Social Stress and Sensorimotor Gating Deficits in Rats

大鼠的社会压力和感觉运动门控缺陷

• 批准号: 6748085
• 负责人: RONALD P. HAMMER
• 金额: $ 38.99万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748085
• 关键词: SDS polyacrylamide gel electrophoresis; behavioral /social science research tag; corticosterone; dopamine; fos protein; immunocytochemistry; laboratory rat; metyrapone; microdialysis; nucleus accumbens; prefrontal lobe /cortex; schizophrenia; sensorimotor system; sensory feedback; social behavior; social psychology; startle reaction; stress; two dimensional gel electrophoresis; western blottings

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.

描述（由申请人提供）：环境压力被认为是引发精神分裂症的发病或复发的脆弱个体。症状包括感觉淹没和认知碎片，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，该定量测试评估在呈现较弱的前脉冲刺激后对声脉冲刺激的惊吓反应的减少。这种声惊吓反应（PPI）的前脉冲抑制在精神分裂症患者和多巴胺能异常的大鼠中脑核和/或前边缘和下边缘前额叶皮层中被破坏。同种动物之间紧张的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。感觉运动门控的动物模型将被用来检查神经生物学反应，导致PPI中断后，反复的社会压力暴露，最初集中在边缘前/边缘下皮层的作用。该项目的具体目标是：（1）确定由反复的社会压力暴露引起的PPI破坏的时间过程，阐明中脑核中D2样受体的参与，（2）确定前边缘/下边缘皮层中的紧张性多巴胺活性是否与社会压力引起的PPI破坏有关，（3）定量和表征重复社会应激后前边缘/下边缘皮质中Fos相关抗原的持续表达，（4）描述反复社会应激暴露后表达Fos相关抗原的皮质神经元的神经解剖学联系，以及（5）确定社会应激诱导的皮质酮水平升高是否通过抑制应激暴露期间的皮质酮合成而导致PPI中断。 总之，这些研究将产生关于突出的社会压力源的细胞和分子效应的新数据，该压力源导致啮齿动物中持久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。