The Role of Notch in Behavioral Plasticity

描述（由申请人提供）：该项目的长期目标是了解Notch介导的细胞间相互作用在成人脑功能中的作用。虽然Notch在动物发育中的作用已被广泛研究，但其在成人神经系统的维持和功能中的作用尚不清楚。最近的研究结果与Notch活性可能影响突触结构和记忆的可能性一致。然而，这些研究都没有直接可视化神经活动对大脑中Notch信号的影响，也没有表明这些信号如何改变大脑功能。提出的研究建立在对黑胃果蝇在单个神经元水平上响应环境输入的Notch激活的直接可视化的基础上。具体来说，Notch在嗅觉受体神经元（orn）中以一种气味特异性的方式被激活。这种反应需要Notch配体Delta，并依赖于功能性嗅觉受体和ORN的突触传递。对于气味的长期行为适应，orn中的Notch活性是必要的，但不是充分的。本研究将探索一种假设，即在长期气味暴露的情况下，Notch调节的orn基因表达改变了神经元的状态，从而导致果蝇行为的改变。我们将通过三个具体目标来验证这一假设：1)确定rn在突触传递中激活Notch通路的机制。2)描述Notch在行为长期适应中的作用。3)确定Notch激活在ORN中引起的细胞和分子变化。这些目标将通过基因、行为和微阵列实验的结合来解决。这项拟议的研究有望详细了解环境刺激如何激活rn中的Notch通路，从而导致感觉神经元的生理变化，最终导致行为改变。这一贡献意义重大，因为它将是在分子水平上确定Notch在行为可塑性和调节长期行为适应的感觉神经元变化中的作用的第一步。这项提议的研究具有创新性，因为它提出了识别和操纵成人大脑中Notch需求的新方法。由于Notch通路在进化上是保守的，理解Notch在果蝇长期行为适应中的作用可能与理解人类的适应和记忆高度相关。神经元适应在药物成瘾和滥用中起着重要作用。对适应机制的深入了解可能会带来治疗成瘾的新方法。此外，随着人类平均年龄的增长，记忆问题变得越来越普遍，了解记忆的分子基础将成为治疗干预的关键。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the role that Notch mediated intercellular interactions play in adult brain function. While the role of Notch in animal development has been extensively studied, its role in the maintenance and function of adult nervous systems is less well understood. Recent findings are consistent with the possibility that Notch activity in neurons may influence synaptic structure and memory. However, none of these studies have allowed direct visualization of the effects of neural activity on Notch signaling in the brain, nor have they indicated how such signaling might alter brain function. The proposed research builds upon a direct visualization of Notch activation in Drosophila melanogaster at the single neuron level in response to environmental input. Specifically, Notch is activated in olfactory receptor neurons (ORNs) in an odorant specific fashion. This response requires the Notch ligand Delta and depends on functional olfactory receptors and synaptic transmission by the ORN. Notch activity in ORNs is necessary but not sufficient for long-term behavioral adaptation to odors. This proposal will explore the hypothesis that in response to chronic odor exposure, Notch regulated gene expression in ORNs alters the state of the neuron, leading to a change in the behavior of the fly. This hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism by which synaptic transmission by ORNs activates the Notch pathway. 2) Characterize the role Notch plays in behavioral long-term adaptation. 3) Identify the cellular and molecular changes induced in the ORN by Notch activation. These aims will be addressed by a combination of genetic, behavioral, and microarray experiments. The pro- posed research is expected to provide a detailed understanding of how an environmental stimulus activates the Notch pathway in ORNs, leading to a change in the physiology of the sensory neuron, which ultimately leads to a change in behavior. This contribution is significant because it will be a first step in defining at a molecular level both the role Notch plays in behavioral plasticity and the changes in sensory neurons that mediate long-term behavioral adaptation. The proposed research is innovative because it presents new approaches to identifying and manipulating the requirement for Notch in the adult brain. Because the Notch pathway is evolutionarily conserved, understanding the role of Notch in long-term behavioral adaptation in flies is likely to be highly relevant to an understanding of both adaptation and memory in humans. Neuronal adaptation plays a role in addiction to drugs of abuse. Insight into the mechanism of adaptation may lead to novel treatments for addiction. Furthermore, as the average age of human populations increase, problems with memory become more common, and understanding the molecular basis of memory will become crucial for therapeutic intervention. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health, because understanding evolutionary conserved signaling pathways in the brain that are involved in memory and adaptation is expected to provide insight into the pathologies of both the aging brain and drug addiction. This research is relevant to the part of NIH's mission that fosters fundamental creative discoveries to improve human health.