Cerebellar timing dysfunction in schizophrenia

描述(申请人提供)：一项翻译研究计划将调查精神分裂症患者小脑介导的计时功能的完整性，并确定可能调节小脑计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根本性障碍有关。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。大脑皮质-小脑-丘脑-皮质(CCTC)环路的异常可能是精神分裂症时间异常的一个来源，CCTC负责流体、时间协调的行为序列。这项拟议的研究将检查该电路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依赖小脑的眨眼条件反射任务进行。主要目标是：(1)全面描述精神分裂症患者眨眼条件反射(EEC)习得和计时异常的性质，并利用兔模型确定可能导致观察到的缺陷的小脑机制；(2)检测与刺激通道和强度相关的主要感觉过程对精神分裂症和兔模型观察到的EBC习得和计时异常的贡献；(3)系统探讨稳定的抗精神病药物治疗对EBC和其他小脑依赖计时措施的影响；以及(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。综上所述，这些研究将确定精神分裂症患者皮质-小脑-丘脑-皮质环路小脑结的功能完整性，并测试可能导致精神分裂症计时缺陷的小脑功能受损模型。这项研究将导致对与一种极其虚弱的心理障碍--精神分裂症--相关的神经机制的了解。更好地了解这些机制将促进对精神分裂症病理生理学的了解，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.