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

• 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
• 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

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.

项目摘要 精神分裂症是一种精神疾病，影响全球约2400万人，并可导致 情绪困扰残疾和寿命缩短认知功能障碍是患者预后的最佳预测因素 在精神分裂症中，目前的药物治疗通常不能治疗认知症状，如工作， 记忆缺陷此外，目前还不清楚某些生物学异常如何与 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，特别是当这些异常在生命周期中发展时， 并且可能受到脑中体内代偿机制的影响。我的研究计划是 研究慢性NMDA受体缺失对前额叶突触功能和结构的影响 皮质，及其对神经网络活动和工作记忆缺陷的潜在影响。具体来说， 计算精神病学项目将集中在检查功能和结构异常的兴奋， 兴奋性突触，它产生的回响神经活动，使信息被保留在 在精神分裂症患者中，工作记忆尤其容易被切断。我将测量功能 前额叶皮层兴奋性-兴奋性突触强度变化的离体切片电生理研究 锥体神经元，我将检查树突棘形态和密度的结构变化，在相同的 神经元共聚焦成像。然后我将利用从这些电生理学和成像中获得的见解， 建立和测试关于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