Deletion of CRH From GABAergic Forebrain Neurons Promotes Stress Resilience and Dampens Stress-Induced Changes in Neuronal Activity

Abstract

Dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in stress-related psychopathologies such as depression and anxiety. Although most studies have linked CRH/CRH receptor 1 signaling to aversive, stress-like behavior, recent work has revealed a crucial role for distinct CRH circuits in maintaining positive emotional valence and appetitive responses under baseline conditions. Here we addressed whether deletion of CRH, specifically from GABAergic forebrain neurons (CrhCKO–GABA mice) differentially affects general behavior under baseline and chronic stress conditions. Expression mapping in CrhCKO–GABA mice revealed absence of Crh in GABAergic neurons of the cortex and limbic regions including the hippocampus, central nucleus of the amygdala and the bed nucleus of the stria terminals, but not in the paraventricular nucleus of hypothalamus. Consequently, conditional CRH knockout animals exhibited no alterations in circadian and stress-induced corticosterone release compared to controls. Under baseline conditions, absence of Crh from forebrain GABAergic neurons resulted in social interaction deficits but had no effect on other behavioral measures including locomotion, anxiety, immobility in the forced swim test, acoustic startle response and fear conditioning. Interestingly, following exposure to chronic social defeat stress, CrhCKO–GABA mice displayed a resilient phenotype, which was accompanied by a dampened, stress-induced expression of immediate early genes c-fos and zif268 in several brain regions. Collectively our data reveals the requirement of GABAergic CRH circuits in maintaining appropriate social behavior in naïve animals and further supports the ability of CRH to promote divergent behavioral states under baseline and severe stress conditions.

Corticotropin-Releasing Factor Induces Functional And Structural Synaptic Remodelling In Acute Stress

“…In contrast, either CRF-R1 or CRF-R2 activation (or both) was sufficient to enhance long-term plasticity (Fig.4h,-i). Our data supports CRF as a positive regulator of synaptic transmission, in agreement with other reports describing CRF generally as a facilitator of excitatory neurotransmission throughout different brain regions (31,55,73,74).…”

“…To confirm our direct stress response in the hippocampus we performed in situ hybridization analysis for immediate early genes crh and cfos . (53–55), in mice 20 minutes after being subjected to FS. We observed a local increase of crh and cfos mRNA expression in the CA1 PC layer (Fig.1h-i), demonstrating an upregulation of immediate early genes in the CA1 PC layer directly after acute stress.…”

Genetic and Neuroimaging Approaches to Understanding Post-Traumatic Stress Disorder

“…A recent study revealed the absence of Crh in the GABAergic neurons by expression mapping in Crh CKO-GABA mice. This absence of Crh from the forebrain GABAergic neurons resulted in social interaction deficits in mice, suggesting the role of CRH in the regulation of social behavior in neuropsychological disorders such as PTSD [89]. The Crh CKO-GABA mice displayed a resilient phenotype upon exposure to chronic social defeat stress accompanied by a stress-induced expression of c-fos and zif268 genes in several regions of the brain.…”

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

“…Stress is a major contributor to the etiology of anxiety and depression (Dedic et al, 2019). We used the EPM and OFT to evaluate the effects of CRS on anxiety-like behavior in pups in FIGURE 1 | Effect of PS on embryo development.…”