Project Summary Recent studies have pointed to roles for the cerebellum beyond its canonical roles in motor coordination, with evidence pointing to prominent roles in the regulation of non-motor behaviors and parallel evidence for the contribution of cerebellar dysfunction to numerous conditions marked by non-motor challenges throughout development1-5. Indeed, our lab has shown that cerebellar function is necessary for social behaviors and for behavioral flexibility6. During the course of our previously funded grant period, we have published multiple studies delineating the presence of critical periods in cerebellar-regulated behaviors, demonstrated a key role for cerebellar CrusI in the regulation of social and repetitive behaviors, and demonstrated an important anatomic circuit between this region and the mPFC in the regulation of these behaviors7-10. Importantly, we also demonstrated that modulation of this circuit is sufficient to improve behaviors in a cerebellar-specific neurodevelopmental model of tuberous sclerosis complex (TSC). However, important questions remain, including whether this circuit has more generalizable importance in models beyond TSC and whether circuit modulation might be sufficient to benefit, not just cerebellar-specific models, but also global, constitutive human disease-relevant models. Moreover, although we have shown that these circuits are necessary for proper performance of these social behaviors, how this circuit communicates and actually contributes to social behaviors remains unknown. In these proposed studies, we hypothesize and show preliminary data to support that these circuits are relevant to both cerebellar-specific and global neurodevelopmental models; that neuronal activity within the cerebellar CrusI-mPFC circuit processes social behaviors; that this communication is necessary for proper social behavior; that disruptions of the mPFC or CrusI impairs this communication; and that social behaviors improve upon improvement of this communication. To evaluate these hypotheses further, we propose the following specific aims: Specific Aim1. Delineate CrusI-mPFC circuit contribution to global/constitutive Cntnap2 mutant mice Specific Aim2. Delineate CrusI-mPFC communication during social behaviors Specific Aim3. Delineate integrity of CrusI-mPFC communication in cerebellar (PC-Tsc1) and constitutive (Cntnap2) mutant mice and evaluate impact of CrusI modulation on this communication In summary, this work will both delineate basic mechanisms underlying the cerebellar and mPFC circuit contributions to social behaviors while also providing a pre-clinical foundation for understanding the impact of circuit-based neuromodulation on these behaviors.