COMPUTATIONAL AND BEHAVIORAL ANALYSIS OF CEREBELLAR INFLUENCE OVER COGNITIVE DEVELOPMENT

Abstract

Specific cerebellar lobules form reciprocal loops with neocortical regions associated with executive functions, yet the functional significance of these connections has not yet been explored. Perinatal cerebellar disruption is associated with later cognitive deficit and autism spectrum disorder, suggesting that during postnatal life, the cerebellum may influence social and cognitive development. Interruption of this process has been termed “developmental diaschisis.” Here I report that pharmacogenetic disruption of cerebellar activity can lead to cognitive and social impairments that depend on the age and location of inactivation. Inactivation was accomplished using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) via lobule-specific injections of construct AAV8-hSynh-M4D( Gi)-mCherry. DREADD agonist clozapine-N-oxide (CNO) was either administered orally from P30 through P56 and then withdrawn for testing (the developmental condition) or administered via intraperitoneal injection at the time of testing (the acute adult condition). In both cases, adult mice were tested in learning ability, perseveration, sociability, exploratory behavior, and anxiety tasks. To analyze the data, we used Principal Component Analysis to define behavioral modes that combined multiple parameters of learning and behavior. Developmental inactivation of Crus II reduced exploratory and social behavior, and developmental inactivation of Crus I caused reduced social interaction, impaired learning ability, and repetitive behavior. These effects were specific to the developmental condition, and were not found when Crus I and II were perturbed acutely in adult mice. Developmental and adult disruption of Lobules VI and VII had complex, age-dependent effects on learning and reversal in the Ymaze assay and anxiety in the Elevated Plus Maze, suggesting that these lobules continue to moderate cognitive behaviors in adulthood. This study provides direct evidence for the developmental diaschisis hypothesis of cerebellar contribution to cognitive and social function.