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相互连接的动态微电路：谷氨酸能兴奋神经元在加工的不同阶段传递信号，以及GABA能中间神经元调节这种信息流并塑造皮质电路动力学。大脑皮层的信号处理很大程度上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，但这个项目关注的是GABA能中间神经元5HT3aR家族，它们的流行率、广度和对皮质功能的贡献以前被低估了。5HT3aR中间神经元约占新皮质中间神经元总数的30%，集中在浅层，构成中间神经元的大多数。在发育过程中，5HT3aR中间神经元起源于尾状神经节隆起(CGE)，在出生后第一周进入皮质内，此后对皮质的功能和可塑性都有贡献。在这里，我们将研究皮质5HT3aR中间神经元在发育过程中的作用，以及它们在躯体感觉皮质和听觉皮质中的功能和可塑性。该方案项目将由三个相互关联的研究项目和两个核心(一个行政核心和一个分子和转基因核心)组成，以支持这三个项目的工作。所有三个项目的重点都将是新皮质第一层(L1)，这是接收上下文信息的主要大脑皮层。L1的所有神经元都是5HT3aR家族的中间神经元。项目1(戈登·菲舍尔)将阐明决定5HT3aR中间神经元群体发展的机制。它将研究控制5HT3aR神经元间前体细胞分化的遗传程序，它们在整个发育过程中的连通性，以及活动(特别关注L类型的钙++信号)在它们在皮质中成熟中的作用。项目2(Bernardo Rudy)将通过关注我们在上一资助期间在L1中确定的中间神经元亚型，促进我们对5HT3aR中间神经元在皮质功能中的作用的理解。具体地说，项目2将调查它们的输入和输出连接以及它们对上下文相关感觉加工的贡献。项目3(由Robert Froemke完成)将考察相同种群对听觉处理和可塑性的贡献。该项目将研究L15HT3aR中间神经元在清醒行为小鼠的听觉识别任务中的作用，并确定这一过程对胆碱能神经调节的需求。这些项目将对5HT3aR群体的发育、可塑性和功能进行全面评估。

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.