SIGNALING AND CIRCUITRY OF SENSORIMOTOR GATING

描述：（改编自申请人摘要） 精神分裂症的症状包括感觉泛滥和认知碎片化 这被认为是感觉运动门控缺陷的结果。 感觉运动门控可以在人类和动物中使用定量测量来测量。 一种测试，用于评估对脉冲刺激的惊吓反应的减少， 呈现较弱的前脉冲刺激。前脉冲抑制（PPI） 精神分裂症患者的惊吓反应被破坏。一个相同的测试 已在动物中用于阐明PPI的潜在机制。急性 将多巴胺激动剂置于丘脑核（NAc）中的给药 通过刺激多巴胺D2样受体破坏PPI。这种影响被阻断了 抗精神病药物预处理或局部D2样受体拮抗剂 局其他几个神经递质系统也有牵连，但 中脑边缘多巴胺系统仍然是这些作用的重要底物。 该项目的长期目标是确定特定的蜂窝和 与精神分裂症感觉运动门控缺陷相关的分子靶点。一个 将使用感觉运动门控的动物模型来检查神经适应性 慢性药物治疗后导致PPI破坏恢复的反应 治疗与急性多巴胺受体激动剂的干扰作用相反， 治疗，我们已经表明，重复治疗减弱了行为， 通过使多巴胺D2样受体脱敏来破坏。的具体目标 该项目是（1）确定多巴胺功能性下调是否 D2-样受体诱导的慢性治疗与D2-样 受体选择性激动剂在一定时间内减弱PPI的破坏 剂量依赖性的方式通过肌动蛋白在NAc，（2）以确定是否减少 Nac中的抑制性G蛋白足以减弱PPI的破坏， 和（3）定义和表征NAc神经元的子集，其功能是 在使用逆行D2受体激动剂治疗后发生改变 即早基因标记物的标记和免疫组化检测。 总之，这些研究将产生关于电路和信号的新数据， 啮齿类动物PPI中断恢复的潜在机制。结果 将促进我们对感觉运动门控缺陷的理解， 从区域水平到细胞和分子水平， 可能为未来的发展提供新的治疗靶点。

DESCRIPTION: (Adapted from applicant's abstract) Symptoms of schizophrenia include sensory flooding and cognitive fragmentation which are thought to be the result of a deficiency in sensorimotor gating. Sensorimotor gating can be measured in humans and animals using a quantitative test that assesses reduction of the startle response to a pulse stimulus after presentation of a weaker prepulse stimuls. Prepulse inhibition (PPI) of the startle response is disrupted in patients with schizophrenia. An identical test has been used in animals to elucidate the mechanisms underlying PPI. Acute administration of dopamine agonists placed into the nucleus accumbens (NAc) disrupts PPI by stimulating dopamine D2-like receptors. This effect is blocked by antipsychotic pretreatment or by local D2-like receptor antagonist administration. Several other neurotransmitter systems are implicated, but the mesolimbic dopamine system remains an important substrate for these effects. The long-range goal of the project is to determine the specific cellular and molecular targets related to sensorimotor gating deficits in schizophrenia. An animal model of sensorimotor gating will be used to examine the neuroadaptive responses leading to recovery of PPI disruption following chronic drug treatment. In contrast to the disrupting effect of acute dopamine agonist treatment, we have shown that repeated treatment attenuates the behavioral disruption by desensitizing dopamine D2-like receptors. The specific aims of the project are (1) to determine whether functional downregulation of dopamine D2-like receptors induced by chronic treatment with a D2-like receptor-selective agonist attenuates disruption of PPI in a time-and dose-dependent manner by actin in the NAc,(2) to ascertain whether reduction of inhibitory G proteins in the Nac is sufficient to attenuate disruption of PPI, and (3) to define and characterize the subset of NAc neurons whose function is altered following chronic D2-receptor agonist treatment using retrograde labeling and immunohistochemical detection of an immediate early gene marker. Together, these studies will produce novel data on the circuitry and signaling mechanisms underlying the recovery of PPI disruption in rodents. The results will advance our understanding of sensorimotor gating deficits win schizophrenia from the regional level to the cellular and molecular levels, and may provide novel therapeutic targets for future development.