Somatosensory Cortical Development and Plasticity

描述（由申请人提供）：神经活动在连接和感觉通路可塑性中的作用是发展神经科学的一个重要课题。大量文献强调了n -甲基D天冬氨酸（NMDA）受体介导的神经活动在神经连接及其可塑性、学习和记忆的发育过程中的重要性，以及在成熟神经系统病理状态下的兴奋毒性。本研究的重点是NMDAR功能基因受损小鼠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图中地形连接和模式发展的一个很好的模型系统。缺乏NMDARs关键亚基的小鼠脑干中的体感觉模式被废除。表达较低水平NMDAR功能的小鼠也表现出沿体感觉通路的模式缺失。兴奋性神经元中NMDARs皮层限制性破坏的小鼠在体感觉体图区域内也表现出严重的皮质模式缺陷。除了轴突和突触后缺陷外，新皮层内体感觉体图的细分也发生了改变。因此，体感觉区域特异性敲除小鼠模型提供了一种很好的方法来剖析NMDARs和下游信号分子在突触前和突触后神经元件的模式化中的作用。本研究的长期目标是揭示NMDAR功能受损后突触后细胞的轴突突和树突突是如何改变的。分子遗传学和神经解剖学相结合的方法将用于阐明这些小鼠的体感觉皮层和丘脑的结构变化。对这种解剖变化的清晰理解将为解剖出哺乳动物感觉通路的模式形成和可塑性的分子机制铺平道路。这些研究可以扩展到研究成人皮层可塑性在学习过程中或作为周围神经损伤的结果的机制。n -甲基D天冬氨酸（NMDA）受体（NMDARs）在神经连接的发育及其可塑性、学习和记忆以及成熟神经系统病理状态下的兴奋毒性中发挥重要作用。在本研究中，我们将通过检测nmdar缺陷小鼠模型的神经缺陷来测试NMDARs在体感觉神经回路发育和可塑性中的作用。

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. A vast body of literature underscores the importance of N-methyl D Aspartate (NMDA) receptor- mediated neural activity 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, somatosensory region-specific knockout mouse models provide an excellent means to dissect out the role of NMDARs and downstream signaling molecules in 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 and thalamus 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. PUBLIC HEALTH RELEVANCE N-methyl D Aspartate (NMDA) receptors (NMDARs) play a major role in development of neural connections and their plasticity, learning and memory, as well as during excitotoxicity in pathological states of the mature nervous system. In this proposal we shall test the role of NMDARs in the development and plasticity of somatosensory neural circuits by examining neural defects in NMDAR-deficient mouse models.