Characterizing sensorimotor gaiting dysfunction in mouse models of schizophrenia

描述(申请人提供)：多项研究已经确定了精神分裂症患者、他们的一级“未受影响的”亲属以及精神分裂症的药物和遗传小鼠模型中的感觉-运动门控缺陷。感觉运动门控的这些缺陷可能是该疾病的一种标志性内表型。在这里，我们建议通过在7个不同的大脑区域植入微电极阵列来直接量化与感觉门控相对应的神经生理机制，这些脑区包括中脑边缘、中皮质和皮质-纹状体-丘脑微电路，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。然后我们将量化精神分裂药物PCP和精神分裂症风险基因DISC1对这些电路机制的影响。我们相信，从目前的提议中得出的对正常感觉运动门控背后的分布式回路的见解，以及遗传和药物操纵扰乱这些回路的机制，将提供对可能导致精神分裂症的神经生理变化的详细网络水平的理解。

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.