Inhibitory mechanisms for sensory map plasticity in cerebral cortex.

描述（申请人提供）：感觉经验有力地调节后期产后发育和脑回路的成人功能，特别是在大脑皮层。介导这一过程的细胞机制尚不清楚，但对理解皮层神经发育障碍（包括自闭症、青少年癫痫和智力低下）具有重要意义。本项目重点研究经验控制大脑皮层兴奋和抑制平衡的新机制。这是在啮齿动物的体感觉皮层中研究的，这是一个典型的皮质功能模型系统。经验依赖的发展和修正（可塑性）的标准模型侧重于兴奋性皮层回路。然而，最近的研究结果表明，抑制回路也显示出强大的可塑性的感觉经验。抑制可塑性的患病率、细胞机制和机制作用在很大程度上是未知的。利用细胞和系统水平的神经生理学技术，我们将识别受感觉经验调节的特定抑制性神经元和回路，表征这种可塑性的细胞机制，并确定其在皮层功能中的作用。我们特别测试了抑制可塑性具有双重作用的假设：维持兴奋-抑制平衡，并在改变感觉使用过程中调节感觉反应的快速稳态。大量初步数据支持这一建议。总的来说，这项工作将扩展我们对皮层发育的理解，超越兴奋电路的基本可塑性，包括快速，强大的抑制可塑性。结果可能为青少年癫痫和自闭症等神经发育障碍提供了新的基础，这些疾病可能是由于兴奋-抑制平衡发育不正常引起的。这项工作可能会导致这些疾病的动物模型的改进和新的治疗策略。

DESCRIPTION (provided by applicant): Sensory experience powerfully regulates late postnatal development and adult function of brain circuits, particularly in the cerebral cortex. The cellular mechanisms that mediate this process are not yet understood, but have major implications for understanding cortical neurodevelopmental disorders, including autism, juvenile epilepsy, and mental retardation. This project focuses on novel mechanisms by which experience controls the balance of excitation and inhibition in cerebral cortex. This is studied in the somatosensory cortex of rodents, which is a canonical model system for cortical function. Standard models of experience-dependent development and modification (plasticity) focus on excitatory cortical circuits. However, recent findings indicate that inhibitory circuits also show robust plasticity by sensory experience. The prevalence, cellular mechanisms, and mechanistic role of inhibitory plasticity are largely unknown. Using cellular and systems-level neurophysiology techniques, we will identify specific inhibitory neurons and circuits that are regulated by sensory experience, characterize the cellular mechanisms for this plasticity, and determine its role in cortical function. We specifically test the hypothesis that inhibitory plasticity has a dual role: to maintain excitatory-inhibitory balance, and to mediate rapid homeostasis of sensory responses during changing sensory use. Substantial preliminary data support the proposal. Overall, this work will extend our understanding of cortical development beyond basic plasticity of excitatory circuits, to include rapid, robust plasticity of inhibition. Results may suggest a novel basis for neurodevelopmental disorders including juvenile epilepsy and autism, which may arise from improper development of excitatory-inhibitory balance. This work may lead to improved animal models and novel therapeutic strategies for these diseases.