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Research has repeatedly shown autism to involve the brain’s cerebellum. However, we have yet to identify the cerebellum-regulated circuits that mediate autism’s core symptoms. Our preliminary data implicate the medial prefrontal cortex (mPFC) as a potential downstream target of the cerebellum, and we hypothesize that ASD behaviors are regulated by specific cerebellar circuits to the mPFC.

To test our hypothesis, we aim to:

1) Confirm functional connectivity between the cerebellum and the mPFC. To do so, we will determine functional connectivity by performing in vivo single unit recordings from neurons in the mPFC while modulating autism-related cerebellar domains with chemogenetics in mouse models of autism.

2) Determine cerebellar-mPFC circuits mediating ASD related behaviors. This is important because past research has shown connections between the cerebellum and the mPFC via the thalamus and ventral tegmental area. Using in vivo optogenetics, we will delineate which of the cerebellar-mPFC circuits mediate autism-related behaviors.

3) Rescue behavioral deficits in mouse models of ASD through modulation of cerebellar-mPFC circuit activity. We will evaluate therapeutic benefit of in vivo optogenetic manipulation of cerebellar-mPFC circuits on autism behaviors in mouse models of tuberous sclerosis and fragile X syndrome.

Therefore the proposed studies will define one of the circuits underlying cerebellar regulation of ASD and delineate the therapeutic benefit of circuit modulation for the treatment of ASD.