Interneuron circuits and brain oscillations in rat models of schizophrenia

描述(申请人提供)：最近，精神分裂症的概念化从多巴胺神经传递错误转变为信息处理的核心缺陷，导致了新一代动物模型的产生，重点放在神经发育方面和其他系统的作用，如NMDA和GABA。重要的是，这些模型显示出与精神分裂症相关的神经认知缺陷的动物等价物，并显示出GABA能神经元间网络组织的特征性异常，特别是在海马区和前额叶皮质，这让人想起精神分裂症患者的情况。GABA能中间神经元参与脑震荡的产生，而脑震荡又是认知过程的关键。他们在精神分裂症患者中的改变被认为是这种疾病特有的神经认知障碍的重要原因。这项拟议的项目将研究这些模型中振荡同步的机制，试图找到结构变化和神经认知缺陷之间的联系。我们假设，在精神分裂症的慢性神经发育动物模型中，神经元回路的病理变化将导致海马区和前额叶皮质的振荡同步性受损，这反过来又导致神经认知缺陷。我们将检验这种损害与局部GABA能中间神经元网络的损害程度相关的具体假设，特别是与小白蛋白阳性篮子和吊灯细胞的丢失有关。将在两个动物模型中测试海马区和前额叶皮质的神经元同步性，每个动物模型都显示出异常，使人想起人类精神分裂症的神经认知缺陷，每个动物模型都显示涉及GABA能机制和小白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，另一种是药物诱导的成年大鼠，基于全身NMDA拮抗。将对电生理信号进行处理，以检测和分析其节律成分(功率谱、相位和相干性)。将对大脑进行海马体、前额叶皮质和内侧隔区的免疫组织学检查，并将电生理学结果与表达小白蛋白的中间神经元减少的程度进行比较。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的理解，并可能为药物开发带来新的策略。公共卫生相关性：当代对精神分裂症的看法认为，认知功能障碍是由于神经元微电路功能障碍造成的主要核心缺陷。众所周知，大脑振荡对认知过程至关重要，精神分裂症患者大脑振荡的改变被认为对这种疾病特有的神经认知障碍有重要贡献。本项目将在精神分裂症的神经发育动物模型中研究参与皮质振荡的神经元网络的功能，试图找到结构变化与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的了解，并将有助于开发新的药物开发策略。

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.