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，并将它们转换为放电率的变化。这一更新应用的重点是活性树枝状电导对这些过程的影响。许多关于运动神经元突触整合的先例工作，包括我们自己的工作，都是在麻醉的准备工作中进行的，在这些准备工作中，树突充当被动的核心导体。在这些情况下，单个突触电流在通向胞体的途中衰减，同时激活的突触电流总和呈线性或略低于线性。然而，在几种类型的非麻醉动物标本中，在脑干和脊髓切片中，运动神经元表达大量活跃的树突电导，这些电导显著改变了突触电流到胞体的传递和不同突触输入系统的整合。在特定目标1下提出的实验旨在检查在未麻醉、去大脑的猫身上研究的运动神经元中突触电流的整合。去大脑准备中下行的单胺能纤维的紧张性活动促进了介导持续内向电流的活性树突电导的表达，导致突触输入的电压依赖性放大。在《特定目的2》中提出的实验将检验用内源性钾通道阻滞剂处理的猫脊髓运动神经元中突触电流的总和，这也被证明在运动神经元中诱导突触电流的电压依赖性放大。具体目标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导入，来研究影响突触电流传递到胞体的树突机制。对运动神经元胞体进行电压钳制，测定不同通道类型药物阻断前后不同钳制电位下的谷氨酸诱发电流。所有的实验项目都将得到计算机模拟的补充，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隔室模型来帮助解释实验数据。总而言之，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换为频率调制的棘波序列输出。

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.