Critical Period Plasticity and Binocular Matching in the Visual Cortex

描述（由申请人提供）：神经系统的最佳功能需要神经回路的选择性连接，其精度是通过出生后的经验依赖的改进来实现的。经验依赖发展的一个经典模型系统是视觉系统中的眼优势可塑性，在早期生命的“关键时期”，单眼眼睑关闭导致皮质反应向非被剥夺的眼睛转移。尽管经过几十年的研究，人们仍然不知道在正常发育过程中，当两只眼睛的输入信息完好无损时，这个关键时期起到了什么作用。在这项资助中，提出的工作旨在确定在关键时期正常视觉诱导的可塑性对皮层功能的影响，并揭示其潜在的分子和突触机制。首先，研究人员将检验关键期可塑性是否驱动正常发育过程中双眼取向偏好的匹配。在小鼠视觉皮层进行单单元记录和双光子钙成像，以确定定向偏好双目匹配的时间过程及其在关键时期对正常视觉体验的要求。其次，由于抑制水平的遗传或药理学改变，已知会改变眼优势可塑性关键时期的时间，研究人员将确定皮质内抑制是否通过调节取向选择性的成熟来控制双眼匹配的时间。细胞内全细胞记录也将在体内进行，以揭示突触抑制在介导双眼定向偏好匹配和调节关键时期时间中的时空模式。最后，我们将对不同发育阶段的双眼分别研究单个皮质神经元的感受野结构，以揭示在关键时期，感受野是如何单眼改变以介导双眼定向偏好匹配的。药理实验也将进行，以确定是否皮质活动和NMDA受体激活是双目匹配过程所必需的。总之，这些研究将揭示正常发育的关键时期的生理作用。由于眼优势可塑性及其关键期是人类弱视和斜视的模型系统，因此充分了解发育过程中正常发生的皮质变化将对理解和治疗这些疾病具有重要意义。

DESCRIPTION (provided by applicant): Optimal functioning of the nervous system requires selective wiring of neural circuits, the precision of which is achieved through experience-dependent refinement after birth. A classical model system of the experience-dependent development is the ocular dominance plasticity in the visual system, where monocular eyelid closure in a "critical period" of early life leads to a shift of cortical responses towards the non-deprived eye. Despite decades of work, it is still unknown what purpose the critical period serves during normal development, when the inputs from the two eyes are intact. In this grant, the proposed work aims to determine what cortical function is shaped by normal vision-induced plasticity during the critical period and to reveal its underlying molecular and synaptic mechanisms. First, the investigators will test whether the critical period plasticity drives the matching of binocular orientation preference during normal development. Both single unit recording and two-photon calcium imaging will be performed in the mouse visual cortex to determine the time course of binocular matching of orientation preference and its requirement of normal visual experience in the critical period. Second, with genetically or pharmacologically altered level of inhibition, which is known to shift the timing of the critical period of ocular dominance plasticity, the investigators will determine whether intracortical inhibition controls the timing of binocular matching by regulating the maturation of orientation selectivity. Intracellular whole cell recording will also be performed in vivo to reveal the spatiotemporal patterns of synaptic inhibition in mediating the binocular matching of orientation preference and in regulating the critical period timing. Finally, the receptive field structure of individual cortical neurons will be studied separately to the two eyes at different developmental stages to reveal how receptive fields change monocularly during the critical period to mediate binocular matching of orientation preference. Pharmacological experiments will also be carried out to determine if cortical activity and NMDA receptor activation are required for the binocular matching process. Together, these studies will reveal a physiological role for the critical period in normal development. Because ocular dominance plasticity and its critical period is a model system for human amblyopia and strabismus, a full understanding of cortical changes that normally take place during development will have important implications for the understanding and treatment of these diseases. PUBLIC HEALTH RELEVANCE: The long-term goal of our research is to reveal the function and development of precise connections between neurons in the nervous system. These studies are of great clinical importance, because many neurological and psychiatric disorders result from miswiring of synaptic connections, such as cortical blindness, seizure, and mental retardation. Our studies will thus contribute to the understanding and treatment of these disorders.