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: 10318693
• 负责人: Jean Carlos Rodriguez Diaz
• 金额: $ 3.96万
• 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/10318693
• 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; 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.

摘要 大脑正确处理信息的能力取决于神经网络的能力 同步并产生伽马频段(30-80赫兹)的振荡。神经网络的能力 产生适当的伽马振荡会慢慢成熟。发展中的网络容易受到环境的影响 侮辱可能会改变它们的发育，导致异常的振荡。伽马振荡中的异常现象 与包括精神分裂症和双相情感障碍在内的精神健康障碍的病理有关。在许多 在这些障碍中，失调的抑制被认为是导致网络功能异常的原因。快速扣球 中间神经元(FSI)是GABA能抑制神经元的一个子集，已知对正常的生成至关重要 伽马振荡。在精神分裂症的多个动物模型中观察到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仿许多表型 在精神分裂症中观察到的包括认知障碍和伽马异常的高龄发病 震荡。抑制NMDAR也可以导致FSI成熟和生理异常，但影响 NMDAR拮抗剂对FSIS产生协调网络活动的能力的了解仍然很少。 这项建议的目标是确定NMDAR在FSIS的能力中的作用 并保持协调的网络活动。本提案F99阶段的短期培训目标是 确定NMDAR如何影响FSIS的成熟和导致网络功能受损的生理过程。这 将通过使用微电极阵列来测量和操纵同步网络活动 药物阻断NMDARs后的成年动物脑切片。我会用蛋白质 通过免疫印迹和免疫组织化学方法进行定量，以确定可能的蛋白质变化 导致FSIS的生理性损害。F99阶段将为#年的K00阶段奠定基础 我将重点确定FSIS的内在属性如何允许它们生成和维护 同步网络活动。单细胞、网络记录、FSIS活体操作的组合 活动和远程网络建模将被纳入，以确定对 同步网络活动。F99和K00训练阶段将为我的长期职业生涯奠定坚实的基础 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 神经网络和环境侮辱的影响。 这项建议将有助于建立在我们对支配如何 神经元相互作用，形成功能网络。此外，这将有助于增进我们对这种联系的理解 在精神分裂症等复杂精神健康疾病背后的分子和网络变化之间。