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，在某些人类成像研究中，事实证明，该表型比识别精神疾病的遗传生物标志物的行为措施更为富有成果的相关目标。使用啮齿动物模型，我们建议研究振荡性的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的振荡网络发育轨迹的干扰。主要重点是海马（HC）和前额叶皮层（PFC）的活动之间的节奏协调受损，这对于成年人的特定认知功能尤为重要，并且也被证明在早期神经发育中起着重要作用。在精神分裂症患者和精神分裂症的慢性动物模型中，HC和PFC之间的功能连通性异常。由于HC和PFC中存在神经元振荡网络的关键元素的病理改变，因此皮质 - 海马同步受损可能源自任何一种或两种结构的病理。我们建议使用一种可以精确定义节奏发电机的空间分布并量化其相互作用的新方法来检查这个问题，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模型中这些相互作用的光谱结构，解剖学，生理和药理学。我们进一步假设，振荡受损也会对皮质网络及其远距离连接的成熟产生不利影响。了解时间动力学及其控制的本体发育是该领域的严重差距区域，因为振荡对于正常的认知AD至关重要，似乎不仅在精神分裂症中受到了损害，而且在自闭症和其他精神疾病中也受到损害。因此，我们还将使用每日电生理记录在精神分裂症的神经发育模型中通过青春期和成年早期进行HC-PFC关系的正常发展及其病理改变；这种纵向设计尚未在先前的研究中尝试。具体目的1是建立PFC-HC相互作用的模式，包括方向信息。我们提出，远程影响HC和PFC之间的神经元活性和γ振荡在两个方向上都是活跃的，并且具有总体HC优势。我们将研究这些双向相互作用的解剖底物及其在需要动态PFC-HC耦合的认知任务中的作用。具体目的2是检查使用NMDA受体拮抗剂和多巴胺D4受体激动剂的精神分裂症药理模型中PFC-HC相互作用受损，除了精神分裂症相关的症状外，还可以显着改变脑振荡并降低需要功能性PFC和HC网络的认知任务。具体目的3是定义振荡网络如何在正常大鼠和精神分裂症的神经发育模型中在周期期间发展。我们提出了一项纵向研究，以研究振荡性同步的成年模式如何发展，何时以及如何以及如何以及如何与正常模型不同。