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Abstract

Corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release and has a key role in stress-related behaviours. In addition, the corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioural adaptation to stress and is causally linked to stress-related emotional disorders. However, there are still unanswered questions. In this study, single-nucleus sequencing was conducted to resolve the heterogeneity of midbrain CRHR1 neurons encompassing dopaminergic, GABAergic and glutamatergic neurons, which was further substantiated by immunostaining. Anterograde and retrograde tracings revealed strong projections of extended amygdala CRH neurons into the VTA and SN. Chemogenetic and optogenetic manipulation demonstrated that activation of CRH neurons in the interstitial nucleus of the posterior limb of the anterior commissure (IPACL), resulted in maladaptive behaviour, arousal and place aversion. Systemic injection of the CRHR1 antagonist R121919 was sufficient to reverses these behaviours indicating a direct role of CRH and CRHR1 in these circuits contributing to the behavioural outcomes. Overall, this study uncovered a novel CRH circuit originating from the IPACL, which is a part of extended amygdala innervating the SN. This circuit is modulated by the CRH/CRHR1-system and is involved in the regulation of arousal and place aversion behaviour.