Identifying Electrically Coupled Networks in vitro

体外识别电耦合网络

• 批准号: 10673919
• 负责人: JULIE S HAAS
• 金额: $ 38.37万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673919
• 关键词: Absence Epilepsy; Acute; Area; Attention; Attention deficit hyperactivity disorder; Binding; Brain; Brain region; Cell Nucleus; Cells; Communication; Computer Models; Coupled; Coupling; Dependence; Discrimination; Disease; Electrical Synapse; Electrophysiology (science); Epilepsy; Gap Junctions; Goals; In Vitro; Interneurons; Investigation; Lead; Link; Maps; Measures; Mediating; Mental Depression; Methods; Modality; Modeling; Modernization; Molecular; Neurons; Opsin; Pathway interactions; Pattern; Phenotype; Physiological; Population; Publishing; Research; Role; Schizophrenia; Sensory; Services; Sleep; Slow-Wave Sleep; Specificity; Synapses; Techniques; Testing; Thalamic structure; Time; Work; connexin 36; design; experience; information processing; insight; molecular subtypes; nervous system disorder; neural; neuronal cell body; novel; novel strategies; optogenetics; patch clamp; segregation; sensory gating; sensory input; sleep epilepsy; success; synaptic depression; transmission process; voltage

Summary We plan to explore the functional topography of electrical synapses in the thalamic reticular nucleus (TRN), a central brain region that controls cortical attention to the sensory surround by gating thalamocortical interactions. During slow-wave of sleep and absence epilepsy, the brain is unresponsive to sensory input; the TRN is thought to focus this neural “searchlight” of attention, and to generate the rhythms that appear as spindles during sleep and sharp-wave discharges in epilepsy. Neuronal communication in the TRN is dominated by the electrical synapses that are formed by connexin36 gap junctions amongst its GABAergic neurons. Our best understanding of electrical synapses is limited by current techniques to pairs of neurons and a single electrical synapse. Here, we will leverage modern optogenetic and focal photostimulation techniques to map electrically coupled networks in molecularly defined populations of GABAergic neurons of the live TRN. Our central hypothesis is that the electrically coupled networks within the TRN link neurons across molecular identity, sensory modality and higher-order and primary relay channels, and thereby regulate thalamocortical transmission. We will test the hypothesis that activity-dependent electrical synaptic depression, which is induced by bursting patterns that are prominent during slow-wave sleep, is global for all synaptic coupling to a strongly bursting neuron, due to its dependence on pan-neuronal T currents. Finally, we will model and experimentally validate how plastic electrically coupled networks finely control the inhibition that TRN neurons deliver to thalamocortical relay cells, and thereby gate thalamocortical communication. Because these synapses are both widespread and underappreciated for their power throughout the mammalian brain, it is crucial to understand the molecular and functional topography and the dynamics of their networks. The significance of this proposal lies in its potential to, for the first time, identify and characterize electrically coupled networks in vitro, both in the TRN and eventually, throughout the brain. This research will make great strides in our understanding of the physiological function and plasticity of electrical synapses, and provide insight into how the TRN controls thalamocortical information processing.

摘要 我们计划探索丘脑网状核(TRN)中电突触的功能拓扑学。 通过选通丘脑皮质来控制皮质对周围感觉的注意力的中央脑区 互动。在睡眠和失神癫痫的慢波期间，大脑对感官输入没有反应； TRN被认为集中了注意力的神经“探照灯”，并产生了看起来像是 睡眠中的纺锤波和癫痫时的尖波放电。TRN中的神经元通讯是 主要由连接蛋白36缝隙连接形成的电突触支配 神经元。我们对电突触的最好理解受到当前技术的限制，仅限于神经元对和 一个单一的电子突触。在这里，我们将利用现代光遗传和聚焦光刺激技术 绘制活的TRN的GABA能神经元的分子定义群体中的电子耦合网络。 我们的中心假设是，TRN内的电耦合网络跨分子连接神经元 同一性、感觉通道以及高级和初级中继通道，从而调节丘脑皮质 变速箱。我们将检验这样一种假设，即依赖于活动的突触电抑制 由在慢波睡眠中突出的爆发模式引起的，对所有突触耦合到 强爆发性神经元，由于其对泛神经元T电流的依赖。最后，我们将建模和 实验验证塑料电耦合网络如何精细控制TRN神经元的抑制 传递到丘脑皮质的中继细胞，从而开启丘脑皮质的通讯。因为这些 突触在哺乳动物的大脑中广泛存在，但由于它们的力量而被忽视。 对了解分子和功能拓扑及其网络的动力学至关重要。这个 这项提议的意义在于，它有可能首次通过电子手段识别和表征 体外耦合网络，既存在于TRN中，最终也贯穿于整个大脑。这项研究将使 在我们理解电突触的生理功能和可塑性方面取得了进展，并提供了 深入了解TRN如何控制丘脑皮质信息处理。