Mechanisms and Function of NF-kappaB Activation at Dendritic Spines

描述(申请人提供)：突触的可塑性是一个基本的过程，被认为是我们大脑适应不断变化的环境和新挑战的非凡能力的基础。它参与神经发育、学习和记忆以及对损伤的反应，并伴随着许多神经退行性疾病常见的细胞凋亡过程。突触重塑是指在突触可塑性过程中改变突触的大小、形状、数量或连接性的过程，被认为是调节突触功能的关键机制。在哺乳动物的大脑中，大多数兴奋性突触发生在树突上，称为棘突。这项研究计划将研究核因子kappa B(NF-：B)转录因子如何发挥功能来调节海马神经元接收的突触接触。有趣的是，核因子-：B本身位于突触，可以被兴奋性活动激活。这些研究将探索突触重构和核因子-B激活之间的关系，以及由此导致的基因表达的变化，这些变化可能会增加树突棘和突触后反应。海马区是生理(学习和记忆)和病理(中风、阿尔茨海默病)神经元功能的明确区域，因此被选为研究神经元核因子-B对树突棘和突触数量影响的模型系统。这项研究将使用成年小鼠和新生小鼠的海马区组织，包括转基因小鼠。具体地说，实验将集中在如何将核因子-B转录因子招募到树突棘或拴在树突棘中，突触激活核因子-：B的途径，以及核因子-：B对树突棘密度和形态的调节，以及对突触生理的潜在功能影响。公共卫生相关性：从这项研究中获得的知识将使我们更好地理解内源性信号级联反应，这些信号级联作用于突触形成和突触重塑的转录因子调节。这些过程对大脑的可塑性和修复具有基本的神经学后果，并被假设为学习和记忆的结构基础。此外，这些研究的目的是阐明突触重构的途径，如核因子-B转录因子本身，如何在正常大脑功能和神经疾病中发挥作用，并为诊断和治疗脑部疾病提供潜在的靶点。

DESCRIPTION (provided by applicant): Plasticity at synapses is a fundamental process believed to underlie the remarkable ability of our brains to adapt to changing environments and new challenges. It is involved in neural development, learning and memory, and response to injury, as well as accompanying the apoptotic process common to many neurodegenerative diseases. Synaptic remodeling, the process of changing the size, shape, number or connectivity of synapses, occurs during plasticity and is thought to be a critical mechanism regulating synaptic function. In the mammalian brain, the majority of excitatory synapses occur on dendritic protrusions termed spines. This research proposal will investigate how the nuclear factor kappa B (NF-:B) transcription factor may function to regulate synaptic contacts received by hippocampal neurons. Interestingly, NF-:B is itself located at synapses and can be activated by excitatory activity. These investigations will explore the relationship between pathways of synaptic remodeling and NF-:B activation, and the resulting changes in gene expression which may augment dendritic spines and postsynaptic responses. The hippocampus has been selected as a model system for studying the effects of neuronal NF-:B on dendritic spine and synapse number because it is a well-defined area of both physiological (learning and memory) as well as pathological (stroke, Alzheimer's disease) neuronal function. The studies will use hippocampal tissue from both adult mice and neonates, including transgenic mice. Specifically, experiments will focus on how the NF-:B transcription factor may be recruited to or tethered in dendritic spines, the pathway of NF-:B activation at synapses, and the regulation of dendritic spine density and morphology by NF-:B with potential functional effects on synaptic physiology. PUBLIC HEALTH RELEVANCE: The knowledge gained from this research will create a better understanding of the endogenous signaling cascades responsible for transcription factor modulation of synapse formation and synaptic remodeling. These processes are of fundamental neurological consequence for brain plasticity and repair and are hypothesized to be a structural basis underlying learning and memory. In addition, it is the aim of these investigations to shed light on how pathways of synaptic remodeling, like the NF-?B transcription factor itself, could operate in both normal brain function as well as in neurological disorders and to provide potential targets for diagnosing and treating brain disease.