The Molecular Basis of Intracortical Projection Neuron Heterogeneity

描述(申请人提供)：大脑皮层是高级大脑功能的所在地，负责感觉、认知过程、自主运动和意识。人类大脑皮层的异常会导致神经和精神疾病，如癫痫、精神分裂症和自闭症。人类大脑皮层功能解剖学的一个关键特征是沿着其切向维度将其组织成功能不同的区域。在大脑发育过程中，高度异质的细胞类型必须准确地组装成这些区域内和这些区域之间的独特神经回路，以控制复杂的行为和认知过程。编码皮质投射神经元亚型识别和突触特异性的分子机制仍然知之甚少。这份提案详细说明了耶鲁大学神经生物学教授Nenad Sestan博士指导下的博士后研究和专业发展的3年计划。该研究员将研究形成皮层内投射神经元异质性和投射同一性的分子基础的机制。这位研究员将以他在神经发育生物学方面的现有专业知识为基础， 显微镜、组织学和细胞生物学。他将在发育中的大脑皮层的结构和功能、神经回路追踪、转录图谱、 单细胞分选和先进的小鼠基因技术，追求以下具体目标：1.听觉皮质相关区域皮质内投射的特征(A2)，2.A2和3中皮质内投射神经元亚型的转录图谱和特征。)破译在A2中建立皮质内投射神经元异质性的分子机制。Sestan博士在皮质发育和基因组学、小鼠遗传学和远程投射电路研究方面的专业知识将提供必要的科学指导和技术能力，以确保成功完成这些目标。这位研究员和赞助商还制定了一份详细的职业技能发展计划。这里提出的研究和培训计划，以及研究员选择的导师，将为研究员的学术生涯目标提供出色的培训，研究大脑皮质的发育神经生物学及其疾病中的功能障碍。

DESCRIPTION (provided by applicant): The cerebral cortex is the seat of higher brain function, responsible for sensory perception, cognitive processes, voluntary movement, and consciousness. Abnormalities of the human cerebral cortex cause neurological and psychiatric disorders, such as epilepsy, schizophrenia, and autism. A key feature of the functional anatomy of the human cerebral cortex is its organization into functionally distinct regions along its tangential dimension. During brain development, highly heterogeneous cell types must precisely assemble into unique neural circuits both within and between these areas to control complex behaviors and cognitive processes. The molecular mechanisms that encode cortical projection neuron subtype identity and synaptic specificity remain poorly understood. This proposal details a 3 year plan for postdoctoral research and professional development under the mentorship of Dr. Nenad Sestan, Professor of Neurobiology at Yale University. The fellow will investigate the mechanisms that form the molecular basis for intra-cortical projection neuron heterogeneity and projection identity. The fellow will build on his existing expertise in neurodevelopmental biology, microscopy, histology, and cell biology. He will further develop new expertise in the structure and function of the developing cerebral cortex, neural circuit tracing, transcriptional profiling, single-cell sorting, and advanced mouse genetic technologies by pursuing the following specific aims: 1.) Characterization of intra-cortical projections in association areas of auditory cortex (A2), 2.) Transcriptional profiling and characterization of intra-cortical projection neuron subtypes in A2, and 3.) Deciphering the molecular mechanisms that establish intra-cortical projection neuron heterogeneity in A2. The expertise of Dr. Sestan in cortical development and genomics, mouse genetics, and studies of long-range projection circuitry will provide the scientific guidance and technical capabilities necessary to ensure successful completion of these aims. The fellow and the sponsor have also developed a detailed plan for professional skills development. The research and training plan proposed here, along with the fellow's choice of mentor, will provide excellent training towards the fellow's goal of an academic career studying the developmental neurobiology of the cerebral cortex and its dysfunction in disease.