Mechanisms of adult forebrain neural circuit regeneration

成人前脑神经回路再生机制

• 批准号: 10362563
• 负责人: DAVID J PERKEL
• 金额: $ 51.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362563
• 关键词: Acoustics; Adult; Agonist; Alzheimer' s Disease; Behavior; Behavioral; Birds; Birth; Brain; Brain-Derived Neurotrophic Factor; Breeding; Calcium; Calcium Channel; Cell Nucleus; Cells; Cessation of life; Collaborations; Complex; Degenerative Disorder; Electrophysiology (science); Endocrinology; Ensure; Genes; Goals; Growth Associated Protein 43; Hormones; Human; Lead; Link; Maintenance; Mediating; Modeling; Molecular; Molecular Biology; Motor Skills; Muscimol; Natural regeneration; Nervous System Trauma; Neuronal Dysfunction; Neuronal Plasticity; Neurons; Newborn Infant; Outcome; Parkinson Disease; Performance; Potassium Channel; Prosencephalon; Proteins; Public Health; Recombinants; Regulation; Research; Research Personnel; Role; Route; Signal Pathway; Signal Transduction; Sparrows; Stroke; Structure; Synapses; System; Testing; Testosterone; Therapeutic; Therapeutic Intervention; Trauma; adult neurogenesis; antagonist; axon growth; bird song; brain repair; cyclopamine; experience; experimental study; inhibitor; injury and repair; interdisciplinary approach; male; migration; morphometry; nervous system disorder; neural circuit; neuroblast; neurogenesis; neuronal cell body; neurophysiology; neurotrophic factor; newborn neuron; postsynaptic; presynaptic; prevent; programs; receptor; reconstruction; repaired; response; stem cells; stereotypy; steroid hormone

Project Summary: The neural circuit that regulates birdsong, a highly precise, learned sensorimotor behavior, excels for study of fundamental mechanisms of adult circuit plasticity. The song system is a unique model of naturally occurring degeneration and compensatory regeneration in a behaviorally relevant neural circuit in adult brains. This circuit shows exaggerated seasonal degeneration and reconstruction via neurogenesis, in response to changes in circulating steroid hormone levels. Our long-term goal is to understand the fundamental mechanisms by which steroid hormones and neurotrophins interact to regulate plasticity of neural circuits and behavior. On a translational level, our goal is to understand how forebrain circuits can regenerate to support performance of complex learned motor skills. The central hypothesis of the proposed aims is that seasonal changes in hormones trigger changes in anterograde and retrograde trophic signaling that lead to remodeling of the HVC-RA circuit and changes in song behavior in adult birds.The goal of this application is to identify the trophic signaling pathways (molecular and electrophysiological) that regulate the the incorporation of newborn neurons to regenerate this circuit. This research will advance the field by elucidating fundamental issues of adult circuit plasticity. This topic is of translational relevance for exploiting endogenous or exogenous stem cells for therapeutic repair of injured or dysfunctional circuits in humans. These fundamental issues include whether new neurons added to adult circuits establish functional connections with efferent nuclei and restore behavior (Aim 1), the role of activity regulated genes in mediating retrograde trophic effects of neuronal activity on presynaptic adult neurogenesis (Aim 2), the role of calcium channels in mediating the transsynaptic neurotrophic regulation of postsynaptic activity (Aim 3), and the role of pre- and/or postsynaptic neuronal activity in maintaining a regenerated adult circuit (Aim 4).

项目摘要： 调节Birdsong的神经回路是一种高度精确的，学到的感觉运动行为，可用于研究 成人电路塑性的基本机制。歌曲系统是自然发生的独特模型 成人大脑中与行为相关的神经回路中的退化和补偿性再生。这 电路显示通过神经发生夸张的季节性变性和重建 循环类固醇激素水平的变化。我们的长期目标是了解基本 类固醇激素和神经营养蛋白相互作用以调节神经回路的可塑性的机制和 行为。在翻译层面上，我们的目标是了解前脑电路如何再生以支持 复杂学习的运动技能的表现。拟议目的的中心假设是季节性 激素的变化触发了导致重塑的顺行和逆行营养信号的变化 HVC-RA电路和成年鸟类歌曲行为的变化。该应用的目的是确定 调节新生儿的掺入的营养信号通路（分子和电生理学） 神经元再生该电路。这项研究将通过阐明 成人电路塑性。该主题对于利用内源性或外源茎的转化相关性 细胞用于人类受伤或功能失调的电路的治疗修复。这些基本问题包括 添加到成人电路中的新神经元是否建立具有传出核并恢复的功能连接 行为（AIM 1），活性调节基因在介导神经元活性逆行营养作用中的作用 在突触前成年神经发生（AIM 2）上，钙通道在介导跨突触中的作用 突触后活性的神经营养性调节（AIM 3）和突触后神经元的作用 维持再生成人电路的活性（AIM 4）。