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。在我们对细胞信号级联如何调节关键转录因子（如NFAT）活性的理解中，仍然存在明显的差距，这些转录因子对可塑性具有关键控制作用。为了与我们理解调节蛋白质合成依赖性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，i）建立神经发育的NFAT依赖性调节，ii）探索NFAT在调节神经递质释放中的作用，以及iii）研究NFAT在活动依赖性可塑性和行为适应中的功能。 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，我们进行了遗传筛选，以确定调节突触发育和可塑性的转录因子，导致NFAT的分离。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经典Ras途径刺激ERK功能。这是特别重要的，因为活性依赖性可塑性的体内模型是稀缺的。我们最近的研究结果表明，NFAT的限制在这个模型的可塑性突触的大小和强度的变化。第三，我们已经建立了行为分析，测试长期适应，学习和记忆的形成。 在拟议的工作中，我们概述了建立在我们的初步数据基础上的实验，并验证了我们的假设，即神经元中的NFAT功能调节长期的行为适应。具体而言，我们提出的实验i）定义的作用，NFAT在长期的嗅觉习惯化的控制，ii），以确定在何种程度上NFAT调节果蝇的学习和记忆形成。结论是，我们希望确定神经元中的NFAT活性如何调节可塑性，从而控制大脑中的适应性变化，这些变化是学习，成瘾和神经疾病的基础。 公共卫生相关性：拟议的项目旨在研究细胞信号和转录机制，通过这些机制，大脑中的适应性变化得以实现。具体来说，我们的目标是研究转录因子NFAT在指导神经元响应刺激而改变的能力中的作用。从这项研究中获得的知识将帮助我们识别学习、药物成瘾和其他神经系统疾病期间神经元回路出现持续改变的遗传和分子途径。

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.