Spatiotemporal Network Dynamics in a Rat Model of Schizophrenia

精神分裂症大鼠模型中的时空网络动力学

• 批准号: 8720463
• 负责人: MINGZHOU DING
• 金额: $ 41.93万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720463
• 关键词: Acute; Address; Adolescence; Adult; Affect; Agonist; Anatomy; Animal Model; Animals; Area; Autistic Disorder; Behavior; Brain; Chronic; Cognition; Cognitive; Communication; Computational Technique; Coupling; Data; Deep Brain Stimulation; Development; Elements; Equilibrium; Frequencies; Genetic Markers; Goals; Growth; Hippocampus (Brain); Human; Image; Impaired cognition; Individual; Lead; Length; Longitudinal Studies; Measures; Mental disorders; Modeling; NMDA receptor antagonist; Neurons; Pathology; Pathway interactions; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiology; Play; Prefrontal Cortex; Process; Public Health; Rattus; Relative (related person); Research; Resistance; Rodent Model; Role; Schizophrenia; Spatial Distribution; Structure; Symptoms; Techniques; Temporal Lobe; Testing; Time; behavior measurement; cognitive function; dopamine D4 receptor; emerging adult; improved; innovation; longitudinal design; neurodevelopment; novel; novel strategies; prenatal; public health relevance; research study; spatiotemporal

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.

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，它已被证明是比用于识别精神疾病遗传生物标志物的行为测量更富有成效的相关目标。使用啮齿动物模型，我们建议研究精神分裂症中的振荡长程同步及其改变，以及从青春期到成年期振荡网络发育轨迹的干扰。主要焦点是海马体 (HC) 和前额皮质 (PFC) 活动之间的节律协调受损，这对于成人的特定认知功能特别重要，并且也被证明在早期神经发育中发挥着重要作用。 HC 和 PFC 之间的功能连接异常已在精神分裂症患者和慢性精神分裂症动物模型中得到证实。由于 HC 和 PFC 中都存在神经元振荡网络关键要素的病理改变，因此皮质-海马同步受损可能源于其中一个或两个结构的病理学。我们建议使用一种新颖的方法来研究这个问题，该方法可以精确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光谱结构、解剖学、生理学和药理学。我们进一步假设，振荡受损也会对皮质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育及其控制是该领域的一个严重空白领域，因为振荡对于正常认知至关重要，并且似乎不仅在精神分裂症中受到损害，而且在自闭症和其他精神疾病中也受到损害。因此，我们还将利用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；先前的研究尚未尝试过这种纵向设计。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，同步 HC 和 PFC 之间的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受损的 PFC-HC 相互作用，这些药物除了精神分裂症相关症状外，还会显着改变大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 是确定正常大鼠和精神分裂症神经发育模型中振荡网络如何在青春期发育。我们提出一项纵向研究，以调查成人振荡同步模式是如何发展的，以及精神分裂症模型中的发展轨迹何时以及如何偏离正常。