Neural Plasticity and Sensorimotor Gating in Rats

大鼠的神经可塑性和感觉运动门控

• 批准号: 7143870
• 负责人: RONALD P. HAMMER
• 金额: $ 27.23万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143870
• 关键词: antiparkinson drugs; auditory stimulus; avoidance behavior; behavior test; behavioral /social science research tag; biological signal transduction; cAMP response element binding protein; cognition disorders; corpus striatum; dopamine agonists; dopamine receptor; immunocytochemistry; in situ hybridization; laboratory rat; neural plasticity; neuroregulation; nucleus accumbens; phencyclidine; psychopharmacology; purinergic receptor; receptor expression; schizophrenia; sensorimotor system; startle reaction

DESCRIPTION (provided by applicant): Symptoms of schizophrenia include various cognitive deficits that are the result of sensorimotor gating deficiency, such as sensory overload, disorganization and thought fragmentation. 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, termed prepulse inhibition (PPI). Normal PPI is disrupted in patients with schizophrenia. An identical test can been used in rats to elucidate the mechanisms underlying PPI disruption, which is produced by dopaminergic abnormalities within the nucleus accumbens. The long-range objective of the project is to determine specific cellular and molecular substrates of PPI regulation and to investigate novel therapies for sensorimotor gating deficits in schizophrenia. An experimental animal model has been used to determine the pharmacology and neural circuitry underlying PPI disruption. This model can predict the efficacy of drugs used to treat schizophrenia. We discovered that repeated treatment with a selective dopamine D2-like receptor agonist reverses PPI disruption in rats, and we described a putative intracellular basis for this PPI recovery. In fact, repeated treatment results in compensatory changes that resemble those produced by atypical antipsychotic drugs. Moreover, this effect occurs selectively in the mesolimbic dopamine system without affecting extrapyramidal brain regions. The proposed efforts will extend our studies of neural substrates underlying PPI regulation by examining the association of molecular changes to the timing of PPI recovery, which will be further characterized using an assay for conditioned avoidance responding. We will also examine the duration of PPI recovery and the effect on phencyclidine-induced PPI disruption. We will investigate the involvement of D2-, D3- and adenosine A2A receptors using selective antagonists, as well as the causative relationship between intracellular cAMP signaling and PPI recovery, using cAMP response element binding protein assays and adeno-associated viral-mediated blockade of cAMP response element binding. Finally, specific target(s) for therapeutic intervention will be identified in characterized neurons of the nucleus accumbens. Together, these studies will elucidate the mechanisms of neural plasticity underlying PPI recovery in rodents, and will provide novel therapeutic targets for schizophrenia.

描述（由申请人提供）：精神分裂症的症状包括由感觉运动门控缺陷导致的各种认知缺陷，例如感觉超载、混乱和思维碎片化。感觉运动门控可以使用定量测试来测量，该测试评估在出现较弱的前脉冲刺激（称为前脉冲抑制（PPI））后对声脉冲刺激的惊吓反应的减少。精神分裂症患者的正常 PPI 受到干扰。可以在大鼠中使用相同的测试来阐明 PPI 破坏的机制，PPI 破坏是由伏隔核内的多巴胺能异常产生的。 该项目的长期目标是确定 PPI 调节的特定细胞和分子底物，并研究治疗精神分裂症感觉运动门控缺陷的新疗法。实验动物模型已用于确定 PPI 破坏的药理学和神经回路。该模型可以预测用于治疗精神分裂症的药物的疗效。我们发现，用选择性多巴胺 D2 样受体激动剂重复治疗可以逆转大鼠的 PPI 破坏，并且我们描述了这种 PPI 恢复的假定细胞内基础。事实上，重复治疗会导致类似于非典型抗精神病药物产生的代偿性变化。此外，这种效应选择性地发生在中脑边缘多巴胺系统中，而不影响锥体外系大脑区域。 拟议的工作将通过检查分子变化与 PPI 恢复时间的关联来扩展我们对 PPI 调节背后的神经底物的研究，这将使用条件性回避反应的测定进一步表征。我们还将检查 PPI 恢复的持续时间以及对苯环己哌啶诱导的 PPI 破坏的影响。我们将使用选择性拮抗剂研究 D2-、D3- 和腺苷 A2A 受体的参与，以及使用 cAMP 反应元件结合蛋白测定和腺相关病毒介导的 cAMP 阻断来研究细胞内 cAMP 信号传导与 PPI 恢复之间的因果关系响应元素绑定。最后，将在伏隔核的特征神经元中确定治疗干预的具体目标。这些研究将共同​​阐明啮齿类动物 PPI 恢复的神经可塑性机制，并为精神分裂症提供新的治疗靶点。