Neural coordination and cognitive disorganization in schizophrenia-related models

描述(由申请人提供)：我们建议将两个平行的进展结合在一起，这为利用动物研究了解精神分裂症及其治疗提供了一个重要的新机会。1)现代临床研究表明，认知缺陷，如认知控制受损，是精神分裂症的核心特征。事实上，认知障碍是精神分裂症的临床特征，最能预测功能结果。2)同时，现在已经建立了动物模型来阐明认知的生理和分子基础。特别是，海马区细胞技术是一项已有30年历史的标准，用于评估啮齿动物长期记忆和认知的神经生物学机制。我们建议在两个已建立的精神分裂症相关动物模型中，即苯环利定(PCP)和新生儿腹侧海马损伤(NVHL)模型中，研究认知控制受损及其神经相关的神经不协调。我们将使用这些动物模型来评估和扩展精神分裂症的不协调假说：认知不协调是精神分裂症的核心缺陷。我们将从三个方面考察不协调假说。1)当NVHL和PCP动物执行两帧位置回避任务时，通过记录位置细胞集合，将神经协调失调与认知控制受损联系起来。我们将测试神经不协调是否与认知控制受损有关，这些任务类似于精神分裂症中受损的认知任务。2)评价抗精神病药物对神经协调障碍和认知控制障碍的影响。我们将测试典型的、非典型的和新的代谢性谷氨酸受体II激动剂抗精神病化合物是否对认知和神经协调产生关联的影响。3)通过测量麻醉动物海马区和内侧前额叶皮质的神经协调性，建立一种高通量的抗精神病药物疗效检测方法。目前对抗精神病药物疗效的分析是基于行为测量(多动、脉搏前抑制)，这些测量似乎更多地与阳性症状有关，而不是与疾病的认知核心有关，这是拟议研究的目标。与公共健康相关：精神分裂症核心的认知缺陷可以理解为支撑健康认知的时间协调神经元放电的基本生理机制的改变。我们将研究精神分裂症大鼠模型中神经协调和认知受损的相关变化，以了解认知相关细胞的激发问题如何导致精神分裂症的核心缺陷。

DESCRIPTION (provided by applicant): We propose to bring together two parallel advances that provide an important new opportunity to harness animal research for understanding schizophrenia and its treatment. 1) Contemporary clinical work indicates that cognitive deficits, such as impaired cognitive control, are a core feature of schizophrenia. In fact, cognitive impairment is the clinical feature of schizophrenia that best predicts functional outcome. 2) In parallel, animal models have now been established to elucidate the physiological and molecular bases of cognition. In particular, hippocampal place-cell technology is a three decades-old standard for assessing the neurobiological mechanisms of long-term memory and cognition in rodents. We propose to investigate impaired cognitive control and its neural correlate, neural discoordination, in two established schizophrenia-related animal models, the Phencyclidine (PCP) and neonatal ventral hippocampal lesion (NVHL) models. We will use these animal models to evaluate and extend the discoordination hypothesis of schizophrenia: cognitive discoordination is the core deficit in schizophrenia. We will investigate the discoordination hypothesis in three aims. 1) Relate neural discoordination to impaired cognitive control by recording place cell ensembles as NVHL and PCP animals perform the two-frame place avoidance task. We will test whether neural discoordination is associated with impaired cognitive control in tasks that are analogous to cognitive tasks that are impaired in schizophrenia. 2) Evaluate effects of antipsychotic medications on neural discoordination and impaired cognitive control. We will test whether typical, atypical, and novel metabotropic glutamate receptor group II agonist antipsychotic compounds produce associated effects on cognition and neural coordination. 3) Develop a high-throughput assay for antipsychotic efficacy by measuring neural coordination in hippocampus and medial prefrontal cortex of anesthetized animals. Current assays of antipsychotic efficacy are based on behavioral measures (hyperactivity, prepulse inhibition) that appear more related to positive symptoms than to the cognitive core of the disease, at which the proposed studies are aimed. PUBLIC HEALTH RELEVANCE: The cognitive deficits at the core of schizophrenia can be understood as alterations in the basic physiological mechanisms of temporally coordinated neuronal firing that underlies healthy cognition. We will study associated alterations of neural coordination and impaired cognition in rat models of schizophrenia to learn how firing problems of cognition-related cells could lead to the core deficits of schizophrenia.