Cerebellar timing dysfunction in schizophrenia

描述（由申请人提供）：一个转化研究项目将调查精神分裂症中小脑介导的定时功能的完整性，并确定可能调节小脑定时网络突触特性的机制。越来越多的理论和经验证据表明，精神分裂症与神经过程和行为时间的基本紊乱有关。这种信息处理的时间协调缺陷，有时被称为认知障碍，可能导致知觉、认知、情感和运动过程的时间协调不良。大脑皮层-小脑-丘脑-皮层（CCTC）回路负责行为序列的流体和时间协调，其异常可能是精神分裂症时间异常的来源。拟议的研究将检查该电路的小脑模式的功能完整性。平行和互补的人类和非人类研究将主要使用小脑依赖的眨眼条件反射任务进行。总体目标是：(1)全面表征精神分裂症中眨眼条件反射（EEC）获得和时间异常的性质，并使用兔子模型确定可能导致观察到的缺陷的小脑机制；(2)研究与刺激方式和强度相关的初级感觉过程对精神分裂症和兔模型中观察到的EBC获取和时间异常的贡献；(3)系统探讨稳定、抗精神病药物治疗对EBC及其他小脑依赖性时间指标的影响；(4)确定精神分裂症患者EBC缺陷的临床、行为和结构神经解剖学相关性。总之，这些研究将确定精神分裂症患者皮质-小脑-丘脑-皮质回路小脑结的功能完整性，并测试可能导致该疾病时间缺陷的小脑功能受损模型。这项研究将使我们了解与一种极其衰弱的心理障碍——精神分裂症——有关的神经机制。更好地了解这些机制将促进对精神分裂症病理生理学的认识，并可能导致确定治疗的神经生物学靶点。

DESCRIPTION (provided by applicant): A translational research program will investigate the integrity of cerebellar-mediated timing functions in schizophrenia and identify mechanisms that may modulate synaptic properties of cerebellar timing networks. Mounting theoretical and empirical evidence indicates that schizophrenia is associated with a fundamental disturbance in the timing of neural processes and behavior. This deficit in the temporal coordination of information processing, sometimes referred to as cognitive dysmetria, may lead to poor temporal coordination of perceptual, cognitive, affective, and motor processes. Abnormalities in a cortico-cerebellar-thalamic-cortical (CCTC) brain circuit, which is responsible for fluid, temporal coordination of sequences of behavior, are a likely source of the timing anomalies in schizophrenia. The proposed research will examine the functional integrity of the cerebellar mode of this circuit. Parallel and complementary human and non-human studies will be conducted primarily using cerebellar-dependent eye-blink conditioning tasks. The overarching aims are to: (1) comprehensively characterize the nature of the eyeblink conditioning (EEC) acquisition and timing abnormalities in schizophrenia and use a rabbit model to identify cerebellar mechanisms that may be responsible for the observed deficits; (2) examine the contribution of primary sensory processes associated with stimulus modality and intensity to the observed EBC acquisition and timing abnormalities in schizophrenia and a rabbit model; (3) systematically explore the effect of stable, antipsychotic medication treatment on EBC and other cerebellar-dependent measures of timing; and (4) determine the clinical, behavioral, and structural neuroanatomical correlates of EBC deficits in schizophrenia. Taken together, the studies will determine the functional integrity of the cerebellar node of the cortico-cerebellar-thalamic-cortical circuit in schizophrenia and test models of impaired cerebellar functioning that may give rise to timing deficits in the disorder. This research will result in knowledge about neural mechanisms associated with an extraordinarily debilitating psychological disorder, schizophrenia. A better understanding of these mechanisms will advance knowledge about the pathophysiology of schizophrenia, and may lead to the identification of neurobiological targets of treatment.