Inhibitory regulation of dendritic calcium signals in the prefrontal cortex

描述(由申请人提供)：前额叶皮质(PFC)兴奋和抑制的失衡与神经精神障碍有关，如精神分裂症、自闭症和癫痫。突触抑制除了影响主要兴奋性神经元的电活动外，还调节神经元的生化过程，如钙信号影响突触的可塑性。然而，GABA能作用的确切细胞和亚细胞机制还不是很清楚。采用光遗传学和双光子显微技术相结合的方法，研究不同GABA能中间神经元介导的突触抑制对PFC树突状钙信号和突触可塑性的影响。这项工作的结果将对健康大脑回路功能中兴奋和抑制之间的动态相互作用提供新的理解，并为神经精神疾病的细胞机制提供未来的研究方向。这项提案中的工作将在耶鲁大学进行，这是一所在心理健康领域有着悠久历史的研究项目。不计其数的学术部门和跨部门项目提供了丰富的智力资源。具体地说，拟议的研究将在希格利实验室进行，该实验室拥有两个多光子显微镜装置，能够进行成像和电生理实验。此外，还有实验室空间可以开发我自己的研究项目，例如一个专门用于病毒注射的外科手术舱。此外，最先进的显微镜核心可用于先进的细胞成像能力，并聘请受过专门培训的成像专家作为额外的技术知识来源。在职业发展方面，神经生物学系主办了许多研讨会和期刊俱乐部，以培养教师、博士后和学生之间的智力和科学互动。我的长期职业目标是促进我们对兴奋性突触强度的短暂和长期变化是如何调节的理解。虽然众所周知，抑制可以作为可塑性的负面调节因素，但它实现这一功能的确切机制尚不清楚。从这次指导培训中，我将获得在大脑皮层回路中使用光学方法研究兴奋性和抑制性突触整合和可塑性的知识和专业知识。我相信，在希格利博士和麦考密克博士的指导下，我将更好地为成功的独立研究生涯做好准备。希格利博士和麦考密克博士是突触生理学领域的专家，他们的科学方法一丝不苟。他们使用多学科方法研究兴奋性传递和可塑性的抑制调节。

DESCRIPTION (provided by applicant): An imbalance of excitation and inhibition in the prefrontal cortex (PFC) is implicated in neuropsychiatric disorders such as schizophrenia, autism, and epilepsy. In addition to shaping the electrical activity of principal excitatory neuron, synaptic inhibition also regulates neuronal biochemical processes, such as calcium signaling to impact synaptic plasticity. However, the precise cellular and sub-cellular mechanisms underlying GABAergic actions are not well understood. Using a combination of optogenetics and two-photon microscopy techniques, the goal of the proposed work is to investigate the impact of synaptic inhibition mediated by distinct GABAergic interneurons on dendritic calcium signaling and synaptic plasticity in the PFC. Results from this work will provide new understanding of the dynamic interplay between excitation and inhibition underlying healthy brain circuit function and suggest future directions of research for cellular mechanisms of neuropsychiatric disease. Work in this proposal will be conducted at Yale University, an institution with a long-standing history f well-established research programs in the field of Mental Health. The countless number of academic departments and interdepartmental programs provides a rich intellectual resource. Specifically, the proposed research will be performed in the Higley laboratory, which has two multi-photon microscope setups capable of both imaging and electrophysiological experiments. In addition, there is lab space for development of my own research program such as a dedicated surgical bay for viral injections. Moreover, a state-of-the-art microscopy core is available for advanced cellular imaging capabilities and employs specially trained imaging experts who act as additional sources of technical knowledge. In terms of career development, the Department of Neurobiology sponsors numerous seminars and journal clubs to cultivate intellectual and scientific interactions among faculty, postdocs and students. My long-term career goal is to advance our understanding of how transient and long-lasting modifications in excitatory synaptic strength are regulated. While it is known that inhibition can serve as a negative regulator of plasticity, the precise mechanisms by which it does so are unclear. From this mentored training, I will obtain knowledge and expertise in the use of optical methods in cortical circuits to study excitatory and inhibitory synaptic integration and plasticity. I am confident that with the guidance of Dr. Higley and Dr. McCormick, who are experts in the field of synapse physiology and are meticulous in their approach to science, I will be better equipped for a successful independent research career examining inhibitory regulation of excitatory transmission and plasticity using a multi-disciplinary approach.