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. ? ? ?
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