Inhibitory Control of Prefrontal Cortex

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。由于缺乏动物模型来研究疾病的特定临床特征与动态和行为相关背景下PFC病理之间的关系，因此无法理解导致这种功能障碍的机制。许多关于这种关系的人类研究都集中在改变前额叶皮层（PFC）背侧区域的代谢激活上，这提供了机制模糊的测量，因为它们主要提供了突触前活动的指标，独立于突触前活动是否导致突触后兴奋、抑制或调节。因此，将人类成像研究的发现转化为实验动物的电生理和其他机制研究是困难的。在过去的几年里，两种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。其中包括死后组织中显示GABA合成标记物减少的“静态”测量和行为个体中报告精神分裂症患者行为参与期间异常振荡神经元活动的“动态”测量。虽然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层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神经元振荡活动中断和认知功能之间的关系。通过对依赖于PFC功能完整性的认知任务的大鼠进行综合记录和药理操作，我们将解决两个特定的假设：(1) PFC中GABA合成的减少会损害认知功能，并通过减少GABA的可用性破坏该区域的神经元活动动态；(2)这种破坏发生在“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）振荡以及单个单元和LFP振荡之间的相位同步的变化。

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.