SIGNALING AND CIRCUITRY OF SENSORIMOTOR GATING

描述：(改编自申请者摘要) 精神分裂症的症状包括感觉泛滥和认知支离破碎 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的 一种评估对脉冲刺激的惊吓反应减少的测试 出现较弱的预脉冲刺激。脉冲前抑制(PPI) 精神分裂症患者的惊吓反应被打乱。一模一样的测试 已经在动物身上用于阐明PPI背后的机制。急性 伏核(NAC)内放置多巴胺激动剂的研究 通过刺激多巴胺D2样受体来扰乱PPI。这种效果被阻断了 通过抗精神病药物预处理或局部D2样受体拮抗剂 行政管理。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效应的重要底物。 该项目的长期目标是确定特定的细胞和 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 导致慢性药物后PPI中断恢复的反应 治疗。与急性多巴胺激动剂的干扰作用相反 治疗，我们已经表明，重复治疗可以减弱行为 通过使多巴胺D2样受体脱敏而中断。的具体目标 该项目是：(1)确定多巴胺功能下调是否 慢性D2样受体诱导的D2样受体 受体选择性激动剂在一段时间内减弱PPI的干扰 通过肌动蛋白在NAC中的剂量依赖方式，(2)确定是否减少 NAC中的抑制性G蛋白足以减弱PPI的破坏， 以及(3)定义和刻画其功能是 慢性D2受体激动剂逆行治疗后的改变 一种即刻早期基因标记物的标记及免疫组织化学检测。 总之，这些研究将产生有关电路和信令的新数据 啮齿动物体内PPI中断恢复的潜在机制。结果是 将促进我们对感觉运动门控缺陷的理解 精神分裂症从区域层面到细胞和分子层面，以及 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.