GSE193417
Cell-Specific Transcriptomic Analysis of CRH+ cells Identifies Unique Cellular Responses to Chronic Stress
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. Overall design: Examination of gene expression in CRH+ cell from post-mortem subgenual anterior cortex of individuals with Major Depressive Disorder or healthy controls