Mechanisms governing development of large-scale networks in visual cortex

视觉皮层大规模网络发展的调控机制

• 批准号: 10558729
• 负责人: Gordon Brawn Smith
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558729
• 关键词: Address; Anatomy; Architecture; Area; Birth; Calcium; Computer Models; Development; Elements; Event; Eye; Ferrets; Functional Imaging; Future; Image; Individual; Investigation; Knowledge; Label; Link; Measures; Mediating; Mental disorders; Neurodevelopmental Disorder; Neurons; Optical Methods; Optics; Pattern; Perception; Population; Positioning Attribute; Primates; Publishing; Research; Schizophrenia; Sensory; Shapes; Stimulus; Structure; Surface; System; Testing; Viral; Visual; Visual Cortex; Visual evoked cortical potential; Work; autism spectrum disorder; excitatory neuron; experimental study; inhibitory neuron; insight; millimeter; nervous system disorder; neural; novel; optogenetics; orientation selectivity; pharmacologic; predictive modeling; recruit; serial imaging; two-photon

Abstract Sensory perception requires the coordinated activity of tens of thousands of neurons, working together in large- scale functional networks. Developmental events define and constrain the ultimate capabilities of these networks, therefore it is essential to understand the mechanisms underlying their formation. In the visual cortex of primates and carnivores, columnar networks of orientation preference extend across millimeters of cortical surface. Prior to eye-opening, such large-scale networks are already evident in correlated spontaneous activity, whose structure can predict future visually-evoked responses. However, a major gap in our ability to relate early network structure to mature sensory function is the lack of knowledge of the circuit mechanisms through which millimeter- scale correlated activity is generated in the early cortex. The experiments in this proposal will address this gap and test the hypothesis that large-scale correlated networks in the early cortex are generated by propagating activity through purely short-range intracortical connections and are refined through the emergence and elaboration of monosynaptic horizontal projections. By employing wide-field calcium imaging in early visual cortex, the experiments in this proposal will directly assess propagation in early spontaneous activity. A key prediction of our hypothesis is the interdependence of cortical domains in generating correlated activity. We will test this by determining whether local pharmacological or optogenetic silencing of cortical activity leads to a global disruption of correlated network activity. In order to identify the contribution of inhibitory neurons to the structure of correlated networks in the early cortex, we will utilize inhibitory-neuron specific labelling and 2-photon calcium imaging, together with targeted optogenetic manipulations. Finally, as these early correlated networks undergo refinement during the same period that long-range horizontal projections begin to elaborate in layer 2/3, we will combine anatomical labeling with longitudinal functional imaging of spontaneous activity. This will allow us to determine whether emerging horizontal connections link domains that are already functionally correlated, or instead act to reshape functional networks in the early visual cortex. Together, these studies will provide critical new insights into the circuit mechanisms governing the formation and refinement of large-scale correlated networks in the early cortex. In doing so, they will provide a key framework for understanding how the patterns of early cortical activity establish the organization of developing cortical networks and impact later sensory perception.

摘要 感官知觉需要成千上万个神经元的协调活动，在大范围内共同工作- 规模功能网络。发展事件定义并限制了这些网络的最终能力， 因此，了解其形成的机制至关重要。在灵长类动物的视觉皮层中 和食肉动物，方向偏好的柱状网络延伸到几毫米的皮层表面。之前 令人大开眼界的是，这种大规模的网络在相关的自发活动中已经很明显， 结构可以预测未来的视觉诱发反应。然而，我们在将早期网络联系起来的能力方面存在一个重大差距， 结构成熟的感觉功能是缺乏知识的电路机制，通过毫米- 在早期皮层中产生与尺度相关的活动。本提案中的实验将解决这一差距 并测试了早期皮层中的大规模相关网络是通过传播 活动通过纯粹的短距离皮层内连接，并通过出现和 单突触水平投射的精细化。通过在早期视觉中使用宽视野钙成像， 皮层，本提案中的实验将直接评估早期自发活动中的传播。一个关键 我们的假设的预测是在产生相关活动的皮质域的相互依赖性。我们将 通过确定皮质活动的局部药理学或光遗传学沉默是否导致 相关网络活动的全球中断。为了确定抑制性神经元对神经元的作用， 在早期皮层相关网络的结构，我们将利用神经元特异性标记和双光子 钙成像以及靶向光遗传学操作。最后，由于这些早期的相关网络 在长距离水平投影开始在层2/3中精细化的同一时期内进行精细化， 我们将联合收割机解剖标记与自发活动的纵向功能成像相结合。这将允许 我们确定是否出现水平连接链接已经功能相关的域， 或者是重塑早期视觉皮层的功能网络。这些研究将提供 关键的新见解电路机制的形成和完善的大规模相关 早期大脑皮层的网络。在这样做的过程中，他们将提供一个关键的框架，以了解模式如何 早期皮层活动的影响建立了发育中的皮层网络的组织，并影响了后来的感觉 perception.