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: 7625016
• 负责人: RONALD P. HAMMER
• 金额: $ 24.93万
• 依托单位: UNIVERSITY OF ARIZONA
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625016
• 关键词: Acoustics; Acute; Address; Adenosine A2A Receptor; Adverse effects; Affect; Agonist; Animal Model; Antipsychotic Agents; Attenuated; Behavioral Assay; Binding; Biological Assay; Brain region; Cognitive deficits; Collaborations; Corpus striatum structure; Coupled; Cyclic AMP; Cyclic AMP Response Element; Cyclic AMP-Responsive DNA-Binding Protein; Data; Dominant-Negative Mutation; Dopamine; Dorsal; Dose; Drug usage; Experimental Animal Model; GTP-Binding Proteins; Letters; Measures; Mediating; Messenger RNA; Modeling; Molecular; Neurobiology; Neuronal Plasticity; Neurons; Nucleus Accumbens; Patients; Pharmaceutical Preparations; Pharmacology; Phencyclidine; Phosphorylation; Physiologic pulse; Process; Quinpirole; Rattus; Receptor Activation; Recombinants; Recovery; Regulation; Research Personnel; Rodent; Rodent Model; Role; Schizophrenia; Sensory; Signal Transduction; Stimulus; Symptoms; System; Testing; Therapeutic; Therapeutic Intervention; Time; Ventral Striatum; Viral; atypical antipsychotic; base; behavioral tolerance; mRNA Expression; mesolimbic system; neural circuit; neuroadaptation; neuromechanism; new therapeutic target; novel; overexpression; prepulse inhibition; programs; protein activation; protein expression; receptor; receptor expression; relating to nervous system; response; ropinirole

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，这些缺陷是感觉运动门控缺陷的结果，如感觉过载、混乱和思维碎片。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（称为前脉冲抑制（PPI））后对声脉冲刺激的惊吓反应的减少。正常PPI在精神分裂症患者中被破坏。在大鼠中可以使用相同的测试来阐明PPI破坏的潜在机制，PPI破坏是由丘脑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，并研究精神分裂症感觉运动门控缺陷的新疗法。实验动物模型已被用来确定药理学和神经回路的PPI中断的基础。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，重复治疗与选择性多巴胺D2样受体激动剂逆转PPI中断大鼠，我们描述了一个假定的细胞内基础，这种PPI恢复。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所产生的变化。此外，这种效应选择性地发生在中脑边缘多巴胺系统中，而不影响锥体外系脑区域。 拟议的努力将扩大我们的研究PPI调节的神经基板通过检查相关的分子变化的PPI恢复的时间，这将进一步特点是使用条件回避反应的测定。我们还将研究PPI恢复的持续时间和对苯环利定诱导的PPI破坏的影响。我们将使用选择性拮抗剂研究D2-，D3-和腺苷A2 A受体的参与，以及细胞内cAMP信号传导和PPI恢复之间的因果关系，使用cAMP反应元件结合蛋白测定和腺相关病毒介导的cAMP反应元件结合阻断。最后，将在特征化的延髓核神经元中鉴定用于治疗干预的特定靶标。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。