VERTEBRATE NEURONAL INTERACTIONS AND ELECTROGENESIS

拟议研究的长期目标是将机械论 关于基本性质和活动相关塑性的信息 脊椎动物已识别神经元之间的突触连接 中枢神经系统对它们所在网络的运行 嵌入了。这些研究中使用的实验模型是金鱼。 Mauner(M-)细胞及其延髓回路。这个神经元介导了一种 来自第八神经的感觉刺激触发的逃避反应，以及 电紧张性和化学突触反应都是由 第八神经输入表现出活动依赖的修饰，即长- 长时程增强(LTP)和抑郁(LTD)。这些突触反应是 内源性调节剂多巴胺也增强了这一功能。树突内 来自M细胞树突的录音将与来自 单一传入和神经刺激，以检验特定的假说。 关于这些修改的机制。第一个目标是测试 假设突触传递的增强是由 多巴胺和LTP共享共同的细胞内调节机制，并且 多巴胺影响各种破伤风疗法的效果 范例。这一建议建立在多巴胺通过一种 CAMP依赖途径。第二个目标是通过以下方式确定机制 将抑制与弱破伤风配对，可诱导出LTD。的作用 将测试代谢性谷氨酸受体和细胞内钙离子。在……里面 这两个目标，突触修改的位置将被确定，与 化合物的药理方法和突触后注射 直接干扰或模仿受牵连的 细胞内调节通路。第三个目标是突触前和突触后 细胞内记录将用于比较LTP和LTD诱导的 在总体响应中具有修改的单个连接，以及 来检验单次强度修改的假设 联系取决于它们最初的效果。我们将特别注意 注意到沉默联系在这些现象中所起的作用。第四个目标 与这些突触和那些突触的短期可塑性有关 在M轴突和突触后的已识别细胞之间 脑干，表现出明显抑郁的连接。特定分子 将在突触前注射探针，以确定分子 释放概率及其可塑性的决定因素。数据 将进行统计分析，包括量化技术 分析。 突触传递的机制将在 拟议的研究与许多与健康有关的问题有关，例如 神经系统的学习记忆与环境适应 功能。沉默的突触连接可能提供了底物 对于神经系统适应，作为经验的函数，在 发展和应对创伤性损伤或中风。

The long-term objective of the proposed research is to relate mechanistic information about the basic properties and activity-dependent plasticity of synaptic connections between identified neurons in the vertebrate central nervous system to the operation of the networks in which they are embedded. The experimental model used in these studies is the goldfish Mauthner (M-) cell and its medullary circuits. This neuron mediates an escape response triggered by sensory stimuli from the eighth nerve, and both the electrotonic and chemical synaptic responses triggered by the eighth nerve input exhibit activity-dependent modifications, namely, long- term potentiation (LTP) and depression (LTD). These synaptic responses are also enhanced by the endogenous modulator dopamine. Intradendritic recordings from the M-cell dendrite will be combined with recordings from single afferents and with nerve stimulation, to test specific hypotheses. about the mechanisms of these modifications. The first aim is to test the hypothesis that the enhancements of synaptic transmission produced by dopamine and LTP share common intracellular regulatory mechanisms, and that dopamine influences the effectiveness of various tetanizing paradigms. This proposal builds on evidence that dopamine acts through a cAMP-dependent pathway. The second aim is to determine the mechanism by which pairing inhibition with a weak tetanus induces LTD. The role of metabotropic glutamate receptors and intracellular Ca++ will be tested. In both aims, the site of the synaptic modification will be determined, with pharmacological methods and postsynaptic injections of compounds that directly interfere with or mimic the effects of the implicated intracellular regulatory pathways. In the third aim, pre- and postsynaptic intracellular recordings will be used to compare the LTP and LTD induced at single connections with modifications in the population responses, and to test the hypothesis that modifications of the strength of single connections depend on their initial efficacy. Particular attention will be paid to the role of silent connections in these phenomena. The fourth aim is concerned with short-term plasticity at these synapses and those between the M-axon and identified cells postsynaptic to it in the brainstem, connections which show a marked depression. Specific molecular probes will be injected presynaptically, to determine the molecular determinants of the probability of release and its plasticity. The data will be analyzed statistically, including the techniques of quantal analysis. The mechanisms of synaptic transmission that will be studied in the proposed research are relevant to numerous health-related issues, such as learning and memory and environmental adaptations of nervous system function. Silent synaptic connections potentially provide the substrate for nervous system adaptation, as a function of experience, during development and in response to traumatic injury or stroke.