Cortical interneuron subtypes adapt to signals from local pyramidal cells

项目总结 大脑皮层执行复杂的计算、整合和认知的不可思议的能力依赖于 其复杂的神经元结构的错综复杂的建筑。大脑皮层主要由密集的 用少量局部抑制性中间神经元点缀的兴奋性神经元。尽管规模很小 在数量上，皮质中间神经元在转录组、形态、电生理上具有惊人的多样性 属性和连接性。一个长期存在的问题是，如何以及为什么大脑皮质 中间神经元是产生和需要的。该提案的目标是了解皮质瘤的亚型 中间神经元适应兴奋性神经元的分子特性，它们与兴奋性神经元配对形成专门的局部 微电路。这一提议的中心假设是，不同亚型的皮质中间神经元与 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同一性 在不同的皮质区域控制着皮质中间神经元亚型的分布和组成。具体的 AIMS将从两个不同的角度来探讨这一假设。使用表达生长抑素的皮质中间神经元 作为一个例子，在目标1中，我使用小鼠遗传工具来针对不同转录亚型的深层 生长抑素中间神经元的板层分布、形态和局部定型 微电路。我将使用解剖和功能测量两种方法来演示选择性连接 不同的锥体神经元亚型。在目标2中，我利用了突变小鼠，在这些突变小鼠中， 兴奋性神经元的一个子集被改变。使用皮质中间神经元的单细胞RNA测序，在 结合针对不同生长抑素中间神经元标记基因的原位杂交，我将 研究兴奋性神经元同一性改变对局部中间神经元组成和同一性的影响。 最后，在目标2中，我测试了锥体神经元是否控制了中间神经元亚型或GUIDE的存活 通过外部线索将中间神经元连接到特定的亚型。大量的初步结果发表在 支持这一建议的意义和可行性的研究计划。这项工作的长期目标是 确定兴奋性神经症亚型之间锁键机制的分子机制 神经元和中间神经元。 这笔奖学金将支持我在成为独立人士的道路上进行下一阶段的培训 神经学家。我的目标是将在此过程中获得的分子神经科学实验技术 培训期间对我以前的电生理技术背景，这将使我能够回答 具有多种方法的科学问题。我的长期职业目标是从事基础科学研究 这将促进我们对大脑的连接和功能的理解。

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.