Regulation of Autism-Relevant Behaviors by Distinct Cerebellar-Prefrontal Cortical Circuits

Long thought to have exclusive roles in motor coordination, the cerebellum is increasingly implicated in the regulation of complex behavior and cognition, while cerebellar dysfunction has been demonstrated in many neuropsychiatric disorders, including autism spectrum disorders (ASD). However, the circuit mechanisms and cerebellar regions underlying the cerebellar contribution to ASD behaviors remain unknown. Here, we demonstrate the importance of cerebellar area right crus1 (Rcrus1) in social and repetitive behaviors. We also demonstrate functional connectivity between the cerebellum and the clinically-implicated medial prefrontal cortex (mPFC), show that mPFC function mediates cerebellar-regulated, ASD-relevant behaviors, and highlight disruptions in connectivity between these disparate regions across a large cohort of mouse models of ASD-linked genes as well as in individuals with ASD. Moreover, we delineate a four-stage, multi-synaptic circuit between the cerebellum and the mPFC, and we provide evidence that modulation across this circuit is sufficient to rescue ASD-relevant behaviors. Additionally, we show that output from two distinct, clinically- implicated cerebellar regions, Rcrus1 and the posterior vermis, culminate on thalamic projections to the mPFC and demonstrate that these two regions mediate the specific rescue of social impairments and repetitive/inflexible behaviors respectively. Taken together, these data highlight neural circuit connections bridging clinically implicated cerebellar and cortical domains that regulate behaviors relevant to both core diagnostic criteria in ASD and raise the intriguing possibility that neuromodulation of these specific circuits may offer therapeutic targets for the treatment of ASD.