Nicotinic modulation of deep layer inhibitory neurons for visual cortical plasticity

烟碱调节深层抑制神经元对视觉皮层可塑性的影响

• 批准号: 10186759
• 负责人: Hirofumi Morishita
• 金额: $ 51.65万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186759
• 关键词: Acute; Adolescent; Adult; Affect; Amblyopia; Behavior; Behavioral Assay; Biological Assay; Brain; Brain Diseases; Brain Injuries; Cells; Characteristics; Data; Discrimination; Drosophila acetylcholine receptor alpha-subunit; Elderly; Electrophysiology (science); Elements; Event; Exercise; Gene Expression; Genetically Engineered Mouse; Goals; Human; Hypersensitivity; In Vitro; Interneurons; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Measurement; Measures; Mediating; Modeling; Molecular; Mus; Neurodevelopmental Disorder; Neurons; Ocular Dominance; Parvalbumins; Physiological; Population; Positioning Attribute; Pyramidal Cells; Recovery; Role; Running; Sensory; Signal Transduction; Slice; Somatostatin; Synapses; System; Testing; Traumatic Brain Injury; Visual; Visual Acuity; Visual Cortex; Visual evoked cortical potential; Water; area striata; base; cell type; critical period; electric impedance; experience; extracellular; functional disability; in vivo; inhibitory neuron; injury and repair; knock-down; monocular deprivation; neuroregulation; novel; optogenetics; patch clamp; positive allosteric modulator; prevent; receptor; relating to nervous system; response; selective expression; therapeutic evaluation; visual plasticity

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.

项目摘要：由于特定少年特定关键时期关闭而导致的皮质可塑性的下降是 从后来的神经发育障碍和脑创伤中恢复的关键阻抗。神经调节 成人皮层中的系统丰富，并且良好的位置可协调经验依赖性 生理事件以促使可怕的可塑性。但是，越来越认识的复杂性 神经调节电路以及神经元亚型的多样性构成挑战，以识别特定 神经调节系统及其皮质靶标可精确恢复可塑性。这项研究的目的是 确定新的分子和电路靶标，以诱导成人大脑的神经调节变化， 重新激活类似少年的可塑性，以通过持久的功能障碍来治疗脑部疾病。使用眼 优势可塑性，一种盛行的主要视觉皮层关键时期可塑性模型，我们将测试 假设在神经调节系统的各种可能组合中及其皮质靶标中 烟碱ACH调节和生长抑素在主要视觉皮层的深层中表达中间神经元 表达特定类型的烟碱ACH亚型作为神经调节电路元件的新型组合 诱导局部电路快速调制以恢复类似少年的视觉皮层可塑性并从 成年时期的弱视。我们将通过充分利用最近开发的 一般设计的小鼠系，以实现亚构和皮质特异性电路选择性 传统细胞类型水平以外的基因表达或神经活动的操纵和测量 分析体内细胞外和体外切片电生理学与光遗传学的结合， 化学遗传学和行为分析。在AIM1中，我们将研究特定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，以触发眼部优势可塑性。 在AIM2中，我们将剖析深层SST调节的兴奋和抑制作用机制 中间神经元触发眼部优势可塑性。在AIM3中，我们将研究从 通过在深层中间神经元中调节nACHR，弱视。成功完成该项目将 照亮新的分子和电路机制，这些机制是触发皮质可塑性的初始级联反应 这将对弱视有直接影响，这种情况有限，成人适用的治疗有限 2-5％的人口，但也用于脑损伤修复，感觉恢复和治疗 具有感知性缺陷的神经发育障碍。