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内策略性植入特定细胞类型是修改或重建情绪回路的潜在新方法。在麻省理工学院获得博士学位和哈佛医学院获得医学博士学位后，我于2001年在马萨诸塞州综合医院完成了精神病学住院医师培训。我曾作为博士后通过住院医师培训与弗朗辛·贝内斯博士共事，她已同意指导这项提议。麦克莱恩医院致力于提供对梅尔曼研究中心的全面准入，包括一个经过批准的动物群体、细胞培养设施、显微镜和成像系统，以及一个电子和共聚焦显微镜中心。我的近期目标是在建立一个能够应用多种方法解决神经科学中复杂问题的协作实验室的同时，增强我的技能。我的长期目标是发展成为一名内科科学家，能够使用不同的方法来研究精神疾病。在五年的资助期内，我将参加课程并接受该机构教职员工的个性化指导，以加强我设计和实施实验、使用行为和分子技术以及使用多元统计分析复杂数据的能力。这些技能将在一系列实验的背景下学习，这些实验旨在调查将细胞成分引入皮质边缘系统的可能性，从而从生物上改变与情绪相关的回路。富含GABA能神经元的细胞悬浮液将被放置在杏仁核内，行为模型将被用来评估这些移植物对恐惧和焦虑的影响。移植的细胞将使用微透析、免疫组织化学、EM和分子生物学技术进行存活和功能整合的评估。初步结果支持这样的假设，即GABA能神经元在移植后可以存活，并增加抑制音，从而减弱恐惧反应。恐惧和焦虑是绝大多数精神症状的主要组成部分；而焦虑症本身比任何其他精神疾病更普遍。这一提议可能会为治疗这些普遍存在的疾病提供新的见解，因为它为研究恐惧反应的细胞和分子功能提供了一种新的方法。

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.