Role of fast spiking interneurons in network synchronization and development

快速尖峰中间神经元在网络同步和发展中的作用

• 批准号: 10460975
• 负责人: Jean Carlos Rodriguez Diaz
• 金额: $ 4.07万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460975
• 关键词: Acute; Adult; Age of Onset; Animal Model; Animals; Attention; Award; Behavioral; Biological Assay; Bipolar Disorder; Brain; Cells; Cognitive deficits; Complex; Computer Models; Data Analyses; Development; Disease; Electrophysiology (science); Environmental Impact; Etiology; Exhibits; Exposure to; Foundations; Functional disorder; Future; Generations; Goals; Hippocampus (Brain); Human; Immunohistochemistry; Impairment; Injections; Interneuron function; Interneurons; Ion Channel; Ketamine; Lead; Link; Long-Term Effects; MK801; Maintenance; Measures; Mediating; Memory; Mental disorders; Microelectrodes; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Oxidative Stress; Parvalbumins; Pathology; Pathway Analysis; Pattern; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Physiological; Physiology; Preparation; Process; Property; Proteins; Public Health; Research; Research Personnel; Research Project Grants; Rodent Model; Role; Schizophrenia; Sensory; Synapses; Techniques; Testing; Training; Transgenic Mice; United States National Institutes of Health; Viral Vector; Western Blotting; Work; antagonist; career; confocal imaging; density; experience; in silico; in vivo; inhibitory neuron; mature animal; neonatal exposure; network models; neural network; novel; patch clamp; prevent; protein expression; skills; training opportunity

SUMMARY The brain's ability to properly process information is dependent on the ability of neuronal networks to synchronize and generate oscillations in the gamma band (30-80 Hz). The ability of neuronal networks to generate proper gamma oscillations matures slowly. Developing networks are susceptible to environmental insults that could alter their development leading to abnormal oscillations. Abnormalities in gamma oscillations are implicated in the pathology of mental health disorders including schizophrenia and bipolar disorder. In many of these disorders, dysregulated inhibition is thought to give rise to abnormalities in network function. Fast spiking interneurons (FSI) are a subset of GABAergic inhibitory neurons known to be crucial for the proper generation of gamma oscillations. Abnormal FSI function has been observed in multiple animal models of schizophrenia. Rodent models using antagonists of N-methyl-D-aspartate receptors (NMDAR) mimic many of the phenotypes observed in schizophrenia including the late age onset of cognitive deficits and abnormalities in gamma oscillations. Inhibition of NMDARs can also lead to abnormalities in FSI maturation and physiology, but the impact of NMDAR antagonists on the ability of FSIs' to generate coordinated network activity remains poorly understood. The objective of this proposal is to determine the role of NMDARs in the capacity of FSIs to generate and sustain coordinated network activity. The short-term training goals for the F99 phase of this proposal are to determine how NMDARs influence FSIs' maturation and physiology leading to impaired network function. This will be achieved by using microelectrode arrays to measure and manipulate synchronous network activity in brain sections obtained from adult animals after pharmacological blockade of NMDARs. I will use protein quantification through western blots and immunohistochemistry to identify changes in proteins that could contribute to the physiological impairment of FSIs. The F99 phase will provide a foundation for the K00 phase in which I will focus on determining how the intrinsic properties of FSIs allow them to generate and maintain synchronous network activity. A combination of single cell, network recordings, in vivo manipulation of FSIs' activity, and in silico network modeling will be incorporated to identify the different properties that contribute to synchronize network activity. The F99 and K00 training phases will provide a strong foundation for my long-term goal of becoming an independent academic researcher focused on determining how neurons participate in neuronal networks and the impact of environmental insults. This proposal will help build upon our understanding of the fundamental principles that govern how neurons interact to form functional networks. Additionally, it will help advance our understanding of the link between molecular and network alteration underlying complex mental health disorders like schizophrenia.

总结 大脑正确处理信息的能力取决于神经元网络的能力， 同步并产生伽马波段（30-80 Hz）的振荡。神经网络的能力， 产生适当的伽马振荡会慢慢成熟发展中的网络易受环境影响 可能会改变其发展，导致异常振荡的侮辱。伽玛振荡衰减 涉及精神健康障碍的病理学，包括精神分裂症和双相情感障碍。在许多 在这些疾病中，失调的抑制被认为引起网络功能的异常。快速扣球 中间神经元（FSI）是GABA能抑制性神经元的一个子集，已知其对正常的生成至关重要 伽马振荡在多种精神分裂症动物模型中观察到FSI功能异常。 使用N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂的啮齿动物模型模拟了许多表型 在精神分裂症中观察到，包括迟发性认知缺陷和γ 振荡抑制NMDAR也可导致FSI成熟和生理异常，但其影响 NMDAR拮抗剂对FSI产生协调网络活性的能力的影响仍然知之甚少。 本提案的目的是确定国家灾害评估和反应机构在金融服务机构能力方面的作用， 并维持协调的网络活动。本提案F99阶段的短期培训目标是 以确定NMDAR如何影响FSI的成熟和生理，从而导致网络功能受损。这 将通过使用微电极阵列来测量和操纵同步网络活动来实现， 从药理学阻断NMDAR后的成年动物获得的脑切片。我会用蛋白质 通过蛋白质印迹和免疫组织化学定量，以确定蛋白质的变化， 导致FSI的生理损伤。F99阶段将为K 00阶段奠定基础， 我将集中精力确定FSI的内在属性如何允许它们生成和维护 同步网络活动。结合单细胞、网络记录、FSI的体内操作， 活动，并在硅片网络建模将被纳入，以确定不同的属性，有助于 同步网络活动。F99和K 00训练阶段将为我的长期工作打下坚实的基础。 目标是成为一名独立的学术研究人员，专注于确定神经元如何参与 神经网络和环境损伤的影响。 这一建议将有助于我们理解指导如何 神经元相互作用形成功能网络。此外，它将有助于促进我们对这种联系的理解， 分子和网络改变之间的联系，这些改变是精神分裂症等复杂精神疾病的基础。