清醒小鼠次级听觉皮层反应特性及其可塑性的突触机制

The secondary auditory cortex (AII) is an essential component of the auditory pathway. Previous studies suggested that AII plays critical roles in advanced brain functions such as speech, auditory related cognition, emotion, learning and memory, and is tightly associated with auditory disorders as well. However, studies about AII are still far from systematic, especially when compared to the primary auditory cortex. The applicant has extensive experience in studying the neuroanatomical, electrophysiological and behavioral aspects of the auditory cortex. The applicant has published 6 papers in SCI database. Among them, there are papers published in prestigious journals like Nature, Nature Neuroscience and Journal of Neuroscience with the applicant as the first author, contribution author and corresponding author. Herein, the applicant propose to establish mouse awake recording system, by combining research approaches such as in vivo extracellular recording, in vivo whole-cell patch-clamp recording, trans-genetic mouse lines, optogenetics and mathematical modeling. The applicant plans to investigate the synaptic mechanisms underlying auditory information processing and plasticity in AII, and three specific projects are included. Answers to these questions are very likely to underpin the applicant's future studies about the interaction between the secondary auditory pathway and animal auditory behavior.

次级听觉皮层是听觉神经通路的重要组成部分。已有的实验证据暗示次级听觉皮层在言语、听觉相关的认知、情绪以及学习记忆等高级脑功能中扮演重要角色，并与听觉障碍紧密相关。然而与初级听觉皮层相比，针对次级听觉皮层的研究严重缺乏系统性。申请人在听觉皮层的解剖学，电生理学和行为学研究等方面具有丰富经验，发表了6篇SCI论文，包括分别在Nature，Nature Neuroscience和Journal of Neuroscience等国际一流神经科学杂志发表的第一作者，贡献作者和通讯作者论文。申请人计划建立清醒小鼠记录系统，结合在体细胞外记录、全细胞膜片钳记录、转基因小鼠、光遗传学技术和数学建模方法，研究次级听觉皮层内信息加工及其可塑性发生的突触机制，具体包括三个课题。这些问题的解决将为申请人下一步研究次级听觉神经回路与动物听觉行为的交互调控奠定基础。

听觉皮层神经元反应特性及其可塑性产生的机制还很不清楚。对听皮层信息处理机制的研究将有助于我们理解由听觉信号诱发的动物行为的神经机制，并有可能为听觉障碍和疾病的诊断、治疗及康复提供新思路。在本项目中，我们使用了活体细胞封接记录、全细胞电压钳/电流钳记录、转基因动物、由病毒辅助的神经环路失踪技术、免疫组化技术以及我们自己开发的半自动脑片图像分析方法，研究了听觉皮层时间信息处理能力发育的突触机制以及高级听觉丘脑与听觉皮层以及其他脑区之间的连接模式。我们发现：（1）处于发育过程中的听觉皮层第IV层神经元的时间信息处理能力存在细胞类型特异性；（2）幼年听觉皮层中第IV层兴奋性神经元接收到的抑制性输入具有幅度更高，时程更长的特点；（3）幼年听觉皮层中抑制性作用的时程对动物的感觉经验非常敏感；（4）听觉皮层第V层椎体神经元在幼年即可表现出类似于成年的对重复性声音刺激的忠实跟随；（5）发育皮层中的第V层具有显著缩短的抑制性突触输入时程；（6）无论是在幼年还是成年听觉皮层中，快速放电神经元都能对快速变化的声音信号做出忠实反应；（7）高级听觉丘脑中的Calbindin和Calretinin神经元的全脑连接网络具有很高的相似度；（8）高级听觉丘脑的背侧和腹侧呈现出明显不同的连接偏好性。我们的研究表明抑制性神经环路是感觉经验对幼年皮层进行调控的主要目标，支持第V层可能是独立于第IV层的重要丘脑输入接收层这一观点，并为揭示高级听觉丘脑-皮层互动的功能性研究提供了解剖学图谱。