Inhibitory Control of Prefrontal Cortex

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一个基本方面。了解这种功能障碍的机制，一直阻碍了动物模型的稀缺性，研究疾病的具体临床特征和PFC病理学之间的关系，在动态和行为相关的背景下。在人类中，许多关于这种关系的研究都集中在前额叶皮层（PFC）背侧区域的代谢活化改变上，这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数，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学和其他机制研究是困难的。在过去的几年里，两个独立的证据已经开始提供线索的机制，可能有助于PFC在精神分裂症的功能障碍。这些措施包括“静态”的措施，在死后组织显示减少GABA合成的标记物和“动态”的措施，在行为的个人，报告异常振荡神经元的活动在个人精神分裂症的行为参与。虽然这些研究结果在理论上有联系，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。该项目的首要目标是建立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。在参与认知任务的大鼠中使用整体记录和药理学操作依赖于PFC的功能完整性，我们将解决两个具体的假设：（1）PFC中GABA合成的减少损害认知功能，并通过减少GABA的可用性来破坏该区域神经元活动的动力学，以及（2）这种破坏发生在“多尺度”上。水平意味着我们将观察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。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。目前治疗这种疾病的方法是次优的。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。

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.