Neural correlates of anxiety in 5-HT1AR knockout mice

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DESCRIPTION (provided by applicant): To prepare the candidate for an independent career in neuroscience research, training and research plans are proposed. The training plan combines formal mentorship, didactics, seminars and meetings to facilitate the acquisition of: (1) laboratory skills related to the breeding, maintenance, and behavioral and neurophysiological characterization of genetically modified mice; (2) a fund of knowledge and ability to think creatively regarding genetic models of psychiatric disease how to exploit them; (3) exposure to issues in the responsible conduct of research; and (4) experience in effective laboratory management. The research plan entails the evaluation of serotonin 1A receptor (5-HT1AR) mutant mice, which have increased anxiety related behaviors. Understanding the effects of 5-HT1AR deletion that lead to this phenotype has the potential to help further define the neurobiology of anxiety disorders, and may help identify new targets for anxiolytic therapies. 5-HT1AR expression is required in the forebrain during development to establish normal anxiety-like behaviors, suggesting that the 5-HT1AR acts early in life to set up neuronal circuits underlying these behaviors. The goal of this project is to identify and characterize neurophysiological consequences of the disruption of 5-HT1A receptor expression that correlate with the anxiety-related phenotype. The following hypotheses will be tested: (1) the lack of 5-HT1AR expression during development results in functional dysregulation of the hippocampus, resulting in the phenotype; and (2) this dysregulation is relevant to innate anxiety-like behaviors in intact mice. Awake, behaving neural recordings will be obtained from the hippocampus, with these Aims: (1) evaluating hippocampal activity in 5-HT1AR knockout mice; (2) evaluating hippocampal activity in animals with a forebrain rescue of 5-HT1AR-deficiency expressed only during development or only in adulthood; (3) investigating the relationship between hippocampal activity and innate anxiety through behavioral and pharmacological manipulations; and (4) comparing neurophysiology behavior relationships across dorsal and ventral hippocampal regions, which may have differential involvement in the mediation of innate anxiety. Completing these plans will suggest new areas of investigation related to anxiety disorders, and provide the candidate with the knowledge and experience necessary to develop and characterize other genetic models of psychiatric illness.