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局差的关键预测指标 在精神分裂症中。不匹配负性（MMN）是与短期事件有关的 潜力（ERP），该指数在 原发性听觉皮层（A1）水平的精神分裂症。调查 因此，猴子中正常MMN产生的机制提供了一种 划定认知潜在机制的强大方法 精神分裂症的功能障碍。旧世界猴子产生类似MMN的活动 就头皮分布和偏差而言，与人类MMN非常相似 依赖。该项目的总体目标是建模神经生理学和 与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中的心脏内MMN记录。对于这个项目， 使用A1的多通道记录评估猴子MMN发电机 结合局灶性神经化学微观渗透。时空模式 使用ERP的组合分析了皮质内MMN的生成 源密度和多单元活动度量。 Phencyclidine（PCP，“天使” 灰尘”）通过 阻断NMDA受体介导的神经传递。 NMDA拮抗剂抑制 A1中的本地MMN生成而不影响先前的强制性ERP产生 组件，与内源性功能障碍的假设一致 NMDA受体介导的神经传递的失调可能有助于 精神分裂症中可见的认知功能障碍的模式。 MMN的缺陷 精神分裂症的产生伴随着长期ISI P1的异常 N1生成，这也可能反映在感觉水平下的大脑功能障碍 皮质。这项研究将评估神经生理和神经化学 关于早期感觉处理潜在病因的假设 精神分裂症的功能障碍。