Neural Transplantation within Amygdalar Circuitry

描述（由申请人提供）：本申请提出，在皮质边缘系统中植入特定类型的细胞是一种潜在的修改或重建情绪回路的新方法。在获得麻省理工学院博士学位和哈佛医学院医学博士学位后，我于2001年在麻省总医院完成了精神病学住院医师实习期。我曾和弗朗辛·贝内斯博士一起做博士后实习医生，她同意指导这个提案。麦克林医院已承诺提供全面访问邮差研究中心，完成批准的动物菌落，细胞培养设施，显微镜和成像系统，以及电子和共聚焦显微镜中心。我的近期目标是增强我的技能，同时建立一个能够应用多种方法来解决神经科学中复杂问题的合作实验室。我的长期目标是成为一名能够运用多种方法研究精神疾病的内科科学家。在5年的资助期内，我将参加该机构的课程并接受教师的个性化指导，以加强我设计和实施实验的能力，运用行为和分子技术，并使用多元统计分析复杂数据。这些技能将在一系列实验的背景下学习，这些实验旨在研究将细胞成分引入皮质边缘系统的可能性，从而“生物改变”与情绪相关的电路。富含gaba能神经元的细胞悬浮液将被放置在杏仁核中，行为模型将被用来评估这些移植物对恐惧和焦虑的影响。移植细胞将通过微透析、免疫组织化学、电镜和分子生物学技术评估其存活和功能整合情况。初步结果支持gaba能神经元在移植后存活并增加抑制张力，从而减轻恐惧反应的假设。恐惧和焦虑是绝大多数精神综合症的主要组成部分；而焦虑症，就其本身而言，比任何其他精神疾病都更为普遍。这一建议可能为这些普遍情况的治疗提供新的见解，因为它提出了研究恐惧反应的细胞和分子功能的新方法。

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.