Nicotinic modulation of deep layer inhibitory neurons for visual cortical plasticity

项目概述：因关闭青少年特有的关键期而导致的皮质可塑性下降是 从神经发育障碍和脑创伤中恢复的关键阻抗。神经调节作用 成人大脑皮质中有丰富的系统，并且处于很好的位置来协调经验依赖 促进强健可塑性的生理事件。然而，越来越多的人认识到 神经调节回路以及神经元亚型的多样性对识别特定的 神经调节系统及其皮质靶点，以精确恢复可塑性。这项研究的目标是 识别新的分子和电路靶点，以诱导成人大脑的神经调节变化，以 重新激活青少年样的可塑性，用于治疗具有持久性功能障碍的脑部疾病。使用目视 优势可塑性，一种流行的初级视皮层关键期可塑性模型，我们将测试 假设，在各种可能的神经调节系统及其皮质靶点的组合中， 初级视皮层深层烟碱型ACh调制和生长抑素表达的中间神经元 表达特定类型的烟碱型ACh亚型作为神经调节电路元件的新组合 诱导快速局部电路调制以恢复幼年样视皮质的可塑性和恢复 成年期的弱视。我们将充分利用最近开发的 基因工程小鼠品系实现亚群和皮质层特异性电路选择性 对超出常规细胞类型水平的基因表达或神经活动的操纵和测量 体内细胞外和体外切片电生理与光遗传学相结合的分析， 化学遗传学和行为分析。在AIM1中，我们将研究特定的nAChR亚单位在 诱导经验依赖的深层中间神经元快速变化以触发眼优势可塑性。 在AIM2中，我们将剖析深层SST调节的兴奋和抑制电路机制 触发眼优势可塑性的中间神经元。在Aim3中，我们将检查从 调节深层中间神经元nAChR表达的弱视。这个项目的成功完成将 阐明了启动触发皮质可塑性的初始级联的新的分子和电路机制， 这将对弱视有直接影响，弱视是一种成人适用治疗有限的疾病，影响 人类人口的2-5%，还用于脑损伤修复、感觉恢复和脑损伤的治疗 神经发育障碍伴感觉知觉障碍。

Project Summary: The decline of cortical plasticity due to closure of the juvenile-specific critical period is the key impedance of recovery from neurodevelopmental disorders and brain trauma in later life. Neuromodulatory systems are abundant in the adult cortex and well-positioned to orchestrate experience-dependent physiological events to prompt robust plasticity. However, an increasingly recognized complexity of neuromodulatory circuits as well as the diversity of neuron subtypes pose a challenge to identify a specific neuromodulatory system and their cortical target to precisely restore plasticity. The goal of this study is to identify novel molecular and circuit targets for inducing neuromodulatory changes in the adult brain, to reactivate juvenile-like plasticity for treating brain disorders with enduring functional impairments. Using ocular dominance plasticity, a prevailing primary visual cortex critical period plasticity model, We will test the hypothesis that, among various possible combinations of neuromodulatory systems, and their cortical targets, nicotinic ACh modulation and somatostatin expressing interneurons in the deep layer of primary visual cortex expressing specific type of nicotinic ACh sub-type as a novel combination of neurmodulatory circuit elements to induce rapid local circuit modulation to restore juvenile-like visual cortex plasticity and recovery from Amblyopia in adulthood. We will test this hypothesis by taking full advantage of the recently developed genetically-engineered mouse lines to achieve sub-population and cortical-layer-specific circuit-selective manipulation and measurement of gene expression or neural activity beyond conventional cell-type level analysis in combination of in vivo extracellular and in vitro slice electrophysiology with optogenetics, chemogenetics, and behavior assay. In Aim1, we will examine the contribution of specific nAChR subuniton inducing experience-dependent rapid change of deep layer interneurons to trigger ocular dominance plasticity. In Aim2, we will dissect the excitatory and inhibitory circuit mechanisms regulated by deep layer SST interneurons to trigger ocular dominance plasticity. In Aim3, we will examine the extent of recovery from Amblyopia by modulating nAChR in deep layer interneurons. Successful completion of this project will illuminate new molecular and circuit mechanisms that gate the initial cascade triggering cortical plasticity, which will have direct implications for Amblyopia, a condition with limited adult-applicable treatment affecting 2–5% of the human population, but also for brain injury repair, sensory recovery, and the treatment of neurodevelopmental disorders with sensory perceptual deficits.