Effects of multiple daily genistein treatments on delayed alternation and a differential reinforcement of low rates of responding task in middle-aged rats

Abstract

The use of extracts that are highly enriched in phytoestrogens, such as genistein, has become popular to promote various aspects of healthy aging, including maintenance of cognitive function. These compounds are promoted to menopausal women as safe, natural alternatives to traditional estrogen therapies, yet their safety and efficacy are poorly understood. Previous research in our lab found that once daily oral treatment of ovariectomized female Long-Evans (LE) rats with the soy phytoestrogen, genistein resulted in subtle deficits in performance on cognitive tasks assessing working memory and response inhibition/timing ability. The present study further modeled exposure of the menopausal woman to genistein by treating 14-month old ovariectomized female LE rats three times daily at a dose of genistein resulting in serum concentrations similar to those that could be achieved in humans consuming either a commercially available soy isoflavone supplement or a diet high in these phytoestrogens. Genistein (3.4 mg/kg) or sucrose control pellets were orally administered to animals daily, 30 min before behavioral testing, and again both 4 and 8 h after the first treatment. The test battery consisted of a delayed spatial alternation task (DSA) that tested working memory and a differential reinforcement of low rates of responding (DRL) task that tested inhibitory control/timing. Genistein treatment impaired DSA performance relative to sucrose controls. Performance on the DRL task was largely unaffected by genistein treatment. Although the impairment measured on DSA was less pronounced than that we have previously reported following chronic treatment with 17β-estradiol, the pattern of the deficit was very similar to that observed with 17β-estradiol.

Figure 1

(A). Proportion correct during DSA testing across five 5-session blocks of testing. Trend analysis by linear contrasts of the learning curves revealed a significant difference between the genistein-treated group (M=0.699) and the sucrose-treated control group (M=0.728), p<0.05. (B). Proportion correct during DSA testing across 25 sessions. The genistein-treated group performed worse across 25 sessions of testing than did the sucrose-treated control group (⁺p<0.10).

Figure 2

(A) Lose-stay errors committed across five 5-session blocks of DSA testing. Trend analysis by linear contrasts of the error rates revealed a difference that approached significance between the genistein-treated (M=113.41) and the sucrose-treated control group (M=98.27), p=0.038. (B) Total lose-stay errors committed on the DSA task across 25 sessions of testing. The genistein-treated group committed more lose-stay errors overall than did the sucrose-treated control group (⁺p<0.10).

Figure 3

Win-stay errors committed across five 5-session blocks of DSA testing. Trend analysis by linear contrasts of the error rates revealed a significant difference between the genistein-treated group (M=185.05) and the sucrose-treated control group (M=170.91), p<0.05.

Figure 4

Ratio of reinforced to non-reinforced lever presses across six 5-session blocks of DRL testing. No differences were measured between treatment groups (p>0.05).

Figure 5

(A) Proportion of total responses in each 2.5 sec interresponse time (IRT) bin during the initial testing block. No differences were measured between treatment groups (p>0.05). (B) Proportion of total responses for each 2.5 sec interresponse time (IRT) bin during the final testing block. No differences were measured between treatment groups (p>0.05).