The Circuit Basis of Cocaine-Induced Orofacial Stereotypies

Background Repeated exposure to psychoactive drugs frequently result in the development of dyskinesias, often involving the face and upper limbs, as in tardive dyskinesia, akathisia, acute dystonia and levodopa-induced dyskinesia. Repeated exposure to cocaine results in choreodystonic dyskinesia, often in the form of orofacial stereotypic behavior. Control of orofacial actions maps to the ventrolateral aspect of the dorsal striatum, motivating our study. Aims & Objectives We aimed to address the neural circuit basis of orofacial stereotypies driven by cocaine, utilizing cutting-edge machine learning and systems neuroscience approaches. Method To this end, we established a paradigm of repeated cocaine exposure in mice, following which mice developed a commitment to orofacial stereotypies. In order to efficiently quantify behavior and support a systems neuroscience analysis of the neural circuit basis of these orofacial stereotypies, we developed a machine-learning based image analysis approach (STEREO) for quantification of mouse behavior. We then utilized fiber photometry, optogenetic and chemogenetic approaches for circuit analysis. Results Following cocaine exposure, mice spent on average ~65% of their time performing orofacial stereotypies, as quantified by STEREO. Optogenetic stimulation of dSPNs in the ventrolateral striatum (VLS) of mice recapitulated this observation, while optogenetic stimulation of VLS iSPNs normalized mouse behavior. Bidirectional chemogenetic modulation consistently alleviated or exacerbated cocaine-induced stereotypies, while calcium photometry associated different signatures of dSPN and iSPN activity with natural vs cocaine-induced orofacial behaviors. Discussion & Conclusions Together, out results unambiguously associate the VLS with the generation of orofacial behaviors, and provide a neural circuit basis for the development of cocaine-induced stereotypies, possibly relevant to the broader spectrum of drug-induced dyskinesias. Our results open the door to a broad spectrum of studies addressing the circuit basis of volitional vs involuntary action, providing mechanistic insights into long-standing questions regarding free will.