EFFECTIVE SYNAPTIC CURRENTS IN MOTONEURONS

我们研究计划的长期目标是了解哺乳动物运动神经元如何整合突触输入并将其转化为放电速率的变化。在这个更新应用的重点是在这些过程中的活性树突电导的影响。许多关于运动神经元突触整合的研究，包括我们自己的研究，都是在麻醉状态下进行的，在麻醉状态下，树突表现为被动的核心导体。在这些条件下，单个突触电流在通往体细胞的途中减弱，同时激活的突触电流呈线性或略低于线性。然而，在几种未麻醉的动物制剂以及脑干和脊髓切片中，运动神经元表达了大量活跃的树突电导，这些电导极大地改变了突触电流向体细胞的传递以及不同突触输入系统的整合。在Specific Aim 1下提出的实验旨在检查运动神经元突触电流的整合，这些运动神经元是在未麻醉、失觉的猫身上研究的。在脱脑准备过程中，下行单胺能纤维的强直活性促进了活跃的树突电导的表达，从而介导持续的内向电流，导致突触输入的电压依赖性放大。在Specific Aim 2中提出的实验将检查猫脊髓运动神经元内钾通道阻滞剂处理后的突触电流的汇总，钾通道阻滞剂也被证明可以诱导运动神经元中突触电流的电压依赖性放大。特异性目的3的实验将利用体外研究的大鼠舌下运动神经元的树突分支上的谷氨酸离子电泳，研究影响突触电流向体细胞转移的树突机制。对运动神经元体进行电压箝位，在不同通道类型的药物阻断前后测量不同箝位电位下的谷氨酸诱发电流。所有的实验项目都将辅以计算机模拟，使用具有不同类型和树突电导分布的运动神经元的区室模型来帮助解释实验数据。总的来说，这些实验和模拟项目将提供关于运动神经元整合多个突触输入的新信息，以及运动神经元如何将突触输入转化为调频尖峰序列输出。

The long-term objective of our research program is to understand how mammalian motoneurons integrate synaptic inputs and transform them into changes in firing rate. The focus in this renewal application is on the effects of active dendritic conductances on these processes. Much of the precedent work on synaptic integration in motoneurons, including our own, has been carried out in anesthetized preparations in which the dendrites behave as passive core conductors. Under these conditions, individual synaptic currents are attenuated en route to the soma, and concurrently activated synaptic currents sum linearly or slightly less than linearly. However, in several types of unanesthetized animal preparations and in brain stem and spinal cord slices, motoneurons express a host of active dendritic conductances that dramatically alter the transmission of synaptic current to the soma and the integration of different synaptic input systems. The experiments proposed under Specific Aim 1 are designed to examine the integration of synaptic currents in motoneurons studied in unanesthetized, decerebrate cats. Tonic activity in descending monoaminergic fibers in the decerebrate preparation facilitates the expression of active dendritic conductances that mediate persistent inward currents, leading to a voltage- dependent amplification of synaptic input. The experiments proposed in Specific Aim 2 will examine the summation of synaptic currents in cat spinal motoneurons treated with internal potassium channel blockers, which have also been shown to induce voltage-dependent amplification of synaptic currents in motoneurons. The experiments in Specific Aim 3 will examine the dendritic mechanisms affecting the transfer of synaptic current to the soma, using glutamate iontophoresis onto dendritic branches of rat hypoglossal motoneurons studied in vitro. The motoneuron soma will be voltage-clamped, and the glutamate-evoked current will be measured at different clamp potentials before and after pharmacological blockade of different channel types. All of the experimental projects will be complemented by computer simulations using compartmental models of motoneurons with different types and distributions of dendritic conductances to help interpret the experimental data. Collectively, these experimental and simulation projects will provide new information on the integration of multiple synaptic inputs by motoneurons, and how motoneurons transform synaptic inputs into frequency- modulated spike trains outputs.