Dopaminergic Modulation of Dendritic Excitability

描述(摘自申请者摘要)：拟议研究的目标 是为了了解多巴胺对信号整合的神经调节作用 在单个锥体神经元的基底和顶端树突中。一个发展中的 精神分裂症病理生理学的神经元模型 多巴胺在前额叶皮质的电生理作用，提示 锥体基端和顶端的树突在质量上被调制 不同的方式。根据该模型，多巴胺抑制兴奋性。 顶端，并增强了基础树突的兴奋性，导致 选择性地将锥体神经元“调谐”为跨皮质联合，或 水平-椎板内输入通路。该模型表明， 前额叶皮质锥体第5层神经元和两者，(1)临床症状， (2)精神分裂症患者的尸检结果。直接 前额叶皮质顶端和基底部树突的同步测量 锥体神经元将有助于我们理解(1)多巴胺在脑内的作用 树突状细胞的兴奋性和信息处理，以及(2)多巴胺在 精神分裂症的发病机制(多巴胺假说)。我们建议使用 最近开发的多点电压敏感染料成像，以期 直接研究突触和突触的波幅和时程 沿基底和顶端树突的反向传播动作电位，以及如何 这些电位受多巴胺D1和D2受体激活的影响。 电压敏感染料成像也将被用来确定多巴胺 树突状细胞兴奋性的诱导改变可以改变动作电位 启动模式，以及多巴胺是否以不同方式调节基础和 同一神经元内的顶端树突。我们的努力是为了提供 精神分裂症新治疗方法的推动力。

DESCRIPTION (From the Applicant's Abstract): The goal of the proposed research is to understand the neuromodulatory effects of dopamine on signal integration in basal and apical dendrites of individual pyramidal neurons. A developing neuronal model for the pathophysiology of schizophrenia, based on the nature of electrophysiological actions of dopamine in the prefrontal cortex, suggests that pyramidal basal and apical dendrites are modulated in a qualitatively different way. According to the model dopamine suppresses the excitability of apical, and enhances the excitability of basal dendrites, resulting in a selective "tuning" of pyramidal neurons to either transcortical-associative, or horizontal-intralaminar input pathways. The model suggests the link between prefrontal cortex pyramidal layer 5 neurons and both, (1) clinical symptoms, and (2) postmortem pathological findings in schizophrenic subjects. Direct simultaneous measurements from apical and basal dendrites of prefrontal cortex pyramidal neurons would facilitate our understanding of (1) dopamine effects on dendritic excitability and information processing, and (2) dopamine's role in the pathogenesis of schizophrenia (dopamine hypothesis). We propose to use recently developed multi-site voltage-sensitive dye imaging, in order to investigate directly the amplitudes and time courses of synaptic and backpropagating action potentials along basal and apical dendrites, and how these potentials are affected by dopamine D1 and D2 receptor activation. Voltage-sensitive dye imaging will also be used to determine whether dopamine induced changes in dendritic excitability can alter the action potential initiation pattern, and whether dopamine differentially modulates basal and apical dendrites within the same neuron. Our efforts are meant to provide the impetus for new therapeutic approaches in schizophrenia.