Mechanisms of adult forebrain neural circuit regeneration

成人前脑神经回路再生机制

• 批准号: 10112966
• 负责人: ELIOT A BRENOWITZ
• 金额: $ 57.38万
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112966
• 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; axon growth; bird song; brain repair; cyclopamine; experience; experimental study; inhibitor/antagonist; 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 cell therapy; 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).

项目概要： 调节鸟鸣的神经回路是一种高度精确的、习得的感觉运动行为，非常适合研究 成人电路可塑性的基本机制。歌曲系统是自然发生的独特模型 成人大脑中行为相关神经回路的退化和代偿性再生。这 电路显示出夸大的季节性退化和通过神经发生的重建，以响应 循环类固醇激素水平的变化。我们的长期目标是了解基本原理 类固醇激素和神经营养素相互作用调节神经回路可塑性的机制 行为。在翻译层面上，我们的目标是了解前脑回路如何再生以支持 复杂的习得运动技能的表现。所提出目标的中心假设是季节性 激素的变化引发顺行和逆行营养信号的变化，从而导致重塑 HVC-RA 回路的变化以及成年鸟类鸣叫行为的变化。本应用的目标是确定 调节新生儿融入的营养信号通路（分子和电生理） 神经元来再生这个电路。这项研究将通过阐明以下基本问题来推动该领域的发展： 成人电路的可塑性。本主题与利用内源或外源干细胞具有转化相关性 用于治疗性修复人类受损或功能失调的回路的细胞。这些基本问题包括 添加到成体回路中的新神经元是否与传出核建立功能连接并恢复 行为（目标 1），活动调节基因在介导神经元活动逆行营养效应中的作用 突触前成人神经发生（目标 2），钙通道在介导跨突触中的作用 突触后活动的神经营养调节（目标 3），以及突触前和/或突触后神经元的作用 维持再生成人回路的活动（目标 4）。