A MOLECULAR CODE FOR CONNECTIVITY IN THE NEOCORTEX

新皮质连接的分子密码

• 批准号: 8639755
• 负责人: Andreas Tolias
• 金额: $ 31.3万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639755
• 关键词: Address; Adhesions; Binding; Biomedical Research; Bipolar Disorder; Brain; Brain Part; Cells; Clinical; Code; Cognition; Cognitive; Complex; Data; Disease; Exhibits; Funding; Gene Expression; Gene Expression Profile; Gene Family; Genetic; Individual; Lead; Machine Learning; Maps; Measures; Mediating; Mental Depression; Methodology; Methods; Molecular; Neocortex; Nervous system structure; Neurons; Pattern; Perception; Printing; Property; Protein Isoforms; Proteins; Psyche structure; RNA; Research; Research Infrastructure; Reverse Transcription; Role; Schizophrenia; Shapes; Signal Transduction; Specific qualifier value; Statistical Methods; Synapses; System; Techniques; Testing; Work; abstracting; autism spectrum disorder; base; brain research; combinatorial; cost; genetic manipulation; information processing; molecular marker; neocortical; neural circuit; neuropsychiatry; novel strategies; patch clamp; public health relevance; research study; synaptogenesis; transcriptome sequencing

DESCRIPTION (provided by applicant): The neocortex consists of billions of neurons with trillions of connections, and is responsible for cognitive tasks such as perception and abstract reasoning. Cortical abnormalities are associated with devastating neuropsychiatric illnesses including autism spectrum disorders and schizophrenia, further underscoring the importance of understanding how the cortex functions. Despite major advances in understanding the properties of individual neurons, we are just beginning to understand the rules that govern the assembly of neocortical circuits. One major unanswered question in the field is whether molecular mechanisms direct the wiring diagram of neural circuits at the level of individual cells. In other words, is there a genetic blue print that governs the local wiring of cortical circuits? Tis question is technically challenging to address because it will require simultaneous analysis of both neuronal connectivity and the gene expression profile at the level of single cortical neurons. Moreover, it will require massive amounts of data to be collected as well as advanced analysis techniques to crack the molecular code of connectivity. We propose to use multi-whole-cell patch clamp recording combined with single-cell reverse transcription (RT)-PCR to investigate whether the clustered protocadherin gene family provides a molecular code for neural circuit assembly. The clustered protocadherins have been shown to be expressed in a combinatorial code in individual neurons, are highly expressed during synaptogenesis, and localize to synapses. Thus, clustered protocadherins are the leading candidate molecules for shaping neocortical circuits. However, their role in instructing specific synapse formation has not been directly tested due to the difficulty of these types of experiments. Furthermore, the challenging aspects of this project make it unlikely to be funded by more traditional mechanisms. The results of these experiments could revolutionize our understanding of neural circuit assembly and lead to a more principled approach to studying neuropsychiatric disorders at the circuit level.

描述（由申请人提供）：新皮质由数十亿个神经元和数万亿个连接组成，负责感知和抽象推理等认知任务。皮质异常与毁灭性的神经精神疾病有关，包括自闭症谱系障碍和精神分裂症，这进一步强调了了解皮质功能的重要性。尽管在理解单个神经元的特性方面取得了重大进展，但我们才刚刚开始了解控制新皮质回路组装的规则。 该领域一个尚未解答的主要问题是分子机制是否在单个细胞水平上指导神经回路的接线图。 换句话说，是否存在控制皮质回路局部布线的基因蓝图？这个问题在技术上很难解决，因为它需要同时分析单个皮层神经元水平的神经元连接性和基因表达谱。此外，还需要收集大量数据以及先进的分析技术来破解连接的分子密码。我们建议使用多全细胞膜片钳记录结合单细胞逆转录（RT）-PCR来研究簇状原钙粘蛋白基因家族是否为神经回路组装提供分子密码。簇状原钙粘蛋白已被证明在单个神经元中以组合代码表达，在突触发生过程中高度表达，并定位于突触。因此，簇状原钙粘蛋白是塑造新皮质回路的主要候选分子。然而，它们在指导特定突触形成中的作用尚未得到证实。 由于此类实验的难度，直接进行了测试。此外，该项目的挑战性方面使其不太可能通过更传统的机制获得资助。这些实验的结果可能会彻底改变我们对神经回路组装的理解，并带来一种更原则性的方法来研究回路水平的神经精神疾病。