Mechanisms of receptive field establishment in mouse visual cortex

描述(申请人提供)：视觉主导人类的感官体验，尤其是视觉皮质对于理解我们周围的世界至关重要。在发育过程中，分子和细胞过程，如突触的形成和细化，塑造了视皮层适当功能的基础电路。因此，清楚地了解支持视觉系统发育的机制将有助于我们解决损害视觉感知的神经发育障碍的能力。本文提出的工作将在突触发育的分子机制和清醒小鼠初级视觉皮质中特定功能反应特性的出现之间提供重要的联系。在具体目标1中，我将确定从睁眼到成年小鼠视觉皮质中几种基本感受场(RF)特性的出现和精炼的时间进程。我将用高密度硅探头测量细胞外单位的活动，这些探头跨越几层皮质，同时将优化的视觉刺激呈现给老鼠。从这些记录中，我将使用最近开发的数据分析技术来量化不同类别细胞的感受场属性-兴奋层、抑制层和特定层-随着它们在发育中的演变。具体地说，我将描述这些不同类型的细胞的定向选择性(OS)、空间频率调谐(SF)和响应线性的个体发育。这将构成对发展的第一个完整描述 这些射频特性在清醒的小鼠视皮层中使用电生理学；它将产生新的细胞类型和层特定信息，这将是我们实验室和其他实验室未来机制研究所需的。在特定的目标2中，我将删除特定的N-甲基-D-天冬氨酸受体(NMDAR)亚单位，NR2B或NR2A，从OS最初出现在视觉系统中的目标细胞类别中删除。这些亚基的差异表达与视觉系统发育的特定发育阶段有关。因此，我将检验这一假设，即NR2B和NR2A分别在视觉皮质(V1)中分别建立和随后的几个RF属性的建立和精炼的不同基础。我将在小鼠发育的关键时间点特别测量上面概述的射频特性，其中NR2B或NR2A已从密集占据视觉皮质IV层的特定兴奋细胞群中删除。这种综合的方法将极大地影响我们对视觉系统功能发展的基础机制的理解。具体地说，我们的针对性研究将增加前所未有的机制知识，即在V1早期发育过程中，何时何地需要NMDAR介导的活动来建立和完善V1反应特性。

DESCRIPTION (provided by applicant): Vision dominates the human sensory experience, and the visual cortex in particular is critical for understanding the world around us. During development, molecular and cellular processes such as synapse formation and refinement shape the circuitry underlying the appropriate function of the visual cortex. Therefore, a clear understanding of the mechanisms that support visual system development would facilitate our ability to address neurodevelopmental disorders that impair visual perception. The work proposed herein will provide an important link between the molecular mechanisms of synaptic development and the emergence of specific functional response properties in the primary visual cortex of the awake mouse. In specific aim 1, I will determine the time-course for the emergence and refinement of several basic receptive field (RF) properties in mouse visual cortex from eye opening to the adult. I will measure extracellular unit activity with high-density silicon probes that span several layers of cortex, while optimized visual stimuli are presented to the mouse. From these recordings, I will use recently developed data analysis techniques to quantify the receptive field properties of distinct classes of cells - excitatory, inhibitory, and specific layers - as they evolve over development. Specifically, I will delineate the ontogeny of orientation selectivity (OS), spatial frequency tuning (SF) and response linearity across these distinct cell types. This will constitute the first complete characterization of the development of these RF properties in the awake mouse visual cortex employing electrophysiology; and it will yield novel cell type and layer specific information that will be required for future mechanistic studies by our lab and others. In specific aim 2, I will delete specific N-methyl-D-Aspartate receptor (NMDAR) subunits, NR2B or NR2A, from a targeted class of cells where OS first arises in the visual system. Differential expression of these subunits relate to specific developmental phases of visual system development. Therefore, I will test the hypothesis that NR2B and NR2A differentially underlie the establishment and subsequent refinement, respectively, of several RF properties in visual cortex (V1). I will specifically measure the RF properties outlined above at key time-points in development in mice where NR2B or NR2A has been deleted from a specific excitatory cell population that densely occupies layer IV of visual cortex. This integrative approach will significantly impact our understanding of the mechanisms that underlie the development of function in the visual system. Specifically, our targeted studies will add unprecedented mechanistic knowledge of where and when NMDAR mediated activity is required for the establishment and refinement of V1 response properties over early development.