Activity-dependent modification of electrical synapse strength

描述(申请人提供)：人类的注意力过程对于基本的生存和更高的学习至关重要，但其基本的神经机制仍然知之甚少。在睡眠的某些阶段和癫痫的类型中，大脑对感官输入没有反应。在睡眠中，负责集中注意力和产生纺锤波的大脑中心是丘脑网状核(TRN)，在那里，电突触是核内神经元之间连接的主要来源。TRN中的神经元在行为上有两种截然不同的模式--爆发和紧张性放电--并由缝隙连接形成的电突触紧密连接。缝隙连接是一种独特的神经元间连接，它以物理方式将相邻神经元的膜与小孔连接起来，允许带电离子和小分子在神经元之间传递。这些突触在哺乳动物的大脑中广泛表达，被认为能使相邻神经元之间的神经元活动同步。一般来说，电突触的强度直接影响连接神经元的同步性或连贯性，特别是它调节TRN的传入输出。然而，神经元活动对电突触强度的影响在很大程度上还没有被探索。我们提出了两个目标，通过评估特定神经元活动模式在调节TRN中电突触强度方面的作用，来解决TRN如何吸引注意力的根本问题。在目标1中，我们将记录和诱导成对的自然TRN活动模式-爆发和紧张性放电-in神经元，以确定协调的尖峰活动是否诱导电突触的变化。在目标2中，我们将通过测试钠基峰电位是否是诱导电突触修饰所必需的，并通过检查这些神经元中显著的低阈值钙电流的贡献来开始剖析突触可塑性的潜在机制。由于电子突触在大脑中广泛存在，这项研究的结果将开辟一个很有前途的新研究领域，并为包括电子突触在内的网络动力学开辟一个新的视角。

DESCRIPTION (provided by applicant): The human process of attention is vital to basic survival and higher learning, yet its basic neurological mechanisms remain poorly understood. During certain stages of sleep and types of epilepsy, the brain is unresponsive to sensory input. The brain center responsible for focusing the neural "searchlight" of attention and for generation spindles during sleep is the thalamic reticular nucleus (TRN), where electrical synapses are a major source of connectivity between neurons in the nucleus. Neurons in the TRN spike in two behaviorally distinct modes - burst and tonic firing - and are densely connected by electrical synapses formed by gap junctions. Gap junctions are a unique type of inter-neuronal connection that physically link membranes of neighboring neurons with small pores, allowing charged ions and small molecules to pass between neurons. These synapses are expressed widely throughout the mammalian brain and are thought to synchronize neuronal activity among coupled neighboring neurons. The strength of electrical synapses, in general, directly affects the synchrony or coherence of connected neurons, and in particular, it modulates the afferent output of the TRN. However, the effect of neuronal activity on electrical synaptic strength has been largely unexplored. We propose two aims that address the fundamental question of how the TRN gates attention by evaluating the role of specific neuronal activity patterns in modifying the strength of electrical synapses in the TRN. In Aim 1, we will record and induce pairings of naturalistic TRN activity patterns - burst and tonic firing - in coupled neurons to determine whether coordinated spiking activity induces changes in electrical synapses. In Aim 2, we will begin to dissect the mechanisms underlying electrical synaptic plasticity by testing whether sodium-based spiking is necessary to induce electrical synaptic modification and by examining the contributions from the prominent low-threshold calcium current in these neurons. Because electrical synapses are widespread throughout the brain, the results of this research will open a promising new field of study and a new perspective on the dynamics of networks that include electrical synapses.