Inhibitory mechanisms for sensory map plasticity in cerebral cortex.

描述(申请人提供)：感官经验有力地调节出生后后期大脑回路的发育和成人的功能，特别是在大脑皮层。调节这一过程的细胞机制尚不清楚，但对理解皮质神经发育障碍有重要意义，包括自闭症、青少年癫痫和智力低下。这个项目关注的是经验控制大脑皮层兴奋和抑制平衡的新机制。这是在啮齿类动物的体感皮质中进行的研究，这是一个典型的皮质功能模型系统。依赖经验的发育和修饰(可塑性)的标准模型侧重于兴奋性皮质回路。然而，最近的发现表明，抑制回路也通过感觉经验显示出强大的可塑性。抑制可塑性的流行、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神经元和回路，表征这种可塑性的细胞机制，并确定其在皮质功能中的作用。我们专门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，以及在改变感觉使用期间调节感觉反应的快速动态平衡。大量的初步数据支持这一提议。总体而言，这项工作将扩展我们对皮层发育的理解，超越兴奋回路的基本可塑性，包括快速、稳健的抑制可塑性。结果可能为包括青少年癫痫和自闭症在内的神经发育障碍提供了一个新的基础，这些障碍可能是由于兴奋-抑制平衡的不正确发展而引起的。这项工作可能导致改进动物模型和针对这些疾病的新治疗策略。

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.