Characterizing sensorimotor gaiting dysfunction in mouse models of schizophrenia

描述（由申请人提供）：多项研究已经在精神分裂症患者、他们的一级“未受影响”亲属以及精神分裂症的药理学和遗传学小鼠模型中发现了感觉运动门控缺陷。这些感觉运动门控的缺陷可能是该疾病的一个标志性的内表型。在这里，我们建议直接量化与小鼠感觉门控相对应的神经生理机制，方法是在7个不同的大脑区域（包括中边缘、中皮层和皮层纹状体丘脑微回路）植入微电极阵列，并在小鼠执行经典的感觉运动门控任务时进行神经生理记录。然后，我们将量化拟精神药物PCP和精神分裂症风险基因DISC1对这些回路机制的影响。我们相信，从目前的建议中获得的对正常感觉运动门控基础的分布式电路的见解，以及遗传和药理学操作破坏这些电路的机制，将为可能导致精神分裂症的神经生理改变提供详细的网络层面的理解。

DESCRIPTION (provided by applicant): Multiple studies have identified sensorimotor gating deficits in patients with schizophrenia, their first degree "unaffected" relatives, and in pharmacological and genetic mouse models of schizophrenia. These deficits in sensorimotor gating may serve as a hallmark endophenotype of the disorder. Here we propose to directly quantify the neurophysiological mechanisms that correspond with sensory gating in mice by implanting arrays of microelectrodes across 7 distinct brain areas comprising mesolimbic, mesocortical, and cortical-striatal-thalamic microcircuits and performing neurophysiological recordings as mice perform a classic sensorimotor gating task. We will then quantify the effect of the psychotomimetic agent PCP and the schizophrenia risk gene DISC1 on these circuit mechanisms. We believe that the insights derived from the current proposal into the distributed circuits that underlie normal sensorimotor gating, and the mechanisms whereby genetic and pharmacological manipulations disrupt these circuits, will provide a detailed network-level understanding of the neurophysiological alterations that may contribute to schizophrenia.