Many of our actions feel automatic. Driving a familiar route to work 'on autopilot'is a common experience - as is taking a wrong turn when today's goal differs from the norm. This is an example of habit learning - a pattern of associations between stimuli and responses, or between patterns of thought, that is acquired over time and, once acquired, become stereotyped and requires effort to overcome. Dysregulation of such habit learning, and of the basal ganglia circuitry that underlies it, is central to obsessive-compulsive disorder, Tourette's syndrome, and related disorders. The mechanisms of habit learning may be of importance to more than one psychiatric disorder. Unfortunately, our knowledge of the mechanisms of information processing and storage in the basal ganglia during striatum-dependent learning remains rudimentary. Targeted genetic manipulations in mice have been a useful tool in the analysis of other forms of learning. We have recently shown regulation by the transcription factor CREB to be critical in normal striatum- dependent learning, using transgenic mice in which CREB's function is specifically disrupted in the striatum. This study represents the first time, to our knowledge, that such specific targeting of the striatum in genetically modified mice has been used to probe the mechanisms of striatum-dependent learning. We now propose to build on this preliminary study through more refined behavioral assays, targeting subregions of the striatum using viral vectors, and characterizing downstream genes important in striatal information processing and storage. This approach takes advantage of my experience in the generation and behavioral analysis of genetically modified mice as well as other experimental approaches in which expertise exists in the Yale community. Clinical expertise in the Yale OCD Research Clinic and Child Study Center allows for a clinically informed research program that will aid me in my development towards independence as a researcher while advancing our understanding of psychiatric disorders in which maladaptive habits wreak havoc in patient's lives. This understanding will pave the way for therapies of the future.
Obsessive-compulsive disorder is the fourth most common psychiatric disorder and a major cause of disability in America and worldwide. The neural circuitry that underlies it is involved in normal habit learning. We seek to understand the mechanisms of this habit learning and of OCD.
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