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

基本信息

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
项目类别：
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

项目摘要

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.

概括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玛波段（30-80 Hz）振荡。神经元网络的能力产生适当的伽马振荡成熟缓慢。发展中的网络容易受到环境的影响可能会改变其发育并导致异常振荡的侮辱。伽马振荡异常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学有关。在许多在这些疾病中，抑制失调被认为会导致网络功能异常。快速扣球中间神经元 (FSI) 是 GABA 能抑制神经元的一个子集，已知对于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，包括晚年出现认知缺陷和伽玛异常振荡。 NMDAR 的抑制也会导致 FSI 成熟和生理学异常，但影响 NMDAR 拮抗剂对 FSI 产生协调网络活动能力的影响仍知之甚少。该提案的目标是确定 NMDAR 在 FSI 生成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确定 NMDAR 如何影响 FSI 的成熟和生理学，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 NMDAR 药物阻断后从成年动物身上获得的脑切片。我会用蛋白质通过蛋白质印迹和免疫组织化学进行定量，以确定蛋白质的变化导致 FSI 的生理损伤。 F99阶段将为K00阶段提供基础我将重点关注确定 FSI 的内在属性如何允许它们生成和维护同步网络活动。单细胞、网络记录、FSI 体内操作的组合活动和计算机网络建模将被纳入，以确定有助于识别不同的属性同步网络活动。 F99和K00训练阶段将为我的长期训练打下坚实的基础成为一名独立的学术研究员，专注于确定神经元如何参与神经元网络和环境损害的影响。该提案将有助于加深我们对管理如何运作的基本原则的理解。神经元相互作用形成功能网络。此外，它将有助于加深我们对链接的理解精神分裂症等复杂心理健康疾病背后的分子和网络改变之间的关系。