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起来，为利用动物研究来理解精神分裂症及其治疗提供一个重要的新机会。1)当代临床工作表明认知缺陷，如认知控制障碍，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，最能预测功能预后。2)与此同时，动物模型已经建立，以阐明认知的生理和分子基础。特别是，海马体位置细胞技术是30年前评估啮齿动物长期记忆和认知的神经生物学机制的标准。我们建议在两种已建立的精神分裂症相关动物模型——苯环利定（PCP）和新生儿海马腹侧病变（NVHL）模型中研究认知控制受损及其神经相关神经失调。我们将使用这些动物模型来评估和扩展精神分裂症的失协调假说：认知失协调是精神分裂症的核心缺陷。我们将从三个方面探讨不协调假说。1)通过记录NVHL和PCP动物在执行两帧位置回避任务时的位置细胞集合，将神经失调与认知控制受损联系起来。我们将测试神经失调是否与类似于精神分裂症中认知任务受损的任务中的认知控制受损有关。2)评估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、非典型的和新型的代谢性谷氨酸受体II组激动剂抗精神病化合物是否对认知和神经协调产生相关影响。3)通过测量麻醉动物海马和内侧前额叶皮质的神经协调能力，建立高通量抗精神病疗效测定方法。目前对抗精神病药物疗效的分析是基于行为测量（多动、脉冲前抑制），这些测量似乎与阳性症状的关系比与疾病的认知核心的关系更大，而这正是拟议研究的目标。公共卫生相关性：精神分裂症的核心认知缺陷可以理解为作为健康认知基础的时间协调神经元放电的基本生理机制的改变。我们将在精神分裂症大鼠模型中研究神经协调和认知受损的相关改变，以了解认知相关细胞的激活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.