The roles of corticotropin-releasing hormone (CRH) in stress-induced cognitive deficits in mice
Abstract
Corticotropin-releasing hormone (CRH) is widely known as a hormone that mediates stress responses via the hypothalamus-pituitary-adrenal (HPA) axis. Besides its neuroendocrine release, CRH is also expressed in various neuron types distributed across brain areas. In the medial prefrontal cortex (mPFC), CRH has been shown to mediate stress-related behavioural and cognitive changes. Recently, our group showed that acute stress impaired spatial working memory in mice, and pharmacological blockade of CRHR1 in the mPFC prevented the stress-induced impairment. However, it remains unknown how stress affects the CRH-CRHR1 signalling in the mPFC relevant to spatial working memory impairment. We hypothesized that stress activates CRH-expressing interneurons in the mPFC and drives their CRH release to signal through CRHR1. We first confirmed that restraint stress increased the activity of CRH neurons in the posterior mPFC by using immunofluorescence for cFos and in vivo GCaMP6 calcium sensor-fibre photometry imaging. Next, we used a newly developed CRH sensor (GRABCRF) in freely behaving mice. Surprisingly, we discovered that extracellular CRH levels in the mPFC decreased during and after the restraint stress. The unexpected decrease in CRH sensor signal is possibly caused by the release of CRH-binding protein (CRHBP), and I provide supporting data that CRHBP profoundly decreases CRH sensor signal in ex vivo and in vivo. This study will help us understand how the CRH system in the mPFC mediates stress-induced working memory deficits.