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）：新皮层由数十亿个具有数万亿个连接的神经元组成，并负责认知任务，例如感知和抽象推理。皮质异常与包括自闭症谱系和精神分裂症在内的毁灭性神经精神疾病有关，进一步强调了了解皮质如何发挥作用的重要性。尽管在理解单个神经元的特性方面取得了重大进展，但我们才开始理解支配新皮层电路组装的规则。 该领域的一个主要未解决的问题是分子机制是否指导单个细胞水平的神经回路的接线图。 换句话说，是否有遗传蓝图控制皮质电路的局部接线？问题在技术上是具有挑战性的，因为它需要同时分析单个皮质神经元水平的神经元连通性和基因表达谱。此外，它将需要收集大量的数据以及高级分析技术，以破解分子连通性。我们建议使用多整体细胞贴片夹记录与单细胞逆转录（RT）-PCR一起研究簇状的原粘蛋白基因家族是否为神经回路组装提供了分子代码。簇状的原始蛋白已显示在单个神经元中的组合代码中表达，在突触发生过程中高度表达，并将其定位于突触。因此，簇状的原钙粘着蛋白是用于塑造新皮质电路的主要候选分子。但是，它们在指导特定突触形成中的作用尚未 由于这些类型的实验的难度，直接测试了测试。此外，该项目的挑战性方面使得不可能由更传统的机制资助。这些实验的结果可以彻底改变我们对神经回路组装的理解，并导致一种更有原则的方法来研究电路水平的神经精神疾病。