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: 7244280
• 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/7244280
• 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; Condition; Corpus striatum structure; Coupled; Cyclic AMP; Cyclic AMP Response Element; Cyclic AMP-Responsive DNA-Binding Protein; Data; Disruption; 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; Protein Overexpression; Pulse taking; Quinpirole; Range; Rattus; Receptor Activation; Recombinants; Recovery; Regulation; Research Personnel; Rodent; Rodent Model; Role; Schizophrenia; Sensory; Signal Transduction; Stimulus; Symptoms; System; Testing; Therapeutic; Therapeutic Intervention; Thinking; Time; Ventral Striatum; Viral; atypical antipsychotic; base; behavioral tolerance; mRNA Expression; mesolimbic system; neural circuit; neuroadaptation; neuromechanism; novel; novel therapeutics; prepulse inhibition; programs; protein activation; protein expression; receptor; receptor expression; relating to nervous system; response; ropinirole; therapeutic target

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、混乱和思维分裂。感觉运动门控可以通过定量测试来测量，该测试评估在出现较弱的预脉冲刺激后，对声脉冲刺激的惊吓反应的减少，称为预脉冲抑制（PPI）。精神分裂症患者正常PPI中断。一个相同的测试可以用在大鼠身上，以阐明PPI中断的机制，这是由伏隔核内多巴胺能异常产生的。