Interneuron circuits and brain oscillations in rat models of schizophrenia

精神分裂症大鼠模型的中间神经元回路和脑振荡

• 批准号: 7799664
• 负责人: BERNAT KOCSIS
• 金额: $ 21.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-07 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799664
• 关键词: Activities of Daily Living; Adult; Animal Model; Animals; Behavior; Behavioral; Brain; Brain Stem; Cells; Characteristics; Chronic; Cognitive; Cognitive deficits; Data; Detection; Development; Disease; Dopamine; Electroencephalography; Electrophysiology (science); Exhibits; Frequencies; Future; Generations; Goals; Hand; Hippocampus (Brain); Histology; Human; Impaired cognition; Impairment; Interneurons; Intervention; Investigation; Lead; Link; Medial; Modeling; N-Methylaspartate; Neurocognitive; Neurocognitive Deficit; Neuronal Dysfunction; Neurons; Parvalbumins; Pathologic; Patients; Pattern; Performance; Pharmaceutical Preparations; Phase; Play; Population; Prefrontal Cortex; Process; Psychotropic Drugs; Rattus; Reporting; Research; Role; Schizophrenia; Signal Transduction; System; Techniques; Testing; Work; base; disease characteristic; drug development; entorhinal cortex; functional disability; gamma-Aminobutyric Acid; information processing; neuronal circuitry; neurotransmission; novel; public health relevance; research study

DESCRIPTION (provided by applicant): The recent shift in the conceptualization of schizophrenia from errors in dopamine neurotransmission to core deficits in information processing gave rise to a new generation of animal models focusing on the neurodevelopmental aspects and on the role of other systems, such as NMDA and GABA. Importantly, these models exhibit the animal equivalents of schizophrenia-related neurocognitive deficits and show characteristic abnormalities in the organization of the GABAergic interneuron networks, specifically in the hippocampus and prefrontal cortex, reminiscent of those in schizophrenic patients. GABAergic interneurons are involved in the generation of brain oscillations which in turn are known to be critical for cognitive processes. Their alterations in schizophrenic patients were proposed to significantly contribute to the neurocognitive impairments characteristic for this disease. The proposed project will examine the mechanisms of oscillatory synchronization in these models in an attempt of finding a link between the structural changes and neurocognitive deficits. We hypothesize that pathologic alterations in the neuronal circuitry in chronic neurodevelopmental animal models of schizophrenia will result in impaired oscillatory synchronization in the hippocampus and prefrontal cortex which in turn contribute to the neurocognitive deficits. We will test the specific hypothesis that this impairment correlates with the extent of damage to the local GABAergic interneuron network and in particular with the loss of parvalbumin positive basket and chandelier cells. Neuronal synchronization in the hippocampus and prefrontal cortex will be tested in two animal models each exhibiting abnormalities reminiscent of the neurocognitive deficits of human schizophrenia and each showing involvement of GABAergic mechanisms and a reduction of parvalbumin positive interneurons. The two models represent chronic conditions but are produced by different interventions; one is a neurodevelopmental model, the other is drug-induced in adult rats and is based on systemic NMDA antagonism. Electrophysiological signals will be processed for detection and analysis of their rhythmic components (power spectra, phase, and coherence). The brains will be processed for immunohistological examination of the hippocampus, prefrontal cortex, and medial septum and the results of electrophysiology will be compared with the extent of the reduction in parvalbumin expressing interneurons. This work will increase our neuronal level understanding of the mechanisms of cognitive deficits in schizophrenia and may lead to new strategies for drug development. PUBLIC HEALTH RELEVANCE: Contemporary views of schizophrenia regard cognitive dysfunction as the primary core deficit due to dysfunction of neuronal microcircuits. Brain oscillations are known to be critical for cognitive processes and their alterations in schizophrenic patients were proposed to significantly contribute to the neurocognitive impairments characteristic for this disease. This project will examine the functioning of neuronal networks involved in cortical oscillations in neurodevelopmental animal models of schizophrenia in an attempt of finding a link between the structural changes and neurocognitive deficits and will thus increase our neuronal level understanding of the mechanisms of cognitive deficits in schizophrenia and will facilitate the development of new strategies for drug development.

描述（由申请人提供）：精神分裂症的概念最近从多巴胺神经传递错误转变为信息处理的核心缺陷，这产生了新一代的动物模型，重点关注神经发育方面和其他系统（如NMDA和GABA）的作用。重要的是，这些模型表现出精神分裂症相关神经认知缺陷的动物等效物，并显示GABA能中间神经元网络组织的特征性异常，特别是在海马和前额叶皮层中，这让人想起精神分裂症患者。GABA能中间神经元参与脑振荡的产生，而脑振荡又被认为是认知过程的关键。他们在精神分裂症患者中的改变被认为是这种疾病的神经认知障碍特征的重要原因。该项目将研究这些模型中的振荡同步机制，试图找到结构变化和神经认知缺陷之间的联系。我们假设，在慢性神经发育的精神分裂症动物模型中，神经元回路的病理改变将导致海马和前额叶皮层的振荡同步受损，这反过来又会导致神经认知缺陷。我们将检验这种损伤与局部GABA能中间神经元网络的损伤程度相关的特定假设，特别是与小白蛋白阳性篮状细胞和枝形细胞的丢失相关。将在两种动物模型中测试海马和前额皮质中的神经元同步，每种动物模型均表现出令人联想起人类精神分裂症的神经认知缺陷的异常，并且每种动物模型均显示出GABA能机制的参与和小清蛋白阳性中间神经元的减少。这两种模型代表慢性疾病，但由不同的干预措施产生;一种是神经发育模型，另一种是成年大鼠中的药物诱导模型，基于全身NMDA拮抗作用。将处理电生理信号，以检测和分析其节律成分（功率谱、相位和相干性）。将处理脑以进行海马、前额皮质和内侧隔的免疫组织学检查，并将电生理学结果与表达小清蛋白的中间神经元的减少程度进行比较。这项工作将增加我们对精神分裂症认知缺陷机制的神经元水平理解，并可能导致药物开发的新策略。公共卫生相关性：精神分裂症的当代观点认为认知功能障碍是由于神经元微电路功能障碍引起的主要核心缺陷。已知脑振荡对认知过程至关重要，并且提出精神分裂症患者的脑振荡改变显著有助于这种疾病的神经认知障碍特征。该项目将研究精神分裂症神经发育动物模型中参与皮层振荡的神经元网络的功能，试图找到结构变化和神经认知缺陷之间的联系，从而增加我们对精神分裂症认知缺陷机制的神经元水平理解，并将促进药物开发新策略的开发。

项目成果

Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist-induced aberrant cortical gamma oscillations.

• DOI: 10.1016/j.biopsych.2011.10.002
• 发表时间: 2012-06-01
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Kocsis, Bernat

Comparison of the effects of acute and chronic administration of ketamine on hippocampal oscillations: relevance for the NMDA receptor hypofunction model of schizophrenia.

• DOI: 10.1007/s00429-011-0351-8
• 发表时间: 2012-04
• 期刊: BRAIN STRUCTURE & FUNCTION
• 影响因子: 3.1
• 作者: Kittelberger, Kara;Hur, Elizabeth E.;Sazegar, Saba;Keshavan, Vidya;Kocsis, Bernat
• 通讯作者: Kocsis, Bernat