The cerebellum has repeatedly been shown to play a role in non-motor behaviors including complex cognitive and social behaviors. Interestingly, cerebellar dysfunction has similarly been implicated in autism spectrum disorders (ASDs) and autism-related behaviors including social interaction deficits, cognitive inflexibility and repetitive behaviors. Human studies have also shown that cerebellar Purkinje Cell loss is one of the most consistent postmortem findings in ASD subjects, and cerebellar injury greatly increases the risk of a later diagnosis of ASD. Although these facts clearly implicate the cerebellum in autism-related behaviors, the role of circuits emanating from the cerebellum to the cerebral cortex remains unknown. Our preliminary data implicate the medial prefrontal cortex (mPFC) as a potential downstream target of the cerebellum, and we hypothesize that ASD-related behaviors are regulated by cerebellar circuits to the mPFC via either VTA or thalamus. We further hypothesize that we can rescue ASD-related behaviors in two mouse models of ASD by selectively manipulating the activity of these circuits. To test this hypothesis, we propose the following specific aims:
Aim 1 : Determine functional connectivity between the cerebellum and the mPFC. We will determine functional connectivity by performing in vivo anesthetized single unit recordings in the left prelimbic mPFC while silencing select Purkinje Cell activity in the cerebellum with chemogenetics.
Aim 2 : Define which cerebellar-mPFC circuits mediate ASD related behaviors. Anatomical connections between the cerebellum and the mPFC have been shown via the thalamus and Ventral Tegmental Area (VTA). We will optogenetically inhibit the activity of these circuits in wild type mice during behavioral assays to induce ASD relevant phenotypes to determine these circuits are necessary for these behaviors.
Aim 3 : Rescue behavioral deficits in mouse models of ASD through modulation of cerebellar-mPFC circuit activity. Behavioral assays will be conducted in mouse models of Tuberous Sclerosis as well as Fragile X Syndrome while optogenetically manipulating cerebellar circuits via the Thalamus or VTA to the mPFC.
This project will determine the influence of cerebellar-cerebral/cortical circuits on behaviors which are the core diagnostic criteria for autism spectrum disorders. Specifically, this work will isolate circuits emanating from the cerebellum to the medial prefrontal cortex using advanced viral tracing techniques, and manipulate those using chemogenetics and optogentics to rescue behavioral deficits in mouse models of autism. This work may identify key brain areas which may be targeted in human subjects to improve the symptoms of impaired social interaction, repetitive behaviors and cognitive inflexibility in those with autism spectrum disorders.
