Chronic stress causes striatal disinhibition mediated by SOM-interneurons

Chronic stress is a major triggering factor for neuropsychiatric disorders including obsessive-compulsive disorder (OCD), a mental health condition characterized by motor stereotypies and striatal overactivation. However, the mechanisms at the cell- and microcircuit-level through which stress triggers motor symptoms is currently unknown. Here, we report that chronic stress (CS) in mice alters dorsomedial striatum (DMS) function, by affecting GABAergic interneuron populations and somatostatin-positive (SOM) interneurons in particular. Specifically, we show that CS impairs communication between SOM interneurons and medium spiny neurons, promoting striatal overactivation / disinhibition and increased motor output. Using probabilistic machine learning for analyzing animal behavior we further demonstrate that in vivo chemogenetic manipulation of SOM interneurons in DMS modulates motor phenotypes in stressed mice. Altogether, we propose a causal link between dysfunction of striatal SOM interneurons and motor symptoms in stress-related neuropsychiatric disorders.