Neural Transplantation within Amygdalar Circuitry

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DESCRIPTION (provided by applicant): The present application proposes that strategic engraftment of specific cell types within the corticolimbic system is a potential new method for modifying or reconstructing emotional circuitry. Having earned a PhD from MIT and an MD from Harvard Medical School, I completed my psychiatry residency in 2001 at the Massachusetts General Hospital. I have worked with Dr. Francine Benes as a post-doc through residency training, and she has agreed to mentor this proposal. McLean Hospital has committed to providing full access to the Mailman Research Center, complete with an approved animal colony, cell culture facilities, microscopy and imaging systems, and a center for electron and confocal microscopy. My immediate goals are to augment my skills while constructing a collaborative laboratory capable of applying diverse methods to address complex questions in neuroscience. My long-term goal is to develop as a physician-scientist capable of employing diverse approaches to investigate mental illness. During the 5-year grant period, I will attend courses and receive individualized instruction from faculty at this institution to strengthen my abilities in designing and implementing experiments, employing behavioral and molecular techniques, and using multivariate statistics to analyze complex data. These skills will be learned in the context of a series of experiments designed to investigate the potential for introducing cellular components into the corticolimbic system, thereby "biologically altering" circuitry associated with emotions. Cell suspensions rich in GABAergic neurons will be placed within the amygdala, and behavioral models will be used to assess the influence of these grafts on fear and anxiety. Transplanted cells will be evaluated for survival and functional integration using microdialysis, immunohistochemistry, EM, and molecular biological techniques. Preliminary results support the hypothesis that GABAergic neurons can survive after transplantation and increase inhibitory tone, thereby attenuating the fear response. Fear and anxiety are major components of the vast majority of psychiatric syndromes; and anxiety disorders, in their own right, are more prevalent than any other mental illness. This proposal may provide new insights into the treatment of these pervasive conditions, as it presents a novel approach to the study of the cellular and molecular function of the fear response.