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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：由于青少年特有关键期的关闭而导致的皮质可塑性下降是晚年神经发育障碍和脑外伤恢复的关键障碍。成人皮层中的系统非常丰富，并且能够很好地协调依赖于经验的然而，人们越来越认识到生理事件的复杂性。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回路提出了挑战这项研究的目标是精确恢复可塑性的神经调节系统及其皮质目标。确定诱导成人大脑神经调节变化的新分子和电路目标，重新激活青少年般的可塑性，以治疗具有持久功能障碍的脑部疾病。主导可塑性，一种流行的初级视觉皮层关键期可塑性模型，我们将测试假设，在神经调节系统及其皮质目标的各种可能组合中，初级视觉皮层深层烟碱乙酰胆碱调节和生长抑素表达中间神经元将特定类型的烟碱乙酰胆碱亚型表达为神经调节回路元件的新型组合诱导快速局部电路调节，以恢复青少年般的视觉皮层可塑性和恢复能力我们将通过充分利用最近开发的成年弱视来检验这一假设。基因工程小鼠品系可实现亚群和皮质层特异性电路选择性超出常规细胞类型水平的基因表达或神经活动的操作和测量体内细胞外和体外切片电生理学与光遗传学相结合的分析，在 Aim1 中，我们将检查特定 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调节的兴奋和抑制回路机制在 Aim3 中，我们将检查从中间神经元中恢复的程度。通过调节深层中间神经元中的 nAChR 来治疗弱视该项目将成功完成。阐明新的分子和电路机制，控制触发皮质可塑性的初始级联，这将对弱视产生直接影响，弱视是一种成人适用治疗有限的疾病 2-5% 的人口，还用于脑损伤修复、感觉恢复和治疗伴有感觉知觉缺陷的神经发育障碍。