AGE-RELATED SPATIAL WORKING MEMORY IMPAIRMENT IS CAUSED BY PREFRONTAL CORTICAL DOPAMINERGIC DYSFUNCTION IN RATS
AGE-RELATED SPATIAL WORKING MEMORY IMPAIRMENT IS CAUSED BY PREFRONTAL CORTICAL DOPAMINERGIC DYSFUNCTION IN RATS
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DOI：
10.1016/j.neuroscience.2009.05.023
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发表时间：
2009-09-15
期刊：
影响因子：
3.3
通讯作者：
Tabira, T.
中科院分区：
文献类型：
--
作者：
Mizoguchi, K.;Shoji, H.;Tabira, T.
在人类和动物的正常衰老过程中，有证据表明前额叶皮质(PFC)依赖的认知缺陷，如工作记忆障碍。尽管工作记忆功能与PFC多巴胺能系统被认为密切相关，但在老年人中，它们之间的关系尚不清楚。本研究旨在阐明PFC多巴胺能活动与年龄相关的工作记忆损害的关系。为此，我们使用T迷宫延迟交替任务，检测了年轻(3月龄)和老年(24月龄)大鼠的工作记忆。结果，与年轻大鼠相比，老年大鼠的延迟交替行为能力受损，这表明与年龄相关的工作记忆受损。此外，免疫组织化学和酶学方法显示，老年大鼠在PFC的初级皮质区的多巴胺能传递减少，并伴有PFC的酪氨酸羟基酶活性减弱，但在腹侧被盖区和黑质中没有。此外，直接用10或30 ng而不是100 ng的D1受体激动剂SKF 81297刺激前额叶皮质，可改善与年龄相关的工作记忆损害，表明SKF 81297的反应是倒“U”型的。最大的SKF 81297反应(30 Ng)可被D1受体拮抗剂SCH 23390取消。因此，与年龄相关的工作记忆损害是通过前额叶终止区多巴胺合成减少导致的PFC多巴胺能传递减少，而不是在投射起源的部位。这一发现提供了直接证据，表明在正常衰老过程中，多巴胺能功能障碍参与了PFC认知缺陷的发展，并有助于了解大脑的衰老生理和病理。(C)2009年IBRO。爱思唯尔有限公司出版。保留所有权利。
There is evidence of prefrontal cortex (PFC)-dependent cognitive deficits, such as working memory impairment, during the normal aging process in humans and animals. Although working memory function and the PFC dopaminergic system are thought to be closely related, the relationship between them in aged subjects remains unclear. The present study was aimed to clarify the involvement of PFC dopaminergic activity in age-related working memory impairment. For this purpose, we examined working memory in young (3-month-old) and aged (24-month-old) rats, using the T-maze delayed alternation task. As a result, delayed alternation performance was impaired in aged rats compared to young rats, indicating age-related working memory impairment. In addition, aged rats showed reduced dopaminergic transmission in the prelimbic cortical region of the PFC, concomitant with attenuated tyrosine hydroxylase activity in the PFC, but not in the ventral tegmental area and substantia nigra, which was evaluated immunohistochemically and enzymatically. Moreover, age-related working memory impairment was improved by direct stimulation of the prelimbic cortical region of the PFC with 10 or 30 ng, but not 100 ng, of a D1 receptor agonist, SKF 81297, indicating that the SKF 81297 response was an inverted "U" pattern. The maximum SKF 81297 response (30 ng) was abolished by a D1 receptor antagonist, SCH 23390. Thus, age-related working memory impairment was through reduced PFC dopaminergic transmission caused by decreased dopamine synthesis in the prefrontal termination region, but not at the site where the projections originate. This finding provides direct evidence showing the involvement of dopaminergic dysfunction in the development of PFC cognitive deficits during the normal aging process and would help to understand the aging physiology and pathology of the brain. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.