Plasticity of Functional Networks in Auditory Cortex

项目总结 在发育中的神经系统中，数以百万计的神经元协调和改进它们的连接，以提供 变得极其复杂的行为，比如说话和语言。这些特定的行为需要 听觉皮质内错综复杂的网络的正常功能。在这项提议中，功能神经网络将 在音调检测行为期间，在皮质柱内使用高速体积成像进行研究 老鼠。除了使用最先进的网络分析来表征这些网络之外，无论这些 网络是否足以驱动行为将通过激活或静默3D连接的神经元进行测试 全息刺激。了解这些网络在正常成年人中的功能将提供独特的 洞察听觉皮质作为决策单位的功能，并为理解 当这些网络中断时会发生什么。 这项建议的另一个主要目标是调查关键时期的网络重组， 大脑皮质发育过程中的显著可塑性时期，在这一时期，眼优势柱形成于 视觉皮层和直视图在听觉系统中变得清晰。以前的研究已经观察到，养育 在此期间，动物在间歇性音调的存在下，皮质空间显著增加 致力于这一基调。尽管对这种语气的反应增强了，但动物很难区分未成年人 在后仰的音调周围演奏的不同音调。矛盾的是，我们实验室的初步结果表明 音调调养极大地减少了对音调做出反应的皮质空间。这项建议旨在 用与上述方法类似的方法协调这些差异，这允许同时 对同一体积内成百上千个神经元进行成像，但在饲养过程中以间歇性音调饲养的小鼠 关键时期。网络分析将揭示重组的程度，并提供对 大脑皮层回路对早期环境声音的反应。 最后，这项建议试图调查哪些细胞类型在 关键时期。在发育中的皮质中，位于皮质下的一组发育短暂的细胞。 板块似乎准备履行这一功能。这些亚板神经元与大脑皮质环路交织在一起 底板到底板、丘脑皮质和第四层的投射。值得注意的是，这些神经元是第一批 对大脑皮层的声音作出反应(甚至在第四层之前)。为了测试下层神经元是否介导大脑皮层 重组、化学和光遗传方法将被用来沉默和激活这些细胞 关键时期。随后将使用体积成像对功能网络进行分析。 了解重组这些回路的机制可能有助于洞察发育原因 在此期间出现的功能障碍的连接，为如何恢复成人的可塑性提供了线索 听觉回路，这可能会改善老年先天性耳聋患者的人工耳蜗植入结果。

PROJECT SUMMARY In the developing nervous system, millions of neurons coordinate and refine their connections to give rise to incredibly complex behavior, such as speech and language. These particular behaviors require the proper function of intricate networks within the auditory cortex. In this proposal, functional neural networks will be investigated using high-speed, volumetric imaging within cortical columns during tone-detection behavior in mice. In addition to characterizing these networks using state-of-the-art network analysis, whether or not these networks are sufficient to drive behavior will be tested by activating or silencing connected neurons with 3D holographic stimulation. Understanding how these networks function in normal adults will provide unique insight into how the auditory cortex functions as a decision-making unit and provide a basis for understanding what happens when these networks are disrupted. Another major goal of this proposal is to investigate network reorganization during the critical period, a remarkable period of plasticity during cortical development in which ocular dominance columns from in the visual cortex and tonotopic maps sharpen in the auditory system. Previous studies have observed that rearing animals in the presence of an intermittent tone during this period dramatically increases the cortical space devoted to that tone. Despite the enhanced response to that tone, animals had difficulty discriminating minor differences in tones played around the reared tone. Paradoxically, preliminary results from our lab indicate that tone rearing dramatically decreases the cortical space that responds to that tone. This proposal seeks to reconcile these differences with similar approaches as those described above, which allows for simultaneous imaging of hundreds to thousands of neurons within a volume, but in mice reared with intermittent tones during the critical period. Network analysis will uncover the extent of the reorganization and provide key insights into how cortical circuits responds to early environmental sounds. Lastly, this proposal seeks to investigate which cell types orchestrate circuit reorganization during the critical period. In the developing cortex, a developmentally transient group of cells located beneath the cortical plate seem poised to fulfill this function. These subplate neurons are interwoven into cortical circuits with local subplate-to-subplate, thalamocortical, and layer IV projections. Quite remarkably, these are the first neurons to respond to sound in the cortex (even before layer IV). To test if subplate neurons mediate cortical reorganization, chemo- and optogenetic approaches will be used to silence and activate these cells during the critical period. Subsequent analysis of functional networks will be performed using volumetric imaging. Understanding the mechanisms that reorganize these circuits may provide insight into developmental causes of dysfunctional wiring that arise during this period and offer clues about how to restore plasticity in adult auditory circuits, which may improve outcomes of cochlear implantation in older, congenitally deaf patients.