Nociceptive Memory: Mechanisms of Hyperexcitability

伤害性记忆：过度兴奋的机制

• 批准号: 7017819
• 负责人: EDGAR T. WALTERS
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 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/7017819
• 关键词: Aplysia; action potentials; cAMP response element binding protein; calcium flux; cyclic GMP; hyperalgesia; in situ hybridization; long term memory; neural facilitation; neural plasticity; neurophysiology; nitric oxide; nociceptors; pain; potassium channel; protein kinase; sensory mechanism; tissue /cell culture; transcription factor

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主要障碍是专门用于记忆的突触区域的巨大复杂性。尽管突触可塑性是记忆研究的主要重点，但更简单的修改，长期过度刺激性（LTH）对于记忆似乎也很重要，尽管它受到了实验性的关注得多。将研究在高度可访问的无脊椎动物Aplysia的感觉和运动神经元的高度可访问的外围轴突中新发现的LTH的特性和机制。该LTH的特征在于与当前记忆模型相关的关键特征，包括1）局部去极化引起的持久修饰，2}限制了对强烈去极化区域的修饰，以及3）对局部蛋白质合成的修饰的依赖性。 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树突及其在戒断行为的短期和长期敏化中的作用。具体问题涉及STH/LTH对长期突触促进的贡献，即诱导STH/LTH的潜在Ca2+信号（如果有）的作用（如果有），其他第二个使者的作用和蛋白质激酶的作用，以及5SOTONIN，TGFBETA1，TGFBETA1，NO和SENSORON和SENSOROIN和SENSORINCE CORTINACTIND IRIDICES of IRISIC STH/LISTERS/LISTISS STH/LISTISS STH/LISTISS的作用。 aplysia中多种神经元中轴突LTH的机制和功能可能指向哺乳动物神经系统中忽视或未识别的可塑性机制，并洞悉对正常记忆和记忆障碍至关重要的基本机制（例如，在案件后发生）以及神经病理疼痛和其他临床治疗均与临床治疗相关的问题。