Properties of Axons and Synaptic Communication in the Neocortex

描述(由申请人提供)：传统上，大脑皮层神经元之间的通信，实际上是大脑大部分区域之间的通信，被认为主要或完全通过脉冲或数字代码中的动作电位的速率和模式来调节。然而，最近我们发现，由动作电位引起的突触电位的平均幅度依赖于突触前神经元的膜电位，并且这些膜电位的变化沿轴突向下传播很长一段距离。这意味着附近皮质神经元之间的信息交流可能使用组合脉冲和分级或模拟和数字代码。在这里，我们将研究这种可能的模拟代码的机制。具体地说，我们将研究皮层神经元的膜电位可以影响神经元在附近细胞中诱导的突触电位幅度的机制。我们将在体外保存的前额叶皮质脑片上进行突触连接的神经元对的全细胞记录。此外，我们还将通过双光子成像来研究突触前胞体移动到不同的膜电位时突触前胞体内钙离子水平的变化可能参与了突触前钙浓度的变化。我们的研究还将检查皮质内轴突的电生理特性，特别是那些可能与检测胞体膜电位变化有关的特性。我们特别感兴趣的是皮质内轴突内电压依赖性K+电流的特性，以及这些电流如何控制轴突的兴奋性。为了详细研究这些，我们将在施加电压钳步骤的过程中对皮质神经元的胞体和轴突进行同步的全细胞膜片钳记录，并检测轴突对不同类型K+通道特异性毒素的反应。通过对特定K+通道被敲除的小鼠皮质内轴突进行全细胞记录，我们将能够检查特定离子通道和亚单位在这些影响中的参与。通过这种突触和轴突电生理研究的结合，我们将实现对大脑皮层内信息交流如何运作的更详细和更完整的了解。这些信息将使我们能够更好地处理轴突和突触沟通障碍，包括多发性硬化症和癫痫。与公共卫生相关：突触传递和轴突的适当功能是神经元的输出，对大脑的正常功能至关重要，特别是大脑皮层。许多神经疾病是由突触和轴突功能障碍引起的。我们的研究将考察大脑皮层突触和轴突功能的重要基本特性。

DESCRIPTION (provided by applicant): Traditionally, communication between neurons in the cerebral cortex, and, indeed, within much of the brain, is believed to be mediated largely or solely through the rate and pattern of action potentials in a pulse or digital code. Recently, however, we have shown that the average amplitude of synaptic potentials evoked by action potentials is dependent upon the membrane potential of the presynaptic neuron and that these membrane potential changes travel long distances down the axon. This means that information communication between nearby cortical neurons may use a combined pulse and graded or analog and digital code. Here we will examine the mechanisms of this possible analog code. Specifically, we will examine the mechanisms by which the membrane potential of cortical neurons can influence the amplitude of synaptic potentials that the neuron induces in nearby cells. We will perform whole cell recordings from synaptically connected pairs of neurons in prefrontal cortical slices maintained in vitro. In addition, we will examine the possible involvement of changes in presynaptic Calcium concentrations through two-photon imaging of Ca2+ levels in presynaptic boutons while their parent soma is moved to different membrane potentials. Our investigations will also examine the electrophysiological properties of intracortical axons, particularly those properties that may be involved in detecting changes in membrane potential at the soma. We are particularly interested in the properties of voltage-dependent K+ currents within intracortical axons and how these may control axonal excitability. To examine these in detail, we will perform simultaneous whole cell patch clamp recordings from the soma and axon of cortical neurons during the application of voltage clamp steps and examine the respond of the axons to the application of toxins that are specific for different types of K+ channel. Be performing whole cell recordings from intracortical axons in mice in which particular K+ channels have been knocked out, we will be able to examine the involvement of specific ionic channels and subunits in these effects. Through this combination of synaptic and axonal electrophysiological investigations, we will achieve a more detailed and integrated understanding of how information communication operates within the cerebral cortex. This information will allow us to better manage disorders of axonal and synaptic communication including multiple sclerosis and epilepsy. PUBLIC HEALTH RELEVANCE: The proper function of synaptic transmission and axons, the output of neurons, is critical to the proper functioning of the brain, particularly the cerebral cortex. Numerous neurological disorders result from disruption of synaptic and axonal function. Our study will examine important basic properties of synaptic and axonal function in the cerebral cortex.