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Nociceptive Memory: Mechanisms of Hyperexcitability

伤害性记忆：过度兴奋的机制

基本信息

批准号：
7231967
负责人：
EDGAR T. WALTERS
金额：
$ 32.44万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7231967
关键词：
Address Aplysia Attention Axon Behavior Behavioral Biochemical Cells Chemicals Clinical Condition Cyclic AMP Cyclic GMP Dendrites Dependence Distal Evolution Ganglia Heterogeneity In Situ In Vitro Injection of therapeutic agent Injury Invertebrates Ion Channel KRP protein Learning Localized MAP Kinase Gene Maintenance Measures Membrane Memory Memory Disorders Methods Modeling Modification Molecular Motor Motor Neurons Myxoid cyst Nerve Nerve Crush Nervous system structure Neurons Nociception Pathway interactions Peripheral Peripheral nerve injury Phosphotransferases Physiological Play Preparation Presynaptic Terminals Procedures Property Protein Biosynthesis Protein Kinase Protein Tyrosine Kinase Reaction Reflex action Research Research Personnel Role Saline Second Messenger Systems Sensory Serotonin Signal Transduction Signal Transduction Pathway Site Staging Stimulus Stroke Synapses Synaptic Transmission Synaptic plasticity System Tail Testing Training Withdrawal behavioral sensitization cell type chelation injured insight neglect nerve injury painful neuropathy prevent programs relating to nervous system response second messenger voltage clamp

项目摘要

A major obstacle to defining cellular and molecular mechanisms of memory is the enormous complexity of synaptic regions specialized for memory. Although synaptic plasticity is the major focus of memory research, a simpler modification, long-term hyperexcitability (LTH), also appears important for memory, even though it has received far less experimental attention. The properties and mechanisms of newly discovered forms of LTH in highly accessible peripheral axons of sensory and motor neurons of the invertebrate, Aplysia, will be investigated. This LTH is characterized by key features associated with current memory models, including 1) long-lasting modifications induced by localized depolarization, 2} restriction of the modifications to intensely depolarized regions, and 3) dependence of the modifications upon local protein synthesis. The proposed studies will use behavioral, electrophysiological, and biochemical methods to investigate physiological and behavioral functions of axonal LTH (as well as short-term hyperexcitability, STH), mechanisms of induction of STH and LTH, mechanisms of expression of STH and LTH, and relationships of STH/LTH in axons to STH/LTH at other neuronal sites including presynaptic terminals and dendrites, and its role in short- and long-term sensitization of withdrawal behavior. Specific questions concern the contributions of STH/LTH to long-term synaptic facilitation, the roles (if any) of potential Ca2+ signals in inducing STH/LTH, the roles of other second messengers and protein kinases, the roles of serotonin, TGFbeta1, NO, and sensorin, and the identification of ionic conductances altered during STH/LTH. Mechanisms and functions of axonal LTH in diverse types of neurons in Aplysia may point to neglected or unrecognized plasticity mechanisms in the mammalian nervous system, and provide insight into fundamental mechanisms important both for normal memory and disorders of memory (such as occur following stroke), as well as for neuropathic pain and other clinical problems related to peripheral nerve injury.

定义记忆的细胞和分子机制的一个主要障碍是专门用于记忆的突触区域的巨大复杂性。虽然突触可塑性是记忆研究的主要焦点，但一种更简单的修饰，即长期超兴奋性（LTH），对记忆也很重要，尽管它受到的实验关注要少得多。我们将研究无脊椎动物Aaplasia的感觉和运动神经元的高度可及外周轴突中新发现的LTH形式的性质和机制。这种LTH的特征在于与当前记忆模型相关的关键特征，包括1）由局部去极化诱导的持久修饰，2）修饰对强烈去极化区域的限制，以及3）修饰对局部蛋白质合成的依赖性。本研究拟采用行为学、电生理学和生物化学方法研究轴突LTH的生理和行为功能（以及短期超兴奋性，STH），STH和LTH的诱导机制，STH和LTH的表达机制，以及轴突中的STH/LTH与包括突触前末梢和树突的其他神经元位点处的STH/LTH的关系，以及它在戒断行为的短期和长期敏化中的作用。具体的问题涉及长期突触促进的STH/LTH的贡献，潜在的Ca 2+信号在诱导STH/LTH的作用（如果有的话），其他第二信使和蛋白激酶的作用，5-羟色胺，TGF β 1，NO和sensorin的作用，并确定在STH/LTH的离子电导改变。轴突LTH在不同类型的神经元中的机制和功能在失智症中可能指向哺乳动物神经系统中被忽视或未被识别的可塑性机制，并提供对正常记忆和记忆障碍（如中风后发生）以及神经性疼痛和与周围神经损伤相关的其他临床问题都重要的基本机制的见解。