Age-related spatial working memory impairment is caused by prefrontal cortical dopaminergic dysfunction in rats

K. Mizoguchi, Hirotaka Shoji, Y. Tanaka, W. Maruyama, T. Tabira

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Abstract

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.

Original languageEnglish
Pages (from-to)1192-1201
Number of pages10
JournalNeuroscience
Volume162
Issue number4
DOIs
Publication statusPublished - 15-09-2009

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Prefrontal Cortex
Short-Term Memory
Ventral Tegmental Area
Spatial Memory
Tyrosine 3-Monooxygenase
Substantia Nigra
Dopamine
Pathology
Brain
SK&F 81297

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Mizoguchi, K. ; Shoji, Hirotaka ; Tanaka, Y. ; Maruyama, W. ; Tabira, T. / Age-related spatial working memory impairment is caused by prefrontal cortical dopaminergic dysfunction in rats. In: Neuroscience. 2009 ; Vol. 162, No. 4. pp. 1192-1201.
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Age-related spatial working memory impairment is caused by prefrontal cortical dopaminergic dysfunction in rats. / Mizoguchi, K.; Shoji, Hirotaka; Tanaka, Y.; Maruyama, W.; Tabira, T.

In: Neuroscience, Vol. 162, No. 4, 15.09.2009, p. 1192-1201.

Research output: Contribution to journalArticle

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