Somatosensory Cortical Development and Plasticity

描述(由申请人提供)：神经活动在感觉通路的连接和可塑性中的作用是发育神经科学中感兴趣的一个主要主题。在过去的十年中，N-甲基-D-天冬氨酸(NMDA)受体介导的神经活动的作用受到了相当大的关注。大量的文献现在强调了NMDAR在神经连接的发展及其可塑性、学习和记忆以及在成熟神经系统病理状态的兴奋性毒性过程中的重要性。这项建议侧重于NMDAR功能遗传受损小鼠的躯体感觉丘脑皮质回路的发展。啮齿动物体感通路是研究体感地形图中的地形图连接和图形发展的一个很好的模型系统。缺乏NMDAR关键亚单位的小鼠脑干中的躯体感觉模式被取消。表达较低水平NMDAR功能的小鼠也显示出在整个躯体感觉通路上都没有模式。兴奋性神经元中NMDAR的皮质受限干扰的小鼠也在躯体感觉身体地图区域的皮质图案方面显示出严重的缺陷。除了轴突和突触后缺陷外，新皮质内躯体感觉体感体图的细分也发生了变化。因此，这些小鼠模型提供了一个很好的方法来剖析NMDAR在躯体感觉身体地图的分离以及突触前和突触后神经元件的模式中的作用。这个建议的长期目标是揭示NMDAR功能受损后突触后细胞的轴突和树突是如何改变的。将使用分子遗传学和神经解剖学相结合的方法来阐明这些小鼠躯体感觉皮质的结构变化。对这些解剖学变化的清楚理解将为剖析哺乳动物发育中感觉通路的模式形成和可塑性的分子机制铺平道路。然后，这些研究可以扩展到研究成人在学习期间或作为周围神经损伤的结果的皮质可塑性的机制。

DESCRIPTION (provided by applicant): The role of neural activity in wiring and plasticity of sensory pathways is a major topic of interest in developmental neuroscience. During the past decade, considerable attention is directed toward the role of N-methyl D Aspartate (NMDA) receptor-mediated neural activity. A vast body of literature now underscores the importance of NMDARs during development of neural connections and their plasticity, learning and memory, as well as during excitotoxicity in pathological states of the mature nervous system. This proposal focuses on the development of somatosensory thalamocortical circuitry in mice with genetically impaired NMDAR function. Rodent somatosensory pathway is an excellent model system to study development of topographic connections and patterning within somatosensory maps. Somatosensory patterns are abolished in the brainstem of mice lacking the critical subunit of the NMDARs. Mice that express lower levels of NMDAR function also show absence of patterning all along the somatosensory pathway. Mice with cortex-restricted disruption of NMDARs in excitatory neurons also display severe defects in cortical patterning within the somatosensory body map region. Aside from axonal and postsynaptic defects, the subdivisions of the somatosensory body map within the neocortex are altered. Thus, these mouse models provide an excellent means to dissect out the role of NMDARs in parcellation of somatosensory body maps, and patterning of pre and postsynaptic neural elements. The long-term objective of this proposal is to reveal how axon arbors and dendritic processes of postsynaptic cells are altered following impaired NMDAR function. Combined molecular genetic and neuroanatomical approaches will be used to elucidate structural changes in the somatosensory cortex of these mice. A clear understanding of such anatomical changes will pave the way for dissecting out molecular mechanisms of pattern formation and plasticity in developing mammalian sensory pathways. These studies could then be expanded to investigate mechanisms of adult cortical plasticity during learning or as a consequence of peripheral nerve damage.