Transcriptional regulation of behavioral adaptation in Drosophila

描述(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。在我们对细胞信号级联如何调节关键转录因子的活性的理解中仍然存在明显的差距，例如NFAT，这些转录因子是关键的可塑性控制因素。为了与我们了解调节蛋白质合成依赖的可塑性的机制的长期目标保持一致，我们的目标是测试NFAT功能的模型，这些模型包括：i)建立NFAT依赖的神经发育调节，ii)探索NFAT在调节神经递质释放中的作用，以及iii)研究NFAT在活动依赖的可塑性和行为适应中的作用。一些进展使我们处于一个独特的位置来分析NFAT在调节长期神经元可塑性中的作用。首先，我们进行了基因筛选，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，我们创建并验证了一个遗传模型，在该模型中，神经活动的诱导通过典型的RAS途径刺激ERK功能。这一点尤其重要，因为活体内依赖活性的可塑性模型很少。我们最近的结果表明，在这种可塑性模型中，NFAT的限制改变了突触的大小和强度。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。在拟议的工作中，我们概述了建立在初步数据基础上的实验，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。具体地说，我们提出的实验一)确定NFAT在控制长期嗅觉习服中的作用，以及二)确定NFAT在多大程度上调节果蝇的学习和记忆形成。在结论中，我们希望确定神经元中的NFAT活动如何调节可塑性，从而控制大脑中导致学习、成瘾和神经疾病的适应性变化。 与公共健康相关：拟议的项目旨在研究细胞信号和转录机制，通过这些机制在大脑中产生适应性变化。具体地说，我们的目标是研究转录因子NFAT在指导神经元对刺激做出反应的能力方面的作用。从这项研究中获得的知识将帮助我们确定在学习、药物成瘾和其他神经疾病过程中神经元回路发生持续变化的遗传和分子途径。

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.