Transcriptional regulation of behavioral adaptation in Drosophila

描述（由申请人提供）：神经元的长期可塑性是大脑适应性变化的基础。对于细胞信号级联如何调节关键转录因子（如NFAT）的活性，我们的理解仍然存在明显的差距，NFAT是关键的可塑性控制因子。为了了解调节蛋白质合成依赖性可塑性的机制，我们的目标是测试NFAT功能模型，1)建立NFAT依赖的神经发育调节，2)探索NFAT在调节神经递质释放中的作用，以及3)研究NFAT在活动依赖性可塑性和行为适应中的功能。一些进展使我们在分析NFAT在调节长期神经元可塑性中的作用方面处于独特的地位。首先，我们进行了遗传筛选，以确定调节突触发育和可塑性的转录因子，从而分离出NFAT。其次，我们已经创建并验证了一个遗传模型，其中神经活动的诱导通过规范的Ras途径刺激ERK功能。这是特别重要的，因为体内模型的活动依赖的可塑性是稀缺的。我们最近的结果表明，在这种可塑性模型中，NFAT限制了突触大小和强度的变化。第三，我们建立了测试长期适应、学习和记忆形成的行为分析。在提议的工作中，我们概述了基于我们的初步数据的实验，并测试了我们的假设，即神经元中的NFAT功能调节长期行为适应。具体来说，我们提出实验i)定义NFAT在控制长期嗅觉习惯中的作用，ii)确定NFAT在果蝇中调节学习和记忆形成的程度。总之，我们希望确定神经元中的NFAT活动如何调节可塑性，从而控制大脑中作为学习、成瘾和神经系统疾病基础的适应性变化。

DESCRIPTION (provided by applicant): Long-term plasticity of neurons underlies adaptive changes in the brain. Appreciable gaps remain in our understanding of how cellular signaling cascades regulate the activity of key transcription factors, such as NFAT, that critically control plasticity. In keeping with our long-term objective of understanding mechanisms that regulate protein synthesis dependent plasticity, we aim to test models of NFAT function that, i) establish NFAT dependent regulation of neural development, ii) explore the role of NFAT in regulating neurotransmitter release, and iii) investigate NFAT function in activity-dependent plasticity and behavioral adaptation. Several advances put us in a unique position to analyze the role of NFAT in regulating long-term neuronal plasticity. First, we have conducted a genetic screen to identify transcription factors that regulate synaptic development and plasticity, leading to the isolation of NFAT. Second, we have created and validated a genetic model in which induction of neural activity stimulates ERK function through a canonical Ras pathway. This is particularly significant since in vivo models for activity-dependent plasticity are scarce. Our recent results show that NFAT constraints changes in synaptic size and strength in this model of plasticity. Third, we have established behavioral assays that test long-term adaptation, learning and memory formation. In the proposed work, we have outlined experiments that build on our preliminary data, and test our hypothesis that NFAT function in neurons regulates long-term behavioral adaptation. Specifically, we propose experiments i) to define the role of NFAT in the control of long-term olfactory habituation and, ii) to determine the extent to which NFAT regulates learning and memory formation in Drosophila. Upon conclusion, we hope to determine how NFAT activity in neurons regulates plasticity thereby controlling adaptive changes in the brain that underlie learning, addiction and neurological disease. PUBLIC HEALTH RELEVANCE: The proposed project aims to study cellular signaling and transcriptional mechanisms by which adaptive changes in the brain are brought about. Specifically, we aim to study the role of a transcription factor, NFAT in directing the ability of neurons to change in response to stimuli. Knowledge gained from this study will help us identify genetic and molecular pathways by which persistent alterations in neuronal circuits arise during learning, drug addiction and other neurological disorders.