Development and function of 5HT3aR-expressing cortical GABAergic interneurons

大脑皮层的功能依赖于高度互联和动态的微电路，微电路由两种类型的神经元组成，谷氨酸能兴奋神经元负责在加工的不同阶段传递信号，GABA能中间神经元(INS)负责调节信息流和塑造皮质电路。大脑皮层的信号处理很大程度上依赖于这些中间神经元的活动。该计划项目的重点是描述一群以前被低估了大小和广度的GABA能INS。这些INS表达离子亲性5-羟色胺受体5HT3a，在发育过程中主要来源于尾神经节隆起(CGE)。初步研究表明，5HT3aR INS约占躯体感觉皮层IN总数的30%，且集中在表层，是IN中最大的一类。这表明它们在大脑皮层关联层的信息处理中很重要。5HT3aR INS是异质性的，但它们通过亲离子受体被5-羟色胺和乙酰胆碱统一而有效地调节。该计划项目将研究皮质5HT3aR INS在大脑皮层发育和功能中的作用。PPG将由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)组成，以支持这三个项目的工作。项目I(戈登·菲舍尔)将阐明决定5HT3aR INS人群发展的机制。它将研究控制5HT3aR INS前体分化的遗传程序，它们在整个发育过程中的连通性，以及活动对它们在皮质中成熟的作用。项目II(Bernardo Rudy)将促进我们对5HT3aR INS在皮质功能中的作用的理解。具体地说，它将检验这一假设，即它们在上下文相关的感觉处理中很重要。它将研究5HT3aR INS的功能连接性，利用光刺激表达通道视紫红质的胆碱能和5-羟色胺能轴突来研究这些皮质下输入对它们的调节，并在体内进行双光子靶向记录，以研究不同行为状态下5HT3aR INS的活性以及它们对运动和感觉刺激的反应。项目III(甘文彪)将研究5HT3aR INS在V层锥体神经元上形成的突触的位置、结构和可塑性，以及这些INS在调节锥体细胞在学习和记忆形成过程中的活动和结构动力学中的作用。

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.