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各种认知缺陷，这是感觉运动门控缺乏症的结果，例如感觉超负荷，混乱和思想碎片化。可以使用定量测试来测量感觉运动门控，该测试评估了较弱的预硫酸刺激刺激（称为PPI）（PPI）的较弱的预硫酸刺激后对声脉冲刺激的减少。精神分裂症患者的正常PPI被破坏。可以在大鼠中使用相同的测试来阐明PPI破坏的机制，PPI破坏是由伏隔核内多巴胺能异常产生的。 该项目的远距离目标是确定PPI调节的特定细胞和分子底物，并研究精神分裂症中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功效。我们发现用选择性多巴胺D2样受体激动剂反复治疗会逆转大鼠的PPI破坏，我们描述了这种PPI恢复的假定细胞内基础。实际上，重复治疗会导致代偿性变化，类似于非典型抗精神病药产生的变化。此外，这种作用在中腹多巴胺系统中有选择性地发生，而不会影响锥体外脑区域。 拟议的努力将通过检查分子变化与PPI恢复时间的关联，扩展我们对PPI调节基础神经底物的研究，这将进一步使用用于条件回避响应的测定法进行。我们还将检查PPI恢复的持续时间以及对苯二肽诱导的PPI破坏的影响。我们将使用选择性拮抗剂来研究D2-，D3-和腺苷A2A受体的参与，以及使用CAMP响应元件结合蛋白分析和腺相关的CAMP反应元件结合元件结合的cAMP反应元件结合蛋白分析和腺相关的病毒介导的阻断型。最后，将在伏隔核的特征神经元中确定治疗干预的特定靶标。总之，这些研究将阐明啮齿动物中PPI恢复的神经可塑性机制，并将为精神分裂症提供新颖的治疗靶标。