Development and function of 5HT3aR-expressing cortical GABAergic interneurons

大脑皮层的功能依赖于由两种神经元组成的高度互联和动态的微回路，谷氨酸能兴奋性神经元通过处理的各个阶段传播信号，gaba能中间神经元（INs）调节这种信息流并塑造皮层回路。大脑皮层的信号处理主要取决于这些中间神经元的活动。该计划项目的重点是表征GABAergic INs的种群，其规模和广度以前被低估了。这些INs表达嗜离子性5 -羟色胺受体5HT3a，主要起源于尾神经节隆起（CGE）的发育过程。初步研究表明，5HT3aR IN约占体感觉皮层内总IN数量的30%，且主要集中在皮层表层，是最大的IN数量。这表明它们在大脑皮层联想层的信息处理中很重要。5HT3aR蛋白是异质的，但它们被5 -羟色胺和乙酰胆碱通过嗜离子受体均匀而有效地调节。本项目将研究皮层5HT3aR蛋白在大脑皮层发育和功能中的作用。PPG将包括三个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），以支持这三个项目的工作。项目一（由Gordon Fishell负责）将阐明决定5HT3aR基因群发展的机制。它将研究控制5HT3aR INs前体分化的遗传程序，它们在发育过程中的连通性以及它们在皮层成熟过程中的作用。项目II （Bernardo Rudy）将推进我们对5HT3aR蛋白在皮质功能中的作用的理解。具体来说，它将检验它们在情境依赖的感觉处理中很重要的假设。本研究将研究5HT3aR INs的功能连接，利用光刺激通道视紫红质表达的胆碱能和血清素能轴突来研究这些皮质下输入对它们的调节，并在体内使用两个光子靶向记录来研究5HT3aR INs在不同行为状态下的活性及其对运动活动和感觉刺激的反应。项目III （Gan wen -彪）将研究5HT3aR蛋白在V层锥体神经元上突触的位置、结构和可塑性，以及这些蛋白在学习记忆形成过程中对锥体细胞活性和结构动力学的调节作用。

The functions of the cerebral cortex depend on highly interconnected and dynamic microcircuits composed of two types of neurons, glutamatergic excitatory neurons that propagate the signals through the various stages of processing and GABAergic interneurons (INs) that regulate this information flow and sculpt cortical circuits. Signal processing in the cortex depends critically on the activity of these interneurons. This Program Project is focused on the characterization of a population of GABAergic INs whose size and breadth have been previously underestimated. These INs express the ionotropic serotonin receptor 5HT3a and largely originate during development from the caudal ganglionic eminence (CGE). Preliminary studies show that 5HT3aR INs represent about 30% of the total IN population in somatosensory cortex, and that they are concentrated in superficial layers, where they represent the largest IN population. This suggests that they are important in the processing of information in the associative layers of cortex. 5HT3aR INs are heterogeneous, but they are uniformly and potently modulated by serotonin and acetylcholine via ionotropic receptors. The Program Project will investigate the roles of cortical 5HT3aR INs on the development and function of the cerebral cortex. The PPG will consist of three research projects and two cores (an Administrative Core and a Molecular and Transgenic Core) to support the work of the three projects. Project I (by Gordon Fishell), will elucidate the mechanisms that determine the development of the 5HT3aR INs population. It will investigate the genetic program that governs the differentiation of 5HT3aR INs precursors, their connectivity throughout development and the role of activity on their maturation in the cortex. Project II (by Bernardo Rudy) will advance our understanding of the role of 5HT3aR INs in cortical function. Specifically, it will test the hypothesis that they are important in context-dependent sensory processing. It will investigate the functional connectivity of 5HT3aR INs, use photostimulation of channelrhodopsin-expressing cholinergic and serotonergic axons to investigate their modulation by these subcortical inputs and two photon targeted recordings in vivo to investigate the activity of 5HT3aR INs during different behavioral states and their response to motor activity and sensory stimulation. Project III (by Wen-Biao Gan) will investigate the location, structure and plasticity of the synapses 5HT3aR INs make on layer V pyramidal neurons and the role of these INs in regulating the activity and structural dynamics of pyramidal cells during learning and memory formation.