Actin-based Neuronal State Changes

基于肌动蛋白的神经元状态变化

基本信息

批准号：
7321299
负责人：
Martha U Gillette
金额：
$ 38.75万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-25 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7321299
关键词：
Actins Aging Alzheimer&apos s Disease American Animals Architecture Ataxia Behavior Behavioral Binding Biochemistry Biological Biological Assay Boxing Brain CREB1 gene Cell Line Cell Nucleus Cell division Cell physiology Cells Chemicals Chromosome Pairing Circadian Rhythms Clock protein Cognition Condition Cultured Cells Cyclic AMP Response Element Cyclic GMP Cytochalasin D Cytoskeletal Proteins Cytoskeleton Darkness Data Depth Development Disease Disease Resistance Drug Addiction Elements Exhibits F-Actin Family Filament Fluorescence Recovery After Photobleaching Functional disorder G Actin Gene Expression Genes Genetic Transcription Glial Fibrillary Acidic Protein Glutamate Receptor Glutamates Goals Green Fluorescent Proteins Health Hippocampus (Brain)Image Inositol Intervention Intracellular Transport Learning Light Localized Long-Term Potentiation Mediating Membrane Memory Memory impairment Mental Retardation Messenger RNA Methods Microfilaments Microtubule-Associated Protein 2 Modeling Modification Molecular Morphogenesis Movement Mus Nature Nerve Degeneration Neurobiology Neuroglia Neurons Optic Nerve Pathology Pathway interactions Pattern Phase response curves Physiological Physiology Polymers Process Property Protein Kinase Public Health Rat Cell Line Rattus Reagent Reporter Reporting Research Personnel Reverse Transcriptase Polymerase Chain Reaction Rhodamine Rhodamines Role Ryanodine Receptor Calcium Release Channel Sensory Signal Pathway Signal Transduction Signal Transduction Pathway Site Sleep Sleep Disorders Slice Stimulus Substance abuse problem Synapses System Testing Time Tissues Transcriptional Activation Transcriptional Regulation actin 2 addiction base behavior change behavior measurement beneficiary cell transformation cis acting element depolymerization disorder prevention enhanced green fluorescent protein experience extracellular immunocytochemistry immunoreactivity insight jasplakinolide latrunculin A molecular dynamics monomer mouse model nervous system disorder neurofilament neuronal cell body neurotransmission novel programs receptor relating to nervous system sensory stimulus suprachiasmatic nucleus tetramethylrhodaminylphalloidine transcription factor

项目摘要

DESCRIPTION (provided by applicant): Dynamic assembly and disassembly of the actin cytoskeleton underlies diverse cellular processes, including cell division, developmental polarity and intracellular transport. These changes can be local or global, transforming cell state. Extracellular signals mediate experience-induced changes of actin dynamics within synaptic microdomains of neurons. Recent evidence suggests that actin dynamics of the cell body, distinct from those in the synapse, also may be necessary for neurons to sense and respond to extracellular stimuli. We predict that this process contributes to plasticity of behavior by altering transcription. Our overarching goal is to understand how experience signals long-term state changes in neurons that, in turn, change behavior. We hypothesize that glutamatergic neurotransmission changes actin organization, and this is permissive for transcriptional activation. We will test this hypothesis in the suprachiasmatic nucleus (SCN), a brain site with established molecular substrates necessary for temporal organization of behavior. The SCN is a cell-based, ~24-h clock driven by spatial and temporal oscillations that regulate transcription. Specifically, we hypothesize that signaling cascades initiated by glutamate engage the actin cytoskeleton of SCN cells, changing localization of key transcriptional regulators that alter clock state. We will examine the nature and necessity of such changes in actin and their effects on transcriptional activation of clock genes. We will evaluate these mechanisms in rat and mouse models: cell cultures, brain slices and behaving animals. Specific aims will: 1) characterize and localize stimulus-induced changes in actin; 2) find the role of actin changes in clock function and behavior, and 3) determine the role of actin changes in regulating transcription. We will use cell biological methods, dynamic imaging, biochemistry, neurobiological measures, and behavioral analyses. The breadth of this systems-based analysis will generate insights into how experience is transformed into long-lasting modification in brain state and behavior. This will enhance the understanding of substrates of long-lasting neural state change, with broad relevance for public health and disease prevention. Dysfunctions in the actin system cause severe neurological disorders, including those of cognition, neurodegeneration, movement and autonomic control. Sleep disorders, learning/memory impairments, drug-addiction and aging will be direct beneficiaries.

描述（由申请人提供）：肌动蛋白细胞骨架的动态组装和拆卸是多种细胞过程，包括细胞分裂，发育极性和细胞内转运。这些变化可以是局部或全局，改变细胞状态。细胞外信号介导了经验诱导的神经元突触微区内肌动蛋白动力学的变化。最近的证据表明，与突触中的肌动蛋白动力学不同，神经元也可能需要对细胞外刺激进行感觉和反应。我们预测，此过程通过改变转录来有助于行为的可塑性。我们的总体目标是了解经验如何表示神经元中的长期状态变化，而神经元又改变行为。我们假设谷氨酸能神经传递会改变肌动蛋白组织，这是转录激活的允许性。我们将在脑部核（SCN）中检验该假设，这是一个大脑部位，具有既定的分子底物是行为时间的必要的分子底物。 SCN是一个基于细胞的〜24小时时钟，由调节转录的空间和时间振荡驱动。具体而言，我们假设谷氨酸引发的信号级联反应与SCN细胞的肌动蛋白细胞骨架相关，从而改变了改变时钟状态的关键转录调节剂的定位。我们将研究肌动蛋白发生这种变化及其对时钟基因转录激活的影响的性质和必要性。我们将在大鼠和小鼠模型中评估这些机制：细胞培养物，脑切片和行为动物。具体目的将：1）表征和定位刺激引起的肌动蛋白变化； 2）找到肌动蛋白在时钟功能和行为中的作用，3）确定肌动蛋白变化在调节转录中的作用。我们将使用细胞生物学方法，动态成像，生物化学，神经生物学测量和行为分析。这种基于系统的分析的广度将对经验如何转化为大脑状态和行为的长期修饰。这将增强对持续神经状态变化的基板的理解，并与预防公共卫生和疾病相关。肌动蛋白系统中的功能障碍会引起严重的神经系统疾病，包括认知，神经退行性，运动和自主控制。睡眠障碍，学习/记忆力障碍，吸毒和衰老将是直接受益人。