Inhibitory Control of Prefrontal Cortex

前额皮质的抑制控制

基本信息

批准号：
8069183
负责人：
BITA MOGHADDAM
金额：
$ 36.48万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-31 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069183
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 Health 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 response uptake

项目摘要

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）：前额叶皮层（PFC）功能障碍是精神分裂症病理生理学的基本方面。在动态和行为相关的环境中，研究了疾病的特定临床特征与PFC病理学之间的关系，因此阻碍了动物模型的稀缺性，因此阻碍了理解导致这种功能障碍的机制。在人类中，这种关系的许多研究集中在改变前额叶皮层（PFC）背侧区域的代谢激活，这些研究主要提供了机械含糊的措施，因为它们主要提供突触前活性的指数，而与这种突触前活性相关的指标是否导致突触后激发，抑制，抑制，抑制，或调节。因此，很难将人类成像研究的发现转化为实验动物的电生理学和其他机械研究。在过去的几年中，两种单独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。其中包括在死后组织中的“静态”测量，显示了GABA合成标记的降低以及在精神分裂症患者行为参与过程中报告异常振荡神经元活性的个体中的“动态”措施。尽管这些发现在理论上已经连接了，但尚无明确的证据表明，PFC中的GABA合成减少是振荡活性和皮质功能障碍受损的潜在原因。该项目的总体目的是建立PFC中GABA合成减少，PFC神经元振荡活性的破坏与认知功能之间的关系。在从事认知任务的大鼠中使用合奏记录和药理学操纵，取决于PFC的功能完整性，我们将解决两个特定的假设：（1）降低PFC中GABA合成的认知功能会损害认知功能并破坏该区域的动态，以降低该区域的含义。单个单位和LFP振荡之间的单个神经元和神经元相互作用，局部场电位（LFP）振荡以及相位同步的变化。公共卫生相关性：精神分裂症是一个主要的公共卫生问题，因为它影响了近1％的人口。当前治疗该疾病的方法是次优的。本研究旨在提供有关该疾病的机械洞察力，这可能有助于发现更好的治疗方法。