Crus control: Left-right specific lateralization of nonmotor cognitive tasks in cerebellar crus I in mice

Abstract

While the cerebellum is canonically recognized as a sensory and motor structure, it boasts extensive connections to regions of the neocortex implicated in cognitive function, affect, and reward. Individuals with autism have been found to have specific lateralization of symptoms in cerebellar crus I. To analyze this pathway and cerebellar influence on distal neocortical structures, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to chemogenetically and reversibly perturb Purkinje cells in right or left crus I of adult mice. DREADD agonist clozapine-N- oxide (CNO) was administered via intraperitoneal injection at the time of testing to induce a unilateral perturbation of crus I. After conducting open field and Y- maze assays, we found lateralization of crus I effects on both exploratory and flexible behavior. Animals with an acute right crus I perturbation demonstrated increased exploration on day 2 of the open field assay, suggesting abnormal habituation to a novel environment. In addition, right crus I mice demonstrated a substantially reduced ability for Y-maze reversal. Using whole brain mapping of c-Fos, a neuronal marker, we found unique structures important for flexible behavior and resulting reduction in crus I Purkinje cell output. This study provides novel evidence that the adult mouse cerebellar crus I is left-right lateralized with respect to reversal learning. An understanding of the relationship between behavior and cerebellar function is essential in working to identify novel therapeutic strategies and targets for individuals with ASD. This work therefore produces meaningful contributions to the field of autism research, especially to the population of adults with ASD who so often are overlooked in autism research.