Activity-dependent mechanisms for memory circuit maturation.

项目摘要 成年人的行为是神经回路的产物，这些神经回路在发育过程中被塑造出来， 基因程序和经验的神经活动的形式。神经系统发育 频繁地显示出对于电路改进至关重要的特征性自发活动。 然而，自发神经活动塑造精致的精确机制 和成熟的非感觉运动电路形状的行为仍然知之甚少。的 果蝇蘑菇体，其良好的解剖特征和良好的作用， 学习行为，是一个理想的系统，因果调查的发展成熟， 高阶神经回路本提案的目的是确定 自发的和诱发的神经活动的成熟，以支持成人学习的行为。在 初步研究，我发现自发的，异步振荡活动在凯尼恩 细胞，蘑菇体的主要内在神经元，特别是在非常年轻的成年人 苍蝇，这在成年的第一周显着下降。我们的结果表明 年轻成体发育中的凯尼恩细胞活性是随后表达 成熟的成年人中强健的习得行为。此外，我确定了青少年激素作为一个 成年早期凯尼恩细胞自发活动成熟的关键调节因子。一 多方面的方法，采用分子遗传学，学习行为分析和状态， 本领域功能性钙成像被提出用于（1）表征保幼激素效应物 基因调节凯尼恩细胞自发神经活动的成熟超过第一个 成年期的一周，（2）剖析激素信号在成熟中的作用， 联想学习行为在独立阶段，我们将（3）研究如何 条件性气味诱发的神经活动在成年后第一周在Kenyon细胞中成熟 电路，提高我们对学习行为的神经基质的理解。实现 为了实现这些目标，我将在学习行为分析方面进行全面的培训， 体积成像技术和计算神经科学方法。我的主要导师 博士克里斯汀·斯科特，我的科学顾问委员会和顾问，以及加州大学伯克利分校 环境为我的科学成长和专业发展提供了绝佳的机会 发展，独特的准备我开始一个成功的独立的科学生涯。 这些努力将导致对根本重要问题的深刻见解， 神经回路和学习行为的活动依赖性成熟。

PROJECT SUMMARY Adult behavior is the product of neural circuits that have been sculpted during development by genetic programs and experience in the form of neural activity. Developing nervous systems frequently display characteristic spontaneous activity that is essential for circuit refinement. However, the precise mechanisms by which spontaneous neural activity sculpts the refinement and maturation of non-sensorimotor circuits to shape behavior remain poorly understood. The Drosophila mushroom body, with its well characterized anatomy and well-established role in learned behavior, is an ideal system for causally investigating the developmental maturation of higher order neural circuits. The goal of this proposal is to identify mechanisms for the maturation of spontaneous and evoked neural activity to support adult learned behavior. In preliminary studies, I discovered spontaneous, asynchronous oscillatory activity in Kenyon cells, the principal intrinsic neurons of the mushroom body, specifically in very young adult flies, which declines significantly over the first week of adulthood. Our results suggest that Kenyon cell activity in young adult development is required for subsequent expression of robust learned behavior in the mature adult. Moreover, I identified Juvenile Hormone as a critical regulator of the maturation of Kenyon cell spontaneous activity in early adulthood. A multifaceted approach employing molecular genetics, learned behavioral analysis and state of the art functional calcium imaging is proposed to (1) characterize Juvenile Hormone effector genes that regulate the maturation of Kenyon cell spontaneous neural activity over the first week of adulthood and (2) dissect the role of hormonal signaling in the maturation of associative learning behavior. In the independent phase, we will (3) investigate how conditioned odor-evoked neural activity matures over the first week of adulthood in Kenyon cell circuits, improving our understanding of the neural substrates for learned behavior. To achieve these goals, I will pursue comprehensive training in learned behavioral assays, state of the art volumetric imaging technologies and computational neuroscience methods. My primary mentor Dr. Kristin Scott, my Scientific Advisory Committee and Consultants, and the UC Berkeley environment provide stellar opportunities for my scientific growth and professional development, uniquely preparing me to launch a successful independent scientific career. These efforts will lead to significant insights into the fundamentally important question of activity-dependent maturation of neural circuits and learned behavior.