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在伽马频带（30-80 Hz）中同步并产生振荡。神经元网络的能力生成适当的γ振荡缓慢成熟。开发网络容易受到环境的影响可能改变其发展导致异常振荡的侮辱。 γ振荡异常与精神分裂症和躁郁症在内的心理健康障碍的病理有关。许多人在这些疾病中，人们认为抑制失调会导致网络功能异常。快速尖峰中间神经元（FSI）是GABA能抑制性神经元的子集，已知对于适当的产生至关重要 γ振荡。在精神分裂症的多种动物模型中，FSI功能异常。使用N-甲基-D-天冬氨酸受体（NMDAR）的拮抗剂模拟许多表型的啮齿动物模型在精神分裂症中观察到，包括伽马认知缺陷和异常的晚期发作振荡。 NMDAR的抑制也可能导致FSI成熟和生理学异常，但影响 NMDAR对FSI产生协调网络活动能力的拮抗剂的了解仍然很少。该建议的目的是确定NMDAR在FSI产生的能力中的作用并维持协调的网络活动。该提案的F99阶段的短期培训目标是确定NMDAR如何影响FSIS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的药理学封锁后，从成年动物获得的脑部切片。我将使用蛋白质通过蛋白质印迹和免疫组织化学进行定量，以鉴定蛋白质的变化有助于FSI的生理障碍。 F99阶段将为K00阶段提供基础我将重点侧重确定FSI的内在属性如何允许它们生成和维护同步网络活动。单细胞的网络记录的组合，在体内操纵FSIS' 活动以及在计算机网络中的建模将合并，以确定有助于同步网络活动。 F99和K00培训阶段将为我的长期提供坚实的基础成为一名专注于神经元如何参与的独立学术研究人员的目标神经元网络和环境侮辱的影响。该建议将有助于我们对管理如何管理的基本原则的理解神经元相互作用以形成功能网络。此外，这将有助于提高我们对链接的理解在分子和网络改变之间，基于精神分裂症等复杂心理健康障碍。