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、其一级“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确定了感觉运动门控缺陷。这些缺陷的感觉运动门控可能作为一个标志性的内表型的障碍。在这里，我们建议直接量化的神经生理机制，对应于小鼠的感觉门控植入阵列的微电极在7个不同的大脑区域，包括中脑边缘，中皮层，和皮质-纹状体-丘脑微电路和执行神经生理记录作为小鼠执行一个经典的感觉运动门控任务。然后，我们将量化拟精神病药物PCP和精神分裂症风险基因DISC 1对这些电路机制的影响。我们相信，从目前的建议到分布式电路的基础上正常的感觉运动门控的见解，遗传和药理学操纵破坏这些电路的机制，将提供一个详细的网络水平的神经生理学改变，可能有助于精神分裂症的理解。

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.