Nociceptive Memory: Mechanisms of Hyperexcitability

确定记忆的细胞和分子机制的一个主要障碍是专门负责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焦点，但一种更简单的修饰，长期超兴奋性(LTH)，似乎对记忆也很重要，尽管它得到的实验关注要少得多。在无脊椎动物海兔的感觉和运动神经元的外周轴突中，新发现的LTH的性质和机制将被研究。这种LTH的特点是与目前的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改，2)强烈去极化区域的修改限制，以及3)修改对局部蛋白质合成的依赖。本研究将利用行为学、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，轴突中STH/LTH与突触前终末和树突等其他神经元部位的STH/LTH的关系，以及它在短期和长期戒断行为敏化中的作用。具体问题涉及STH/LTH在长期突触易化中的作用，潜在的钙信号在诱导STH/LTH中的作用(如果有的话)，其他第二信使和蛋白激酶的作用，5-羟色胺、TGFbeta1、NO和感觉素的作用，以及在STH/LTH过程中离子电导的变化。海兔不同类型神经元中轴突LTH的机制和功能可能指向哺乳动物神经系统中被忽视或未被认识的可塑性机制，并为了解对正常记忆和记忆障碍(如中风后发生的)以及神经病理性疼痛和其他与周围神经损伤相关的临床问题至关重要的基本机制提供了洞察。

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.