Biochemical characterization of the CRH receptor 1 brain expression pattern and its genetic dissection in neurotransmitter-specific circuits: Inhibitory role on the HPA axis activity and unexpected anxiolytic effects on stress-induced anxiety

Abstract

The corticotropin-releasing hormone (CRH) possesses a dual property acting as a secretagogue controlling the hypothalamic-pituitary-adrenal (HPA) axis and as a neuromodulator within extrahypothalmic sites in order to orchestrate the neuroendocrine and behavioral adaptation to stress. However, it is largely unclear, which neurotransmitter systems are direct targets of CRH and which neurotransmitter circuits are involved in modulating CRH-R1-dependent behaviors. In order to ultimately dissect the neurotransmitter identity of neurons expressing the CRHR1 we comprehensively mapped CRHR1 expression throughout the brain by histochemical means and by using a newly developed CRHR1-EGFP reporter mouse line. We fully recapitulated these mapping results by applying a genetic strategy where we selectively ablated CRH-R1 in glutamatergic, GABAergic, dopaminergic or serotonergic circuits of the mouse brain or in the entire CNS – an approach which subsequently allowed us to delineate the specific impact of each neurotransmitter system on CRH-R1-dependent behaviors and HPA-axis functioning. Using these mouse lines we found that anxiogenic effects of CRHR1 are mediated by glutamatergic neurotransmission in the forebrain and uncovered a previously unknown anxiolytic role of CRHR1 that is mediated by dopaminergic circuits of the midbrain. Finally, the endocrinological profile observed in these different mouse lines suggests a role for hypothalamic CRHR1 in the negative feedback control of the HPA axis.