Inhibitory Control of Prefrontal Cortex

描述(申请人提供)：前额叶皮质(PFC)功能障碍是精神分裂症病理生理学的基本方面。由于缺乏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病理之间的关系的动物模型，阻碍了对这种功能障碍的机制的理解。在人类中，许多关于这种关系的研究都集中在前额叶皮质背侧区域的代谢激活变化上，这些区域提供了机械上模糊的测量，因为它们主要提供了突触前活动的指标，而与这种突触前活动是否导致突触后兴奋、抑制或调制无关。因此，将人类成像研究的结果转化为实验室动物的电生理和其他机制研究一直是困难的。在过去的几年里，两条不同的证据已经开始为精神分裂症患者PFC功能障碍的机制提供线索。这些措施包括在死后组织中显示GABA合成标志物减少的静态测量，以及在精神分裂症患者的行为参与期间报告异常振荡神经元活动的行为个体的“动态”测量。尽管这些发现在理论上是有联系的，但没有明确的证据表明，PFC中GABA合成减少是振荡活动受损和皮质功能障碍的潜在原因。这个项目的总体目标是建立PFC中GABA合成减少、PFC神经元振荡活动中断和认知功能之间的关系。利用集合录音和药物操作，我们将解决两个特定的假设：(1)在PFC中，GABA合成减少会损害认知功能，并通过减少GABA的可获得性来扰乱该区域神经元活动的动力学；(2)这种干扰发生在“多尺度”水平上，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)振荡以及单个单位和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并不理想。本研究旨在提供对这种疾病的机制洞察，这可能有助于发现更好的治疗方法。

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.