Neural Plasticity and Sensorimotor Gating in Rats

描述(申请人提供)：精神分裂症的症状包括由感觉运动门控缺陷引起的各种认知缺陷，如感觉超负荷、组织混乱和思维碎片化。感觉运动门控可以使用定量测试来测量，该测试评估在呈现较弱的预脉冲刺激(称为预脉冲抑制(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被打乱。在大鼠身上可以使用相同的测试来阐明PPI中断的机制，PPI中断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，并探索治疗精神分裂症感觉运动门控缺陷的新疗法。一个实验动物模型已经被用来确定PPI中断背后的药理学和神经电路。这个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，重复使用选择性多巴胺D2样受体激动剂可以逆转大鼠PPI的破坏，我们描述了这种PPI恢复的假定细胞内基础。事实上，重复治疗会导致代偿性变化，类似于非典型抗精神病药物产生的变化。此外，这种效应选择性地发生在中脑边缘多巴胺系统中，而不影响锥体外脑区域。 建议的努力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调节的神经底物的研究，这将使用条件性回避反应的测试来进一步表征。我们还将研究PPI恢复的持续时间以及对苯环利定诱导的PPI中断的影响。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，以及细胞内cAMP信号与PPI恢复的原因关系，方法是采用cAMP反应元件结合蛋白分析和腺相关病毒介导的阻断cAMP反应元件结合的方法。最后，将在伏核的特征性神经元中确定用于治疗干预的特定靶点(S)。总之，这些研究将阐明啮齿动物PPI恢复的神经可塑性机制，并将为精神分裂症提供新的治疗靶点。

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.