INVOLVEMENT OF DOPAMINERGIC AND CHOLINERGIC SYSTEMS IN SOCIAL ISOLATION-INDUCED DEFICITS IN SOCIAL AFFILIATION AND CONDITIONAL FEAR MEMORY IN MICE
INVOLVEMENT OF DOPAMINERGIC AND CHOLINERGIC SYSTEMS IN SOCIAL ISOLATION-INDUCED DEFICITS IN SOCIAL AFFILIATION AND CONDITIONAL FEAR MEMORY IN MICE
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DOI：
10.1016/j.neuroscience.2015.04.064
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发表时间：
2015-07-23
期刊：
影响因子：
3.3
通讯作者：
Matsumoto, K.
中科院分区：
文献类型：
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作者：
Okada, R.;Fujiwara, H.;Matsumoto, K.
断奶后的啮齿动物社会隔离饲养（SI）可诱发多种行为异常，包括注意缺陷多动障碍样行为。为了更好地理解SI诱导的行为异常，我们在此研究了SI对社会关系和条件性恐惧记忆的影响以及这些影响的神经机制。实验前，将4周龄的雄性小鼠分组饲养（GH）或社会隔离2-4周。分别在6周和7周时进行社会关系测试和恐惧记忆条件反射。SI小鼠在社会联系测试和恐惧记忆条件反射之前30分钟全身施用盐水或测试药物。情境和听觉恐惧记忆被阐明后1和4天的恐惧条件。SI小鼠的社会关系和上下文和听觉恐惧记忆弱于GH小鼠。多巴胺转运体抑制剂哌醋甲酯（MPH）可改善SI诱导的社会关系缺失，D-1受体拮抗剂SCH 23390可减弱MPH的作用，而D-2受体拮抗剂舒必利则无此作用。另一方面，他克林，乙酰胆碱酯酶抑制剂，对这种赤字没有影响。相比之下，他克林以毒蕈碱受体拮抗剂东莨菪碱逆转的方式改善了SI诱导的恐惧记忆缺陷，而MPH对记忆缺陷没有影响。神经化学研究表明，SI下调磷酸化形式的神经信号蛋白，钙调蛋白依赖性激酶II（p-CaMKII），环AMP反应元件结合蛋白（p-CREB），以及早期生长反应蛋白-1（Egr-1）在海马的表达水平。在恐惧条件反射前给予MPH或他克林对完成听觉恐惧记忆测试后阐明的神经信号蛋白的磷酸化形式的水平没有影响;然而，当在给予测试药物后30分钟进行分析时，他克林以东莨菪碱可逆的方式显著减弱了SI诱导的p-CaMKII，p-CREB和Egr-1的减少。我们的研究结果表明，SI诱导的赤字在社会联系和条件性恐惧记忆介导的功能改变，中央多巴胺和胆碱能系统，分别。(C)2015年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Post-weaning social isolation rearing (SI) in rodents elicits various behavioral abnormalities including attention deficit hyperactivity disorder-like behaviors. In order to obtain a better understanding of SI-induced behavioral abnormalities, we herein investigated the effects of SI on social affiliation and conditioned fear memory as well as the neuronal mechanism(s) underlying these effects. Four-week-old male mice were group-housed (GH) or socially isolated for 2-4 weeks before the experiments. The social affiliation test and fear memory conditioning were conducted at the age of 6 and 7 weeks, respectively. SI mice were systemically administered saline or test drugs 30 min before the social affiliation test and fear memory conditioning. Contextual and auditory fear memories were elucidated 1 and 4 days after fear conditioning. Social affiliation and contextual and auditory fear memories were weaker in SI mice than in GH mice. Methylphenidate (MPH), an inhibitor for dopamine transporters, ameliorated the SI-induced social affiliation deficit and the effect was attenuated by SCH23390, a D-1 receptor antagonist, but not by sulpiride, a D-2 receptor antagonist. On the other hand, tacrine, an acetylcholinesterase inhibitor, had no effect on this deficit. In contrast, tacrine improved SI-induced deficits in fear memories in a manner that was reversed by the muscarinic receptor antagonist scopolamine, while MPH had no effect on memory deficits. Neurochemical studies revealed that SI down-regulated the expression levels of the phosphorylated forms of neuro-signaling proteins, calmodulin-dependent kinase II (p-CaMKII), and cyclic AMP-responsive element binding protein (p-CREB), as well as early growth response protein-1 (Egr-1) in the hippocampus. The administration of MPH or tacrine before fear conditioning had no effect on the levels of the phosphorylated forms of the neuro-signaling proteins elucidated following completion of the auditory fear memory test; however, when analyzed 30 min after the administration of the test drugs, tacrine significantly attenuated the SI-induced decrease in p-CaMKII, p-CREB, and Egr-1 in a manner reversible by scopolamine. Our results suggest that SI-induced deficits in social affiliation and conditioned fear memory were mediated by functional alterations to central dopaminergic and cholinergic systems, respectively. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.