Spatiotemporal Network Dynamics in a Rat Model of Schizophrenia

描述（由申请人提供）：振荡网络动力学提供了一种中间表型，在一些人类成像研究中，已被证明是识别精神疾病遗传生物标志物的比行为测量更有效的相关目标。利用啮齿类动物模型，我们建议研究振荡远程同步及其在精神分裂症中的改变，以及从青春期到成年期振荡网络发育轨迹的紊乱。主要的焦点是海马体（HC）和前额叶皮层（PFC）活动之间的节律性协调受损，这对成人的特定认知功能尤其重要，并且在早期神经发育中也起着重要作用。在精神分裂症患者和精神分裂症慢性动物模型中，HC和PFC之间的异常功能连接已被证实。由于HC和PFC均存在神经元振荡网络关键要素的病理改变，皮质-海马同步受损可能源于其中一种或两种结构的病理。我们建议使用一种新的方法来研究这个问题，这种方法可以精确地定义节奏发生器的空间分布，并量化它们的相互作用，包括基本的方向性影响。我们将系统地研究正常大鼠和精神分裂症药理学模型中这些相互作用的谱结构、解剖学、生理学和药理学。我们进一步假设，受损的振荡也会对皮层网络及其远程连接的成熟产生不利影响。了解时间动力学的个体发生及其控制是该领域的一个严重空白区域，因为振荡对正常认知至关重要，似乎不仅在精神分裂症中受到损害，在自闭症和其他精神疾病中也是如此。因此，我们也将通过日常电生理记录来研究青春期和成年早期HC-PFC关系的正常发展及其在精神分裂症神经发育模型中的病理改变；这样的纵向设计在以前的研究中没有尝试过。具体目标1是建立PFC- HC相互作用的模式，包括方向信息。我们认为，在HC和PFC之间同步神经元活动和伽马振荡的远程影响在两个方向上都是活跃的，总体上HC占主导地位。我们将研究这些双向相互作用的解剖学基础及其在需要动态PFC-HC耦合的认知任务中的作用。具体目标2是使用NMDA受体拮抗剂和多巴胺D4受体激动剂检查精神分裂症药理学模型中PFC-HC相互作用受损，除了精神分裂症相关症状外，已知PFC-HC受体激动剂可显著改变脑振荡并降低需要功能性PFC和HC网络的认知任务的表现。具体目标3是定义振荡网络如何发展通过青春期的正常大鼠和精神分裂症的神经发育模型。我们提出了一项纵向研究，以调查成人模式的振荡同步是如何发展的，以及何时以及如何在精神分裂症模型中偏离正常的发展轨迹。

DESCRIPTION (provided by applicant): Oscillatory network dynamics provide an intermediate phenotype that, in some human imaging studies, has proven to be a more fruitful correlation target than behavioral measures for identifying genetic biomarkers of psychiatric disorders. Using rodent models, we propose to study oscillatory long-range synchronization and its alterations in schizophrenia, as well as disturbances in developmental trajectories of oscillatory networks from adolescence to adulthood. The primary focus is the impaired rhythmic coordination between activities in the hippocampus (HC) and prefrontal cortex (PFC) which is particularly important for specific cognitive functions in the adult and was also shown to play an important role in early neurodevelopment. Abnormal functional connectivity between HC and PFC has been demonstrated in schizophrenic patients and in chronic animal models of schizophrenia. Since pathological alterations of the key elements of neuronal oscillatory networks are present in both HC and PFC, impaired cortico-hippocampal synchronization can originate from the pathology of either or both structures. We propose to examine this issue using a novel approach that can precisely define the spatial distribution of rhythmic generators and quantify their interactions, including the essential directional influences. We will systematically investigate the spectral structure, the anatomy, physiology, and pharmacology of these interactions in normal rats and in pharmacological models of schizophrenia. We further hypothesize that impaired oscillations also adversely affect the maturation of cortical networks and their long-range connections. Understanding the ontogeny of temporal dynamics and their control is a severe gap area in the field, because oscillations are critical for normal cognition ad seem to be impaired not just in schizophrenia, but also in autism, and other mental illnesses. Thus we will also investigate the normal development of HC-PFC relationship through adolescence and early adulthood and its pathological alterations in a neurodevelopmental model of schizophrenia using daily electrophysiological recordings; such a longitudinal design has not been attempted in prior studies. Specific Aim 1 is to establish the pattern of PFC- HC interactions including directional information. We propose that long-range influences synchronizing neuronal activity and gamma oscillations between HC and PFC are active in both directions, with an overall HC dominance. We will investigate the anatomical substrate of these bidirectional interactions and their role in a cognitive task which requires dynamic PFC-HC coupling. Specific Aim 2 is to examine the impaired PFC-HC interactions in pharmacological models of schizophrenia using NMDA receptor antagonists and dopamine D4 receptor agonists which, besides schizophrenia-relevant symptoms, are known to significantly alter brain oscillations and to reduce performance on cognitive tasks requiring functional PFC and HC networks. Specific Aim 3 is to define how oscillation networks develop through the periadolescent period in normal rats and in a neurodevelopmental model of schizophrenia. We propose a longitudinal study to investigate how the adult pattern of oscillatory synchronization develops and when and how the developmental trajectories in the schizophrenia model diverge from normal.