Exploring corticostriatal dynamics associated with action control deficits in Neurexin1 alpha mutant mice

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Project Summary: A number of neurodevelopmental disorders including autism spectrum disorder, attention- deficit/hyperactivity disorder and Tourette syndrome exhibit characteristic motor-related symptoms such as repetitive or impulsive action patterns. It is possible that these behaviors are a result of dysregulated action control mechanisms mediated via cortico-basal-thalamic pathway disruption. However, it is not currently understood how alterations in these circuits give rise to the deficits in action control commonly observed in these disorders. Copy number variation of genes encoding for synaptic adhesion molecules, such as Neurexin1α (Νrxn1α), have been shown to confer a significantly increased risk for these disorders, however, the underlying neural etiopathology is currently unknown. Recent findings in acute striatal slices have revealed that loss of Νrxn1α function results in decreased synaptic strength of medial prefrontal cortical inputs to the indirect pathway of the dorsal striatum, providing a potential neural mechanism for irregular action control. However, it is unclear whether these synaptic deficits confer variations to larger scale neural dynamics related to action control dysfunction in vivo. I hypothesize that these Νrxn1α mutations drive action control deficits (Aim 1) via mutation-associated corticostriatal circuit alterations specific to the indirect pathway (Aim 2) in Nrxn1a KO mice. To assay multiple key aspects of action control, I will employ a novel treadmill-based operant task that allows for the comprehensive study of action initiation, suppression, and modulation. Using dual-site in vivo electrophysiological techniques, I plan to describe the underlying corticostriatal population recruitment related to task performance in two fronto-striatal circuits (mPFC→DMS and M2→DLS) in both Νrxn1α WT and Νrxn1α KO mice. These findings will provide valuable insight into the neural pathology involved in many neuropsychiatric and neurodevelopmental disorders as well as elucidate corticostriatal neural mechanisms involved in action control regulation.