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.
Highlights
Since its discovery in 1981 by Wylie Vale and colleagues (Vale et al, 1981), the neuropeptide corticotropin-releasing hormone (CRH) has become known as the key orchestrator of the neuroendocrine, autonomic and behavioral responses to stress (Deussing, 2013; Janssen and Kozicz, 2013; Dedic et al, 2017; Deussing and Chen, 2018)
Using sensitive in situ hybridization (ISH) methods, we recently mapped the neurochemical identity of Crh neurons across the mouse brain, revealing an overwhelming majority of GABAergic (Gad65/67-positive) CRH neurons in the cortex, hippocampus, central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), which has been reported by others (Kubota et al, 2011; Kubota, 2013; Dedic et al, 2018a; Gunn et al, 2019)
In order to dissect the role of Crh in GABAergic circuits we crossed the recently generated Crhflox/flox mice with Dlx5/6-Cre transgenic mice (Rodríguez et al, 2000; Kamprath et al, 2006; Monory et al, 2006), in which Cre is driven by the regulatory sequences of the Dlx5/Dlx6 homeobox genes expressed in migrating, forebrain GABAergic neurons during development (E10)
Summary
Since its discovery in 1981 by Wylie Vale and colleagues (Vale et al, 1981), the neuropeptide corticotropin-releasing hormone (CRH) has become known as the key orchestrator of the neuroendocrine, autonomic and behavioral responses to stress (Deussing, 2013; Janssen and Kozicz, 2013; Dedic et al, 2017; Deussing and Chen, 2018). Our work extended these findings by identifying the source of the “anxiolytic” CRH neurons These represent a distinct subpopulation of GABAergic, long-range projecting neurons in the extended amygdala that target CRHR1 on dopaminergic VTA neurons to positively modulate emotional behavior by regulating dopaminergic neurotransmission (Dedic et al, 2018a). These findings were obtained from naïve animals, which poses the question as to whether specific CRH circuits might modulate different behaviors under baseline and stressful conditions. Whether severe stress is able to switch CRH action from positive to negative in the context of anxiety, social and/or depression-like behavior, remains largely unexplored
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