Role of Active Synaptic Integration in Motoneuron Output

描述（由申请人提供）：运动神经元似乎有能力根据来自脑干的神经调节输入，强烈地放大自己的输入。这种放大似乎优先影响波动的突触输入，而不是稳定的。在某些输入情况下，这种效应会导致我们所说的“直接”模式触发。该项目的目的是研究这种放大，并了解“快速”持续向内电流（PIC）在产生这种放大中所起的作用。该项目的具体目标是：1)量化突触输入的“快速”树突放大；2)表征直接模式发射；3)评估直接模式发射的可能机制。关于这个项目与健康的关系，这种放大可以解释由于受伤或疾病导致的下行脑干输入中断的情况下出现的深刻弱点。总的来说，随着神经调节剂对运动神经元行为的影响越来越明显，运动神经元的研究近年来一直处于不断变化的状态。这个项目的意义在于它代表了这个革命性变革时期的高潮，汇集了许多最近的数据以及这里提出的工作预期的结果。为了形成基于稳定输入以及输入动力学和神经调节影响的运动神经元输入处理的新观点，预期的实验方法利用了一种基于其激活动力学分离离子电流的新方法。这种方法允许在测量运动神经元放电和测量细胞内体内实验中的离子电流之间的瞬时切换。此外，动态突触事件产生的电流的电压钳记录可以在电流钳期间检查放大和重新注入，以确定它们对单个尖峰时间和一般放电速率的影响。

DESCRIPTION (provided by applicant): Motoneurons appear to have the ability to strongly amplify their own inputs based on neuromodulatory input from the brainstem. This amplification appears to preferentially effect fluctuating, rather than steady, synaptic input. In some input situations this effect results in what we refer to as "direct" mode firing. The objective of this project is to examine this amplification and to understand the role that a "fast" persistent inward current (PIC) plays in generating this amplification. The specific aims for this project are: 1) to quantify "fast" dendritic amplification of synaptic inputs; 2) to characterize direct mode firing; 3) to evaluate possible mechanisms for direct mode firing. In regards to the health relatedness of this project, this amplification may explain the profound weakness that occurs in cases of descending brainstem input disruption due to injury or disease. Overall, motoneuron research has been in a state of flux for several years as the effect of neuromodulators on motoneuron behavior has become increasingly apparent. The significance of this project is that it represents the culmination of this revolutionary period of change, bringing together much of the recent data along with the results anticipated from the work proposed here. In order to form this new view of motoneuron input processing based on steady inputs as well as input dynamics and neuromodulatory influences, the intended experimental approach utilizes a novel means of separating ionic currents based on their kinetics of activation. This approach permits instantaneous switching between measuring motoneuron firing and measuring ionic currents in intracellular in vivo experiments. Furthermore, voltage-clamp recording of currents generated by dynamic synaptic events can be examined for amplification and re-injected during current-clamp to determine their effect on the timing of individual spikes and firing rate in general.