Functional, structural, and computational consequences of NMDA receptor ablation at medial prefrontal cortex synapses

内侧前额皮质突触 NMDA 受体消融的功能、结构和计算后果

基本信息

批准号：
10677047
负责人：
Rachel Dick
金额：
$ 3.5万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677047
关键词：
AMPA Receptors Ablation Acids Acute Address Affect Apical Architecture Autopsy Behavioral Biological Brain Brain region Cells Chronic Complex Confocal Microscopy Data Dendritic Spines Development Diameter Dyes Electrophysiology (science)Excitatory Synapse Foundations Frequencies Functional disorder Future Goals Image Impaired cognition Lead Length Longevity Mathematics Measures Medial Memory Loss Memory impairment Mental disorders Mentorship Minnesota Modeling Morphology Mus N-Methyl-D-Aspartate Receptors Neurobehavioral Manifestations Neurons Patient-Focused Outcomes Patients Pattern Persons Pharmacological Treatment Pharmacology Study Population Prefrontal Cortex Primates Probability Process Psychiatry Pyramidal Cells Receptor Down-Regulation Research Role Schizophrenia Short-Term Memory Site Slice Structural defect Synapses Testing Tissues Training United States National Institutes of Health Universities Vertebral column Visualization brain abnormalities career cognitive function computational neuroscience confocal imaging density disability emotional distress excitatory neuron experimental study genome editing hippocampal pyramidal neuron improved in vivo insight mathematical model network models neural neural circuit neural network neural repair neurobiotin neuroregulation neurotransmission neurotransmitter release nonhuman primate patch clamp pharmacologic postsynaptic presynaptic receptor downregulation receptor expression synaptic function transmission process

项目摘要

Project Summary Schizophrenia is a psychiatric disorder that affects approximately 24 million people worldwide and can lead to emotional distress, disability, and reduced lifespan. Cognitive dysfunction is the best predictor of patient outcome in schizophrenia, yet current pharmacological treatments often fail to treat cognitive symptoms such as working memory deficits. In addition, it is not yet understood how certain biological abnormalities associated with schizophrenia – for example, decreased cortical expression of N-methyl-D-aspartate (NMDA) receptors – lead to changes in brain circuit function, especially when these abnormalities progress over the course of the lifespan and may be affected by in vivo compensatory mechanisms in the brain. My proposed research seeks to investigate the effects of chronic NMDA receptor loss upon synaptic function and architecture in the prefrontal cortex, and its potential implications for neural network activity and working memory deficits. Specifically, this computational psychiatry project will focus on examining functional and structural abnormalities at excitatory-to- excitatory synapses, which produce the reverberant neural activity that allows information to be retained in working memory and are particularly vulnerable to disconnection in schizophrenia. I will measure functional changes in excitatory-to-excitatory synaptic strength using ex vivo slice electrophysiology in prefrontal cortex pyramidal neurons, and I will examine structural changes in dendritic spine morphology and density in the same neurons using confocal imaging. I will then leverage insights gained from these electrophysiology and imaging experiments to build and test predictions regarding stability and synchrony of brain activity in a spiking network model.

项目概要精神分裂症是一种精神疾病，影响全球约 2400 万人，并可导致情绪困扰、残疾和认知功能障碍是患者预后的最佳预测指标。在精神分裂症中，目前的药物治疗往往无法治疗认知症状，例如工作此外，目前尚不清楚某些生物学异常与记忆缺陷有何关联。精神分裂症 – 例如，N-甲基-D-天冬氨酸 (NMDA) 受体的皮质表达减少 – 导致大脑回路功能的变化，尤其是当这些异常在一生中不断发展时并且可能受到大脑体内补偿机制的影响。研究慢性 NMDA 受体丧失对前额叶突触功能和结构的影响皮层，及其对神经网络活动和工作记忆缺陷的潜在影响。计算精神病学项目将侧重于检查兴奋性到-的功能和结构异常兴奋性突触，产生混响神经活动，使信息能够保留在工作记忆，特别容易在精神分裂症中脱节，我将测量功能。使用前额皮质离体切片电生理学研究兴奋性到兴奋性突触强度的变化锥体神经元，我将在相同的情况下检查树突棘形态和密度的结构变化然后，我将利用从这些电生理学和成像中获得的见解。建立和测试有关尖峰网络中大脑活动的稳定性和同步性的预测的实验模型。