Inhibitory Control of Prefrontal Cortex

前额皮质的抑制控制

• 批准号: 7738748
• 负责人: BITA MOGHADDAM
• 金额: $ 38.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-31 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738748
• 关键词: 4-Aminobutyrate aminotransferase; Acids; Address; Affect; Aftercare; Animal Model; Animals; Attention; Autopsy; Behavior; Behavioral; Benzodiazepines; Biochemical; Bolus Infusion; Boxing; Carboxy-Lyases; Clinical; Cognitive; Control Animal; Cues; Dimensions; Discrimination; Disease; Dorsal; Dose; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Event; Flumazenil; Functional disorder; GABA-A Receptor; Generations; Hippocampus (Brain); Human; Image; Impaired cognition; Impairment; Implant; Individual; Infusion procedures; Injection of therapeutic agent; Interneurons; Knowledge; Laboratory Animals; Learning; Light; Link; Measures; Metabolic Activation; Metabolism; Methods; Microdialysis; Neurons; Pathology; Performance; Pharmaceutical Preparations; Phase; Population; Prefrontal Cortex; Public Health; Rattus; Reporting; Rodent; Schizophrenia; Shunt Device; Slice; Stimulus; Synapses; Testing; Tissues; Translating; Vigabatrin; Work; cognitive function; extracellular; gamma-Aminobutyric Acid; indexing; inhibitor/antagonist; insight; local drug delivery; motor control; neurotransmission; postsynaptic; presynaptic; public health relevance; response; uptake

DESCRIPTION (provided by applicant): Prefrontal cortex (PFC) dysfunction is a fundamental aspect of the pathophysiology of schizophrenia. Understanding the mechanisms that contribute to this dysfunction has been hindered by the scarcity of animal models that study the relationship between specific clinical features of the illness and PFC pathology in dynamic and behaviorally relevant contexts. Many studies of this relationship in humans have focused on altered metabolic activation of dorsal regions of prefrontal cortex (PFC) which provide mechanistically vague measures because they primarily provide an index of presynaptic activity, independent of whether this presynaptic activity results in postsynaptic excitation, inhibition, or modulation. Thus, translating the findings of human imaging studies to electrophysiological and other mechanistic studies in laboratory animals has been difficult. In the past few years, two separate lines of evidence have begun to provide clues about the mechanisms that may contribute to the dysfunction of PFC in schizophrenia. These include "static" measures in postmortem tissue showing reductions in the markers of GABA synthesis and "dynamic" measures in behaving individuals that report abnormal oscillatory neuronal activity during behavioral engagement in individuals with schizophrenia. Although these findings have been theoretically linked, there is no clear evidence that reduced GABA synthesis in the PFC is a potential cause of impaired oscillatory activity and cortical dysfunction. The overarching aim of this project is to establish a relationship between reduced GABA synthesis in the PFC, disruptions in oscillatory activity of PFC neurons, and cognitive functioning. Using ensemble recordings and pharmacological manipulations in rats engaged in cognitive tasks dependent on the functional integrity of PFC we will address two specific hypotheses: (1) that reduced GABA synthesis in the PFC impairs cognitive functioning and disrupts the dynamics of neuronal activity in this region by reducing GABA availability and (2) that this disruption occurs at "multi- scale" levels meaning that we will observe changes in single neuron and neuron-pair interactions, local field potential (LFP) oscillations, and phase synchrony between single units and LFP oscillations. PUBLIC HEALTH RELEVANCE: Schizophrenia is a major public health problem because it affects nearly 1% of population. Present methods of treating this disorder are suboptimal. The present study aims to provide mechanistic insight about this disease which may help with the discovery of better treatments.

描述（由申请人提供）：前额皮质（PFC）功能障碍是精神分裂症病理生理学的一个基本方面。由于缺乏动物模型，无法在动态和行为相关的背景下研究疾病的特定临床特征与 PFC 病理学之间的关系，从而阻碍了对导致这种功能障碍的机制的理解。关于人类这种关系的许多研究都集中在前额皮质（PFC）背侧区域代谢激活的改变上，这些区域提供了机械上模糊的测量，因为它们主要提供突触前活动的指数，而与突触前活动是否导致突触后兴奋、抑制或调节无关。因此，将人类成像研究的结果转化为实验动物的电生理学和其他机制研究一直很困难。在过去的几年中，两条不同的证据已经开始提供有关可能导致精神分裂症 PFC 功能障碍的机制的线索。其中包括死后组织中显示 GABA 合成标记物减少的“静态”测量，以及行为个体的“动态”测量，报告精神分裂症患者在行为参与过程中出现异常的振荡神经元活动。尽管这些发现在理论上是相关的，但没有明确的证据表明 PFC 中 GABA 合成的减少是振荡活动受损和皮质功能障碍的潜在原因。该项目的总体目标是建立 PFC 中 GABA 合成减少、PFC 神经元振荡活动破坏和认知功能之间的关系。使用依赖于 PFC 功能完整性的认知任务的大鼠的整体记录和药理操作，我们将提出两个具体假设：（1）PFC 中 GABA 合成的减少会损害认知功能，并通过减少 GABA 可用性来破坏该区域神经元活动的动态；（2）这种破坏发生在“多尺度”水平，这意味着我们将观察到 单个神经元和神经元对相互作用、局部场电位 (LFP) 振荡以及单个单元和 LFP 振荡之间的相位同步的变化。公共卫生相关性：精神分裂症是一个主要的公共卫生问题，因为它影响着近 1% 的人口。目前治疗这种疾病的方法不是最理想的。本研究旨在提供有关这种疾病的机制见解，这可能有助于发现更好的治疗方法。