Development and Function of 5HT3aR-Expressing Cortical GABAergic Interneurons

大脑皮层的功能依赖于由两种类型的神经元组成的高度互连和动态的微电路：通过处理的各个阶段传播信号的多巴胺能兴奋性神经元，以及调节这种信息流并塑造皮层电路动力学的GABA能中间神经元。皮质中的信号处理关键取决于特定中间神经元亚型的活动。虽然PV和SST中间神经元群体已经得到了很好的研究，但该计划项目的重点是GABA能中间神经元的5HT3aR家族，其患病率，广度和对皮质功能的贡献以前被低估了。5HT3aR中间神经元占新皮层中总中间神经元群体的约30%，并且集中在表面联合层内，其中它们构成中间神经元的大部分。在发育过程中，5HT3aR中间神经元起源于尾神经节隆起（CGE），在出生后第一周后期定位在皮质内，并有助于此后皮质的功能和可塑性。在这里，我们将探讨皮质5HT3aR中间神经元在发育过程中的作用，以及它们在躯体感觉和听觉皮质中的功能和可塑性。该计划项目将包括三个相互关联的研究项目和两个核心（行政核心和分子和转基因核心），以支持三个项目的工作。所有三个项目的重点将是新皮层第一层（L1），主要皮层接收上下文信息。L1中的所有神经元都是5HT3aR家族的中间神经元。项目1（Gordon Fishell）将阐明决定5HT3aR中间神经元群体发育的机制。它将研究控制5HT3aR中间神经元前体分化的遗传程序，它们在整个发育过程中的连接性以及活动（特别关注L型Ca++信号传导）对它们在皮质中成熟的作用。项目2（Bernardo Rudy）将通过关注我们在前一个资助期内在L1中确定的中间神经元亚型，来促进我们对5HT3aR中间神经元在皮质功能中的作用的理解。具体来说，项目2将研究它们的输入和输出连接以及它们对上下文相关感觉处理的贡献。项目3（Robert Froemke）将研究相同人群对听觉处理和可塑性的贡献。本项目将研究L1 5HT3aR中间神经元在清醒行为小鼠听觉识别任务中的作用，并确定该过程中胆碱能神经调节的要求。这些项目将共同提供对5HT3aR群体发育、可塑性和功能的全面评估。

The functions of the cerebral cortex rely upon highly interconnected and dynamic microcircuits composed of two types of neurons: glutamatergic excitatory neurons that propagate signals through the various stages of processing, and GABAergic interneurons that regulate this information flow and sculpt cortical circuit dynamics. Signal processing in the cortex critically depends on the activity of specific interneuron subtypes. While the PV and SST interneuron populations have been well studied, this Program Project is focused on the 5HT3aR family of GABAergic interneurons whose prevalence, breadth and contributions to cortical function have been previously underestimated. 5HT3aR interneurons represent about 30% of the total interneuron population in the neocortex and are concentrated within the superficial associative layers, where they comprise the majority of interneurons. During development, 5HT3aR interneurons originate from the caudal ganglionic eminence (CGE), become positioned within the cortex late during the first postnatal week and contribute to both the function and plasticity of the cortex thereafter. Here we will investigate the roles of cortical 5HT3aR interneurons during development, as well as their function and plasticity within the somatosensory and auditory cortices. The Program Project will consist of three interrelated research projects and two cores (an Administrative Core and a Molecular and Transgenic Core) to support the work of the three projects. A focus of all three projects will be neocortical layer 1 (L1), the main cortical layer receiving contextual information. All neurons in L1 are interneurons of the 5HT3aR family. Project 1 (by Gordon Fishell), will elucidate the mechanisms that determine the development of the 5HT3aR interneuron population. It will investigate the genetic program that governs the differentiation of 5HT3aR interneuron precursors, their connectivity throughout development and the role of activity (with a particular focus on L-type Ca++ signaling) on their maturation in the cortex. Project 2 (by Bernardo Rudy) will advance our understanding of the role of 5HT3aR interneurons in cortical function by focusing on the interneuron subtypes that we have identified in L1 during the previous funding period. Specifically, Project 2 will investigate their input and output connectivity and their contributions to context-dependent sensory processing. Project 3 (by Robert Froemke) will examine the contributions of the same populations to both auditory processing and plasticity. This project will examine the role of L1 5HT3aR interneurons in awake behaving mice in an auditory recognition task and determine the requirement of cholinergic neuromodulation for this process. Together these projects will provide a comprehensive assessment of the 5HT3aR populations’ development, plasticity and function.