Nicotinic modulation of deep layer inhibitory neurons for visual cortical plasticity

项目摘要：由于青少年特定关键期的关闭而导致的皮质可塑性下降是 神经发育障碍和脑创伤的康复在以后的生活中的关键阻抗。神经调节 成年人的大脑皮层中有大量的神经系统，它们能够很好地协调依赖于经验的神经系统。 生理事件，以促进强大的可塑性。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 神经调节系统和他们的皮质目标，以精确地恢复可塑性。本研究的目的是 确定用于诱导成人大脑神经调节变化的新分子和电路靶点， 重新激活青少年般的可塑性，用于治疗具有持久功能障碍的大脑疾病。使用目镜 优势可塑性，一个流行的初级视皮层关键期可塑性模型，我们将测试 假设，在神经调节系统的各种可能组合中，以及它们的皮质靶点， 初级视皮层深层烟碱样ACh调节和生长抑素表达的中间神经元 表达特定类型的烟碱ACh亚型作为神经调节回路元件的新组合 诱导快速局部回路调制，以恢复青少年样视觉皮层可塑性和从 成人弱视。我们将充分利用最近开发的 基因工程小鼠品系，以实现亚群和皮质层特异性电路选择性 超越常规细胞类型水平的基因表达或神经活性的操作和测量 将体内细胞外和体外切片电生理学与光遗传学相结合进行分析， 化学遗传学和行为分析。在Aim 1中，我们将研究特定的nAChR亚基的贡献。 诱导深层中间神经元的经验依赖性快速变化以触发眼优势可塑性。 在Aim 2中，我们将剖析深层SST调节的兴奋和抑制回路机制 interneurons触发ocular眼优势plasticity可塑性.在目标3中，我们将研究从 弱视通过调节深层中间神经元nAChR该项目的成功完成将 阐明了新的分子和电路机制，门的初始级联触发皮层可塑性， 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， 占人类人口的2-5%，也用于脑损伤修复、感觉恢复和 具有感觉知觉缺陷的神经发育障碍。

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.