Serotonergic Regulation of Behavioral Disinhibition

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DESCRIPTION (provided by applicant): Disinhibited behaviors (such as inattention, agitation, and poor socialization) are a significant problem that often accompanies mid- to late-stage dementia. These behaviors are likely caused in part by dysfunction of brain serotonin systems. This research plan addresses the role of serotonin 2C receptors (5-HT2CRs) in the control of behavioral inhibition. The research plan also provides a framework to guide the applicant's transition from senior fellow in geriatric medicine to an independent investigator who will make high quality contributions to the field of behavioral neuroscience. The studies proposed herein will test the primary hypothesis that 5-HT2C receptors regulate behavioral inhibition both by enhancing dopaminergic neurotransmission and diminishing GABA-ergic neurotransmission in the mesolimbic system. The specific aims of this project will test this hypothesis by demonstrating in wildtype and "knockout" mice lacking the 5-HT2C receptor that 1) 5-HT2CRs contribute to serotonergic influence on behavioral inhibition through regulation of mesolimbic dopamine activity, and 2) 5-HT2CRs contribute to serotonergic influence on behavioral inhibition through the regulation of GABA-ergic neurotransmission. Mice with targeted deletion of specific neurotransmitter receptors are ideal models to determine individual receptor contributions toward behavioral inhibition; furthermore, this data can be applied to the study of behavioral disturbances in aged subjects. Experimental design and methods to test these hypotheses are grounded in whole animal studies of behavior (including tests of exploration, sensorimotor gating, social interaction, locomotor coordination, locomotor activity, and anxiety-related behaviors). Neurochemical (microdialysis) and neuroanatomical studies (including in situ mRNA hybridization, and receptor immunocytochemistry) will be utilized to evaluate potential mechanisms underlying behaviors observed in wildtype and 5-HT2CR mutant mice. The applicant will take advantage of the many strengths unique to UCSF, including a highly reknowned faculty in both the basic sciences of Neuroscience and Genetics, and the clinical sciences of Medicine, Neurology, and Geriatrics. Data from this study will answer key questions regarding the mechanism of serotonin influences on control of behavioral inhibition, and will provide the groundwork to identify specific pharmacological interventions that may be successful in treating this refractory problem.