Cortical interneuron subtypes adapt to signals from local pyramidal cells

皮质中间神经元亚型适应局部锥体细胞的信号

• 批准号: 10312853
• 负责人: Jingjing Wu
• 金额: $ 7.11万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312853
• 关键词: Affect; Anatomy; Architecture; Brain; Cell Death; Cerebral cortex; Cognition; Collaborations; Complex; Coupled; Cues; Data; Development; Electrophysiology (science); Epilepsy; Fellowship; Functional disorder; Genes; Genetic; Glutamates; Goals; Hand; In Situ Hybridization; Instruction; Interneuron function; Interneurons; Knockout Mice; Knowledge; Laboratories; Logic; Maps; Measures; Minority Groups; Molecular; Morphology; Mutant Strains Mice; Nature; Neurodevelopmental Disorder; Neurons; Neurosciences; Output; Pattern; Play; Population; Positioning Attribute; Property; Proteins; Pyramidal Cells; Pyramidal Tracts; Research; Role; Schizophrenia; Signal Transduction; Slice; Somatostatin; Stereotyping; Synapses; Techniques; Testing; Tetanus Toxin; Training; Variant; Work; autism spectrum disorder; career; design; excitatory neuron; experimental study; genetic approach; hippocampal pyramidal neuron; insight; migration; mouse genetics; nerve supply; nervous system disorder; prevent; rabies viral tracing; single-cell RNA sequencing; tool; transcriptome; transcriptomics; vesicular release

PROJECT SUMMARY The incredible ability of the cerebral cortex to perform sophisticated computation, integration, and cognition relies on the intricate building of its complex neuronal architecture. The cerebral cortex primarily consists of densely packed excitatory neurons that are embellished with a small set of local inhibitory interneurons. Despite the small number, cortical interneurons have astonishing diversity in their transcriptome, morphology, electrophysiological property, and connectivity. A long-standing question is to understand how and why the diversity among cortical interneurons is generated and needed. The goal of the proposal is to understand how the subtypes of cortical interneurons adapt to the molecular identity of the excitatory neurons to which they pair to form specialized local microcircuits. The central hypothesis of this proposal is that distinct subtypes of cortical interneurons partner with different types of excitatory neurons. In other words, the composition and molecular identity of excitatory neurons in different cortical regions govern the distribution and composition of cortical interneuron subtypes. The specific aims will approach this hypothesis from two different angles. Using somatostatin-expressing cortical interneurons as an example, In Aim 1 I use mouse genetic tools to target different transcriptomic subtypes of deep-layer somatostatin interneurons to investigate their laminar distribution, morphology, and stereotyped local microcircuitry. I will use both anatomical and functional measures to demonstrate the selective connectivity towards different pyramidal neuron subtypes. In Aim 2, I utilize mutant mice in which the molecular identities of a subset of excitatory neurons are altered. Using single-cell RNA sequencing of cortical interneurons, in combination with in situ hybridization against marker genes for different somatostatin interneurons, I will investigate the effects of altering excitatory neuron identity on the composition and identity of local interneurons. Finally, in Aim 2 I test whether pyramidal neurons govern the survival of interneuron subtypes or guide interneurons to specific subtypes through extrinsic cues. Substantial preliminary results are presented in the research plan supporting the significance and feasibility of this proposal. The long-term objective of this work is to identify the molecular mechanisms underlying the lock-and-key mechanisms between subtypes of excitatory neurons and interneurons. This fellowship will support the next stage of training in my path towards becoming an independent neuroscientist. I aim to integrate the molecular neuroscience experimental techniques acquired during this training period to my previous electrophysiological technical background, which will enable me to answer scientific questions with multiple approaches. My long-term career goal is to conduct basic scientific research that will advance our understanding of the wiring and function of the brain.

项目摘要 大脑皮层执行复杂计算、整合和认知的惊人能力依赖于 复杂的神经元结构的复杂构建。大脑皮层主要由密集的 密集的兴奋性神经元，点缀着一小部分局部抑制性中间神经元。虽小 皮质中间神经元在转录组、形态、电生理功能和神经元的功能上具有惊人的多样性。 属性和连通性。一个长期存在的问题是要了解大脑皮层神经元之间的差异是如何以及为什么的， interneurons产生和需要。该提案的目标是了解皮质神经元的亚型 中间神经元适应兴奋性神经元的分子身份，它们与兴奋性神经元配对以形成专门的局部神经元。 微型电路这一提议的中心假设是，皮层中间神经元的不同亚型与 不同类型的兴奋性神经元。换句话说，兴奋性神经元的组成和分子特性 在不同的皮质区域支配皮质中间神经元亚型的分布和组成。具体 Aims将从两个不同的角度探讨这一假设。使用表达生长抑素的皮层中间神经元 作为一个例子，在目标1中，我使用小鼠遗传工具来靶向不同的深层转录组亚型， 生长抑素中间神经元，研究其层状分布，形态，和刻板的局部 微电路我将使用解剖学和功能测量来证明选择性连接 不同的锥体神经元亚型。在目标2中，我利用突变小鼠，其中 兴奋性神经元的子集被改变。使用皮层中间神经元的单细胞RNA测序， 结合对不同生长抑素中间神经元标记基因的原位杂交，我将 研究改变兴奋性神经元特性对局部中间神经元的组成和特性的影响。 最后，在目标2中，我测试锥体神经元是否支配中间神经元亚型的存活或指导 interneurons特定亚型通过外部线索。大量的初步结果在 研究计划支持这一建议的意义和可行性。这项工作的长期目标是 以确定兴奋性神经元亚型之间的锁和钥匙机制的分子机制， 神经元和中间神经元。 这个奖学金将支持下一阶段的培训，在我的道路上成为一个独立的 神经学家我的目标是整合在此期间获得的分子神经科学实验技术 培训期间，我以前的电生理技术背景，这将使我能够回答 用多种方法解决科学问题。我的长期职业目标是从事基础科研 这将促进我们对大脑线路和功能的理解。