Cortical circuits for the integration of parallel short-latency auditory pathways

项目总结 我们的大脑如何通过整合来自平行感觉通路的信息来实现连贯的感知 在空间和时间上的分布仍然是神经科学的一个中心问题。在听觉系统中，声音 信息通过丘脑(“初级”)和非丘脑(“次级”)通路到达大脑皮质。这个 非记忆通路通常被描述为多感官信息的较慢整合者，在 与lemnisal通路作为快速可靠的声音输入中继器的作用形成对比。然而， 非丘脑通路在驱动快速皮质反应中的作用以及它们如何与 声音处理过程中的lemnisal通路仍然是有争议的问题。我们初步的电生理学 实验表明，初级和次级听皮层的第6层(L6)都能接收到 其潜伏期可以短于L4词汇输入的声音输入。令人惊讶的是，我们的逆行追踪 表明该短潜伏期L6输入起源于听觉丘脑的非强直部分， 支持非丘脑通路在快速感觉加工中的作用。在这个令人兴奋的发现的基础上， 我们将结合解剖示踪、体外/体内电生理学、光遗传学和行为学来描绘 这一非经典通路，并确定它如何与丘疹通路相互作用来调节皮质 感官处理。具体地说，我们将检验这样一种假设，即短潜伏期非词汇性输入到 L6以时序依赖的方式调节皮层声音的加工，并控制调谐和时间 声音响应的保真度。为了实现这一目标，本项目旨在(1)勾勒出快速的非 解剖示踪法和活体示踪法研究耳蜗核至听皮质的丘脑通路 单位记录，(2)通过以下方式确定非词汇输入对皮层细胞类型的突触影响 在皮质切片中进行定向全细胞记录，同时激活L6靶向 丘脑输入，以及(3)通过以下方式确定快速非词汇输入在活体皮质声音处理中的作用 在执行声音的小鼠的单位记录期间，光遗传操作丘脑输入到L6- 引导性行为。通过我们的研究，我们试图提供对听觉的更全面的理解 在两条主要的上升通道上进行处理。由于L4和L6上平行丘脑皮质输入是 这个项目的结果将在感官模式中保守，将为可推广的 感觉统合的大脑皮层回路的基本原理。归根结底，这些研究将有助于未来 不仅针对听力障碍，而且针对其他感觉统合的靶向治疗的发展 功能障碍。

PROJECT SUMMARY How our brain achieves coherent perception by integrating information from parallel sensory pathways distributed across space and time remains a central question in neuroscience. In the auditory system, sound information reaches the cortex via the lemniscal (“primary”) and non-lemniscal (“secondary”) pathways. The non-lemniscal pathways have often been described as slower integrators of multi-sensory information, in contrast to the roles of the lemniscal pathways as fast and reliable relays for sound inputs. However, the contribution of the non-lemniscal pathways in driving fast cortical responses and how they interact with the lemniscal pathways during sound processing are still matters of debate. Our preliminary electrophysiology experiments show that layer 6 (L6) of not only the primary but also the secondary auditory cortex receives sound inputs whose latency can be shorter than the L4 lemniscal inputs. Surprisingly, our retrograde tracing demonstrates that this short-latency L6 input originates from the non-tonotopic parts of the auditory thalamus, supporting the role of the non-lemniscal pathway in fast sensory processing. Building on this exciting finding, we will combine anatomical tracing, in vitro/in vivo electrophysiology, optogenetics, and behavior to delineate this non-classical pathway and determine how it interacts with the lemniscal pathway to regulate cortical sensory processing. Specifically, we will examine the hypothesis that short-latency non-lemniscal inputs onto L6 regulate cortical sound processing in a timing-dependent manner and control the tuning and temporal fidelity of sound responses. To achieve this goal, this project aims to (1) Delineate the anatomy of the fast non- lemniscal pathway from the cochlear nucleus to the auditory cortex using both anatomical tracing and in vivo unit recordings, (2) Determine the synaptic impact of the non-lemniscal input onto cortical cell types by performing targeted whole-cell recordings in cortical slices while simultaneously activating L6-targeting thalamic inputs, and (3) Identify the roles of the fast non-lemniscal input in cortical sound processing in vivo by optogenetically manipulating thalamic inputs onto L6 during unit recordings in the mice performing sound- guided behaviors. Through our research, we seek to provide a more holistic understanding of auditory processing across the two major ascending pathways. Since parallel thalamocortical inputs onto L4 and L6 are conserved across sensory modalities, results from this project will provide insights into the generalizable principles underlying the cortical circuitry of sensory integration. Ultimately, these studies will help the future development of targeted treatments for not only hearing disorders but also other sensory integration dysfunctions.