Mechanisms of adult forebrain neural circuit regeneration

项目摘要： 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， 成人回路可塑性的基本机制。歌声系统是一种独特的自然发生的 退化和补偿性再生的行为相关的神经回路在成年人的大脑。这 回路显示了夸张的季节性变性和通过神经发生重建，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 类固醇激素和神经营养因子相互作用调节神经回路可塑性的机制， 行为在翻译水平上，我们的目标是了解前脑回路如何再生，以支持 复杂的运动技能的表现。所提出的目标的中心假设是， 激素的变化触发顺行和逆行营养信号的变化，导致重塑 的HVC-RA电路和成年鸟类的鸣叫行为的变化。本申请的目的是确定 营养信号通路（分子和电生理学），调节新生儿 神经元来再生这个回路。这项研究将通过阐明以下基本问题来推进该领域： 成人回路可塑性这一话题对于翻译中如何利用内源或外源词干具有重要意义 用于治疗性修复人类受损或功能障碍的回路的细胞。这些基本问题包括 加入成人回路的新神经元是否与传出核团建立了功能性连接， 行为（目的1），活动调节基因在介导神经元活动的逆行营养效应中的作用 在突触前成人神经发生（目的2），钙通道在介导跨突触的作用， 突触后活动的神经营养调节（目的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性（目标4）。

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).