MECHANISMS OF COGNITIVE DYSFUNCTION IN SCHIZOPHRENIA

精神分裂症认知功能障碍的机制

• 批准号: 6625387
• 负责人: DANIEL C. JAVITT
• 金额: $ 30.47万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6625387
• 关键词: GABA receptor; Macaca; NMDA receptors; auditory cortex; auditory pathways; behavioral /social science research tag; behavioral habituation /sensitization; biological models; brain mapping; cognition; cognition disorders; disease /disorder etiology; electrodes; electrophysiology; evoked potentials; excitatory aminoacid; functional magnetic resonance imaging; inhibitor /antagonist; model design /development; neural transmission; neurochemistry; neuropathology; neurophysiology; neurotransmitters; nitric oxide; schizophrenia

DESCRIPTION (Adapted from Applicant's abstract): Persistent cognitive dysfunction is a key predictor of chronic disability and poor long-term outcome in schizophrenia. Mismatch negativity (MMN) is a short-latency event-related potential (ERP) that provides an objective index of cognitive dysfunction in schizophrenia at the level of primary auditory cortex (A1). Investigation into mechanisms underlying normal MMN generation in monkeys, therefore, provides a powerful approach for delineating potential mechanisms underlying cognitive dysfunction in schizophrenia. Old World monkeys generate MMN-like activity that closely resembles human MMN in terms of scalp distribution and deviance dependence. The overall goal of this project is to model neurophysiological and neurochemical mechanisms associated with cognitive dysfunction in schizophrenia by utilization of intracortical MMN recordings in monkey A1. For this project, monkey MMN generators are assessed using multichannel recordings from A1 coupled with focal neurochemical micromanipulation. The spatiotemporal pattern of intracortical MMN generation is analyzed using a combination of ERP, current source density, and multiunit activity measures. Phencyclidine (PCP, "angel dust") induces schizophrenia-like cognitive dysfunction and psychosis by blocking NMDA receptor-mediated neurotransmission. NMDA antagonists inhibit local MMN generation in A1 without affecting generation of prior obligatory ERP components, consistent with the hypothesis that endogenous dysfunction of dysregulation of NMDA receptor-mediated neurotransmission might contribute to the pattern of cognitive dysfunction seen in schizophrenia. Deficits in MMN generation in schizophrenia are accompanied by abnormalities in long-ISI P1 and N1 generation, which may also reflect brain dysfunction at the level of sensory cortex. This study will evaluate neurophysiological and neurochemical hypotheses concerning potential etiology of early sensory processing dysfunction in schizophrenia.

描述（改编自申请人的摘要）：持久认知 功能障碍是慢性残疾和长期结果不佳的关键预测因素 在精神分裂症中。失配负性 (MMN) 是一种与短延迟事件相关的 电位（ERP）提供了认知功能障碍的客观指标 初级听觉皮层水平的精神分裂症（A1）。调查 因此，猴子正常 MMN 生成的机制提供了一个 描述认知潜在机制的有力方法 精神分裂症的功能障碍。旧大陆猴子产生类似 MMN 的活动 在头皮分布和偏差方面与人类 MMN 非常相似 依赖性。该项目的总体目标是模拟神经生理学和 精神分裂症认知功能障碍相关的神经化学机制 通过利用猴子 A1 的皮质内 MMN 记录。对于这个项目， 使用 A1 的多通道录音评估猴子 MMN 生成器 与局部神经化学显微操作相结合。时空格局 结合 ERP、当前的 MMN 生成分析 源密度和多单元活动测量。苯环己哌啶（PCP，“天使 灰尘”）通过以下方式诱发精神分裂症样认知功能障碍和精神病 阻断 NMDA 受体介导的神经传递。 NMDA拮抗剂抑制 A1 中的本地 MMN 生成，不影响先前强制性 ERP 的生成 成分，与内源性功能障碍的假设一致 NMDA 受体介导的神经传递失调可能导致 精神分裂症中出现的认知功能障碍模式。 MMN 赤字 精神分裂症的产生伴随着长 ISI P1 和 N1代，也可能反映了感觉层面的大脑功能障碍 皮质。这项研究将评估神经生理学和神经化学 关于早期感觉处理的潜在病因学的假设 精神分裂症的功能障碍。