Identifying Electrically Coupled Networks in vitro

体外识别电耦合网络

• 批准号: 10504163
• 负责人: JULIE S HAAS
• 金额: $ 35.98万
• 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/10504163
• 关键词: Absence Epilepsy; Acute; Area; Attention; 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; 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; neuronal cell body; novel; novel strategies; optogenetics; patch clamp; relating to nervous system; 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.

总结 我们计划探索丘脑网状核（TRN）电突触的功能地形图， 通过门控丘脑皮层来控制皮层对周围感觉的注意力的中枢脑区 交互.在睡眠慢波和失神癫痫期间，大脑对感觉输入没有反应; TRN被认为可以集中注意力的神经“探照灯”，并产生看似如此的节奏 睡眠中的纺锤波和癫痫中的尖波放电。TRN中的神经元通信是 由GABA能神经元之间的连接蛋白36间隙连接形成的电突触主导 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， 一个电突触在这里，我们将利用现代光遗传学和局灶性光刺激技术 在活体TRN的GABA能神经元的分子定义群体中绘制电耦合网络。 我们的中心假设是TRN内的电耦合网络将神经元跨分子连接起来， 身份、感觉形态和高阶和初级中继通道，从而调节丘脑皮质 传输我们将检验活动依赖性电突触抑制的假设， 由在慢波睡眠期间突出的突发模式引起的，对于所有突触耦合到 强烈爆发的神经元，由于其依赖于泛神经元T电流。最后，我们将建立模型， 实验验证了可塑性电耦合网络如何精细地控制TRN神经元的抑制， 传递到丘脑皮层中继细胞，从而控制丘脑皮层通讯。因为这些 突触在哺乳动物的大脑中分布广泛，但它们的力量却没有得到充分的认识， 这对理解分子和功能拓扑及其网络的动力学至关重要。的 这项建议的意义在于它的潜力，第一次，识别和表征电气 在体外的耦合网络，无论是在TRN，并最终在整个大脑。这项研究将使伟大 在我们对电突触的生理功能和可塑性的理解方面取得了重大进展，并提供了 深入了解TRN如何控制丘脑皮质信息处理。