproductive behaviors more quickly than their control counterparts over the course of 3 weeks of testing, showing shorter latencies to mount, intromit, and ejaculate compared to controls prior to the final week of testing. We also characterized LBN-induced gene transcription changes across sex in the medial preoptic area (mPOA) which underlies reproductive behaviors. Interestingly, there was no effect of LBN on puberty onset (as measured by preputial separation) or masculinization of the sexually dimorphic nucleus of the preoptic area (SDN/POA; as measured by calbindin immunoreactivity) in males, suggesting LBN may not exert effects on hormone-dependent measures until after puberty.
2022-02-15 | GSE174753 | GEO
Project description:Genome-wide translational profiling of amygdala Crh-expressing
| PRJNA659794 | ENA
Project description:Rationale: A previous transcriptome meta-analysis revealed significantly lower levels of corticotropin-releasing hormone (CRH) mRNA in corticolimbic brain regions in major depressive disorder (MDD) subjects. Rodent studies show that cortical CRH is mostly expressed in GABAergic neurons; however, the characteristic features of CRH+ cells in human brain cortex and their association with MDD are largely unknown. Methods: Subgenual anterior cingulate cortex (sgACC) of human subjects without brain disorders were labeled using fluorescent in situ hybridization (FISH) for CRH and markers of excitatory (SLC17A7), inhibitory (GAD1) neurons, as well as markers of other interneuron subpopulations (PVALB, SST, VIP). MDD-associated changes in CRH+ cell density and cellular CRH expression (n=6/group) were analyzed. RNA-sequencing was performed on sgACC CRH+ neurons from comparison and MDD subjects (n=6/group), and analyzed for group differences. Results: About 80% of CRH+ cells were GABAergic and 17.5% were glutamatergic. CRH+ GABAergic neurons co-expressed VIP (52%), SST (7%), or PVALB (7%). MDD subjects displayed lower CRH mRNA levels in GABAergic neurons relative to comparison subjects without changes in cell density. CRH+ neurons show transcriptomic profile suggesting lower excitability and less GABA release and reuptake. Further analyses suggested that these molecular changes are not mediated by altered glucocorticoid feedback and potentially occur downstream for a common modulator of neurotrophic function. Summary: CRH+ cells in human sgACC are a heterogeneous population of GABAergic neurons, although largely co-expressing VIP. MDD is associated with reduced markers of inhibitory function of CRH+ neurons.
2022-02-22 | GSE193417 | GEO
Project description:MCF7 cells were stimulated with vehicle or 100nM corticotropin releasing hormone (CRH) for 24h. The effect of CRH on the expression of genes relevant to estrogen signalling was investigated by using the Human Estrogen Receptor Signaling RT² Profiler™ PCR Array (SABioscience Corp).
2013-07-02 | GSE47958 | GEO