Grant: Project Grant

The striatum is a brain region, strongly linked with the neocortex, that mediates fundamental behaviors related to motor control, cognition, motivation, reward processing and emotion regulation. Dysfunction within the striatum contributes to neurodegenerative and psychiatric disorders including addiction, depression, and anxiety. Recent work from our laboratory has shown that the striatum exhibits synchronized rhythms in genes that produce circadian (i.e., daily) rhythms in striatal neurons. Increasingly, studies point to the involvement of circadian clock genes in pathologies related to striatal dysfunction, including depression and anxiety. Currently, the contribution of disrupted striatal clock gene expression to these disorders is poorly understood. We will use genetic manipulation and molecular, electrophysiological, and behavioral methods to study the effects of targeted deletion of core clock genes, Bmal1 and Per2 from striatal medium spiny neurons (MSNs), which make up approximately 95% of the entire neuronal population of the striatum, and which have been implicated in a range of behaviors and pathological conditions. In preliminary work, we generated and validated mouse lines in which Bmal1 or Per2 is deleted from MSNs. Using these novel mouse lines, as well as virus injections to selectively delete clock genes from striatal subregions and different MSNs types in adult male and female mice, we will determine how deletion of core clock genes from MSNs affects performance on a range of behavioral tests to assess how disruption of striatal circadian rhythms result in changes in depression and anxiety-like behaviors. Studying the consequences of targeted clock gene manipulations within the striatum provides a powerful approach to determine the role of striatal clock genes in normal behavior, as well as the involvement of these genes in mechanisms of striatal-dependent disease states.