Investigating the microcircuit role of striatal fast-spiking interneurons in Obsessive-Compulsive disorder

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ABSTRACT Obsessive-compulsive disorder (OCD), and related obsessive-compulsive (OC) spectrum disorders, are characterized by an inability to suppress unwanted repetitive behaviors. Human imaging work implicates cortico- basal ganglia circuits in these disorders, but there is little information about the specific cell-types or microcircuitry involved. The striatum is the main input structure of the BG and receives massive cortical innervation. Fast- spiking interneurons (FSIs) in the striatum are strongly implicated in the ability to choose suppress or select behaviors, which is a key deficit in OCD and OC spectrum disorders. Additionally, abnormalities in FSIs have are associated with disorders involving aberrant behavioral suppression or selection. Thus, my central hypothesis is that deficient striatal FSI function causes hyperactivity in striatal output neurons and plays a role in OCD-like behaviors. A compelling mouse model of OCD-like behaviors (Sapap3-KO) is associated with decreased cortical drive onto principal striatal cells. These principal cells, however, are hyperactive in vivo. This suggests deficient local inhibition leads to OCD-relevant behaviors, and FSIs are the strongest local inhibitory neurons in striatum. This proposal will 1) examine differences in striatal FSI intrinsic excitability between Sapap3-KO and healthy WT mice, 2) investigate differences in corticostriatal functional synapses onto striatal FSIs and FSI synapses onto MSNs in Sapap3-KO and healthy WT mice, and 3) determine whether directly increasing synchronous FSI activity can restore normal behavioral and neuronal activity in OCD-like mice. This research will culminate in knowledge on specific microcircuits involved in OCD-like symptoms and striatal FSI function underlying behavioral suppression. The integrated research and training plan will provide valuable expertise in ex vivo and in vivo electrophysiology, behavior, and optogenetics. These skills are critical for the applicant’s ultimate goals of transitioning into an independent investigator, and integrating circuit, systems, and translational neuroscience to understand behavioral symptoms of OC spectrum disorders.