Closed-loop recruitment of striatal parvalbumin interneurons prevents the onset of compulsive behaviours

ABSTRACT A prominent electrophysiological feature of compulsive behaviours is striatal hyperactivity, yet, its underlying regulatory processes still need to be characterised. Within the striatum, parvalbumin-positive interneurons (PVI) exert a powerful feed-forward inhibition essential for the regulation of striatal activity and are implied in the suppression of prepotent inappropriate actions. To investigate the potential role of striatal PVI in regulating striatal activity and compulsive behaviours, we used the Sapap3 knockout mice (Sapap3-KO), which exhibit compulsive-like self-grooming. We first showed that the number of compulsive-like events in Sapap3-KO mice was reduced to normal levels by continuous optogenetic activation of striatal PVI in the centromedial striatum. To narrow down the critical time window of striatal PVI recruitment for regulating compulsive-like grooming, we then developed a novel closed-loop optogenetic stimulation pipeline. Upon a predictive biomarker of grooming onsets, characterised by a transient power increase of 1-4 Hz frequency band in the orbitofrontal cortex, we provided real-time closed-loop stimulation of striatal PVI. This targeted closed-loop optogenetics approach reduced grooming events as efficiently as continuous recruitment of striatal PVI with a reduction of stimulation time of 87%. Together, these results demonstrated that recruitment of striatal PVI at the initiation of the compulsive events is sufficient to drastically reduce compulsive-like behaviours and pave the way for targeted closed-loop therapeutic protocols.