Functions of electrical synapses in inhibitory networks

抑制网络中电突触的功能

• 批准号: 8792635
• 负责人: Barry W Connors
• 金额: $ 42.79万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792635
• 关键词: Action Potentials; Axon; Brain; Cell Nucleus; Cells; Communication; Connexins; Coupled; Coupling; Data; Dependence; Electrical Synapse; Electrophysiology (science); Epilepsy; Excision; Gap Junctions; Gene Expression; Gene Mutation; Genes; Genetic; Goals; Health; In Vitro; Inhibitory Synapse; Interneurons; Investigation; Ions; Knock-out; Knockout Mice; Knowledge; Learning; Location; Measurement; Mental disorders; Methods; Motor; Mus; Mutation; Neocortex; Neurologic Dysfunctions; Neurons; Opsin; Optics; Organism; Parvalbumins; Pathway interactions; Pattern; Phase; Physiological; Physiology; Play; Probability; Process; Property; Prosencephalon; Reporter Genes; Role; Sensory; Shapes; Somatostatin; Structure; Synapses; System; Testing; Thalamic structure; Time; Ursidae Family; barrel cortex; base; biophysical properties; cell type; cognitive function; connexin 36; developmental disease; excitatory neuron; gap junction channel; in vitro Model; in vivo; inhibitory neuron; mind control; neocortical; nervous system disorder; novel; optogenetics; protein expression; relating to nervous system; research study; response; somatosensory; sound; tool

DESCRIPTION (provided by applicant): 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 no 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 o 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.

描述（由申请人提供）：该项目将研究哺乳动物前脑抑制回路中电气突触的功能。 “电突触”是互连神经元的间隙连接，它们是快速的双向通信途径。关于哺乳动物电突触的基本生物物理特性，其位置以及它们对间隙连接蛋白connexin36（CX36）的依赖，已经知道了相当多的知识。间隙连接可以强烈影响成对和小组神经元组中的时机，相位，同步，概率和作用率的速率，但是我们仍然不知道电气突触如何有助于较大的网络功能。长期以来，前脑电路的复杂性一直是一种障碍，但是现在可以在这些问题上带来强大的新遗传和光学工具。值得注意的是，在成熟的丘脑和新皮层中，电突触几乎完全出现在GABA能神经元之间。这些连接非常具体。它们通常在皮质中相同亚型的抑制性神经元互连，而成熟前脑中的兴奋性细胞很少表达它们。这项研究将重点关注丘脑的抑制性神经元的电气突触的作用（特别是在丘脑丘脑网状网状核，TRN中）和新皮层（桶形皮质）中神经元的几个亚型。有三个特定的目标。首先是确定在丘脑皮质网络活性中的电气突触的作用，特别是慢速（Delta，Theta）和快速（伽马）网络振荡在体外和体内研究。我们将使用电生理学，从皮质和丘脑抑制细胞亚型中选择性缺失CX36，以及光遗传学来控制特定的神经元和轴突途径。第二个目的是检验以下假设：电突触在丘脑皮质和皮质丘脑途径激活的强大进料抑制回路中起重要作用。第三个目的是定义TRN和NeoCortex的体感段中间隙连接耦合网络的空间和细胞类型特定组织。抑制回路是通用的，对于所有感觉，运动和认知功能至关重要。电突触是抑制回路的无处不在成分。抑制作用的异常与多种神经，精神病和发育障碍有关，间隙连接基因的突变与癫痫和其他神经功能障碍有关。我们的研究将有助于阐明前脑抑制系统中电突触的相关性和功能。