Social Stress and Sensorimotor Gating Deficits in Rats

描述(由申请人提供)：环境应激源被认为在易受伤害的个人中触发精神分裂症的发病或复发。症状包括感觉泛滥和认知碎裂，这是感觉运动门控缺陷的结果。感觉运动门控可以使用定量测试来测量，该测试评估在呈现较弱的预脉冲刺激后对声脉冲刺激的惊吓反应的减少。精神分裂症患者和伏隔核和/或前额叶皮质多巴胺能异常的大鼠，这种对声学惊厥反应(PPI)的预脉冲抑制被破坏。同种动物之间的紧张社会互动会导致这种多巴胺功能障碍，并扰乱PPI。 该项目的长期目标是确定社会压力产生精神分裂症症状的细胞和分子机制。一个感觉运动门控的动物模型将被用来检验在反复的社会应激暴露后导致PPI中断的神经生物学反应，最初集中在前额叶/下缘皮质的作用。该项目的具体目标是(1)确定反复社会应激引起的PPI中断的时间过程，阐明伏隔核中D2样受体的参与；(2)确定前缘/下缘皮质的紧张性多巴胺活动是否与社会应激诱导的PPI中断有关；(3)量化和表征反复社会应激后Fos相关抗原(S)在上缘/下缘皮质中的持续表达；(4)表征反复社会应激后表达Fos相关抗原的皮质神经元的神经解剖联系。以及(5)确定社会应激引起的皮质酮水平升高是否通过抑制应激期间皮质酮的合成而导致PPI中断。 总之，这些研究将产生关于一种显著的社会压力源的细胞和分子效应的新数据，这种压力源会导致啮齿动物长期的感觉运动门控缺陷，并可能引发患者精神分裂症的发作或复发。

DESCRIPTION (provided by applicant): Environmental stressors are thought to trigger the onset or relapse of schizophrenia in vulnerable individuals. Symptoms include sensory flooding and cognitive fragmentation, which are the result of sensorimotor gating deficits. Sensorimotor gating can be measured using a quantitative test that assesses reduction of the startle response to an acoustic pulse stimulus after presentation of a weaker prepulse stimulus. Such prepulse inhibition of the acoustic startle response (PPI) is disrupted in patients with schizophrenia and in rats with dopaminergic abnormalities in the nucleus accumbens and/or prelimbic and infralimbic prefrontal cortex. A stressful social interaction between conspecific animals causes such dopamine dysfunction, and disrupts PPI. The long-range goal of this project is to determine the cellular and molecular mechanisms by which social stress can produce symptoms of schizophrenia. An animal model of sensorimotor gating will be used to examine the neurobiological responses leading to PPI disruption after repeated social stress exposure, initially focusing on the role of prelimbic/infralimbic cortex. The specific aims of the project are (1) to determine the time course of PPI disruption induced by repeated social stress exposure, elucidating the involvement of D2-like receptors in the nucleus accumbens, (2) to ascertain whether tonic dopamine activity in prelimbic/infralimbic cortex is related to social stress-induced PPI disruption, (3) to quantify and characterize the persistent expression of Fos-related antigen(s) in prelimbic/infralimbic cortex following repeated social stress, (4) to characterize the neuroanatomical connections of cortical neurons expressing Fos-related antigens after repeated social stress exposure, and (5) to determine whether social stress-induced elevation of corticosterone level leads to PPI disruption by inhibiting corticosterone synthesis during stress exposure. Together, these studies will produce novel data on the cellular and molecular effects of a salient social stressor, which causes long-lasting sensorimotor gating deficits in rodents, and may trigger the onset or relapse of schizophrenia in patients.