Plasticity of Functional Networks in Auditory Cortex

项目摘要 在发育中的神经系统中，数以百万计的神经元协调和完善它们的连接， 发展成令人难以置信的复杂行为，比如说话和语言。这些特殊的行为需要 听觉皮层内复杂网络的正常功能。在这个提议中，函数神经网络将 在音调检测行为期间，使用皮质柱内的高速体积成像进行研究， 小鼠除了使用最先进的网络分析来表征这些网络之外， 网络是否足以驱动行为将通过激活或沉默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 深入了解听觉皮层如何作为决策单位发挥作用，并为理解 当这些网络被破坏时会发生什么。 该提案的另一个主要目标是在关键时期调查网络重组， 在皮层发育过程中的一个显著的可塑性时期，其中眼优势柱从 视觉皮层和音调图在听觉系统中变得清晰。先前的研究发现， 在此期间，动物在间歇性音调的存在下， 专注于这种语气。尽管对这种音调的反应增强了，但动物们很难区分小调， 不同的音调围绕着饲养的音调。奇怪的是，我们实验室的初步结果表明， 声调的提高会显著地减少对该声调作出反应的皮层空间。这项建议旨在 用与上述类似的方法调和这些差异， 在一个体积内的数百到数千个神经元的成像，但在小鼠中， 关键时期。网络分析将揭示重组的程度，并提供关键的见解， 大脑皮层回路对早期环境声音的反应 最后，这项建议旨在调查哪些细胞类型在脑缺血期间协调电路重组。 关键时期。在发育中的皮层中，位于皮层下的一组发育短暂的细胞， 似乎是为了实现这一功能。这些亚板神经元交织成皮质回路， 亚板到亚板、丘脑皮质和IV层投射。非常值得注意的是，这些是第一批 对声音的反应在皮层（甚至在第四层之前）。为了测试板下神经元是否介导皮层 重组，化学和光遗传学方法将用于沉默和激活这些细胞， 关键时期。功能网络的后续分析将使用体积成像进行。 了解重组这些回路的机制可能有助于深入了解发育原因 这一时期出现的神经线路功能障碍，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人工耳蜗植入的结果。

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.