THE ROLE OF PURKINJE CELLS IN COGNITIVE AND AFFECTIVE DEVELOPMENT

Abstract

Discovery of reciprocal cerebello-thalamo-cortical loops have substantiated a link between specific lobules within the cerebellum and the cognitive and affective functions associated distant forebrain regions. Additionally, abnormalities in these loops are thought to be involved in the pathogenesis of Autism Spectrum Disorder (ASD). This study investigates cerebellar mechanisms by which experience guides cognitive and affective functions in distant brain regions. Purkinje cell activity was manipulated in either lobule VI or crus I to determine what role Purkinje cell signaling plays in the maturation and exhibition of social preference and flexible learning. Purkinje cell activity was perturbed acutely in adulthood to probe lobule-specific roles of Purkinje cells during behavior. Purkinje cell activity was perturbed chronically during development to assess how Purkinje cells influence neocortical development. Wireless optoelectronic devices were used to stimulate lobule VI Purkinje cells in a precise temporal manner during social chamber testing to probe whether decreasing cerebellar output in a temporal fashion alters social behavior. Acute and developmental perturbation was achieved using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Acute DREADD inhibition of Purkinje cells in both lobule VI and crus I lead to a profound decrease in flexible learning. Furthermore, Acute DREADD expression in lobule VI showed a slight increase in social preference. Optogenetic stimulation of Purkinje cells in lobule VI during moments of mouse-novel mouse or mouse-novel object interaction lead to pronounced indifference between the novel mouse and novel object.