Functions of electrical synapses in inhibitory networks

项目摘要/摘要 这个项目将研究电突触在哺乳动物抑制回路中的功能。 前脑。“电突触”是连接神经元的缝隙连接，它们起着快速、 双向沟通途径。我们对基本的生物物理学有相当多的了解。 哺乳动物电突触的特性、位置及其对缝隙连接的依赖 连接蛋白36(Cx36)。缝隙结可以强烈地影响定时、相位、同步性、概率、 和动作电位在神经元对和小群中的比率，但我们仍然不知道如何电 突触有助于更大的网络功能。前脑回路的复杂性长期以来一直是一个 这是一种障碍，但现在可以利用强大的新的遗传和光学工具来解决这些问题。 值得注意的是，在成熟的丘脑和新皮质中，电突触几乎只发生在 GABA能神经元。这些连接是非常特殊的；它们通常将 在皮质中有相同的亚型，而成熟前脑中的兴奋细胞很少表达它们。这 研究将集中在电突触在连接抑制神经元的作用上。 丘脑(特别是在躯体感觉丘脑网状核中)和几种亚型 新皮质(桶状皮质)中的中间神经元。有三个具体目标。第一个是确定 电突触在丘脑皮质网络活动中的作用，特别是慢(Deltatheta)和FAST (伽马)网络振荡在体外和体内研究。我们将使用电生理学，选择性删除 来自皮质和丘脑抑制细胞亚型的Cx36，以及控制特定神经元的光遗传学 和轴突通路。第二个目标是验证这样一个假设，即电性突触在 在丘脑和皮质激活的强大前馈抑制环路中的作用 小路。第三个目标是定义缝隙连接耦合的空间和像元类型特定组织 TRN和新皮质的躯体感觉节段的网络。 抑制回路是普遍存在的，对所有感觉、运动和认知功能都是必不可少的；电的 突触是抑制回路中普遍存在的成分。抑制的异常与一种 各种各样的神经、精神和发育障碍以及缝隙连接基因突变 与癫痫和其他神经功能障碍有关。我们的调查将有助于澄清 电突触在前脑抑制系统中的相关性和功能。

PROJECT SUMMARY/ABSTRACT This project will investigate the functions of electrical synapses within inhibitory circuits of the mammalian forebrain. "Electrical synapses" are gap junctions that interconnect neurons, and they serve as rapid, bidirectional communication pathways. A considerable amount is known about the basic biophysical properties of mammalian electrical synapses, their locations, and their dependence on the gap junction protein connexin36 (Cx36). Gap junctions can strongly influence the timing, phase, synchrony, probability, and rate of action potentials in pairs and small groups of neurons, yet we still do not know how electrical synapses contribute to larger network functions. The complexity of forebrain circuits has long been an impediment, but powerful new genetic and optical tools can now be brought to bear on these issues. Remarkably, in the mature thalamus and neocortex electrical synapses occur almost exclusively between GABAergic neurons. These junctions are quite specific; they usually interconnect inhibitory neurons of the same subtype in the cortex, and excitatory cells in the mature forebrain rarely express them. This investigation will focus on the roles of electrical synapses that interconnect inhibitory neurons of the thalamus (specifically in the somatosensory thalamic reticular nucleus, TRN), and several subtypes of interneurons in the neocortex (barrel cortex). There are three specific aims. The first is to determine the roles of electrical synapses in thalamocortical network activity, specifically slow (delta, theta) and fast (gamma) network oscillations studied in vitro and in vivo. We will use electrophysiology, selective deletion of Cx36 from subtypes of cortical and thalamic inhibitory cells, and optogenetics to control specific neurons and axonal pathways. The second aim is to test the hypothesis that electrical synapses play an important role in the powerful feedforward inhibitory circuits activated by both thalamocortical and corticothalamic pathways. The third aim is to define the spatial and cell type-specific organization of gap junction-coupled networks in somatosensory segments of the TRN and neocortex. Inhibitory circuits are universal, and essential for all sensory, motor, and cognitive functions; electrical synapses are ubiquitous components of inhibitory circuits. Abnormalities of inhibition are implicated in a wide variety of neurological, psychiatric, and developmental disorders, and mutations in gap junction genes are associated with epilepsy and other neurological dysfunctions. Our investigation will help to clarify the relevance and functions of electrical synapses in inhibitory systems of the forebrain.