Mechanisms of adult forebrain neural circuit regeneration

项目总结： 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，非常适合于研究 成体电路可塑性的基本机制。歌唱系统是自然发生的独特模式 成人大脑中与行为相关的神经回路的退化和补偿性再生。这 电路显示夸大的季节性退化和通过神经发生重建，作为对 循环中类固醇激素水平的变化。我们的长期目标是理解 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。在翻译层面上，我们的目标是了解前脑回路如何再生以支持 表现复杂，学到了运动技能。提议的目标的中心假设是季节性的 激素的变化触发顺行和逆行营养信号的变化，从而导致重构 HVC-RA回路和成年鸟类鸣叫行为的变化。这个应用程序的目标是识别 调节新生儿结合的营养信号通路(分子和电生理) 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动该领域的发展 成人回路可塑性。本主题对于开发内源或外源茎具有翻译相关性。 用于治疗修复人类受损或功能失调的神经回路的细胞。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功能联系并恢复 行为(目标1)，活动调节基因在调节神经元活动的逆行营养效应中的作用 关于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)。

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).