Testosterone and dihydrotestosterone differentially improve cognition in aged female mice

Abstract

Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to 24-mo-old gonadally intact female mice treated for 6 wk with silastic capsules containing either testosterone (T) or dihydrotestosterone (DHT) or empty capsules (placebo). Compared with placebo-treated mice, spatial memory retention in the water maze was enhanced by testosterone treatment, but not DHT treatment. In contrast, DHT treatment improved passive avoidance (PA) retention, while T treatment only did so marginally. These data support that androgen supplementation in old female mice improves cognitive performance differentially depending upon the type of hormone treatment and cognitive task.

Figure 1.

Plasma T and DHT levels for mice supplemented with either T (n = 6) or DHT (n = 6) or given placebo (n = 5; empty capsules). *P < 0.05 vs. placebo treated group by Duncan's post-hoc test following ANOVA. ^#P < 0.05 vs. DHT-treated group by Duncan's post-hoc test following ANOVA.

Figure 2.

Measures of anxiety (A) and activity (B) in the open field. Neither T nor DHT supplementation significantly changed anxiety or activity.

Figure 3.

Novel object (A), novel location (B) recognition performance, and total exploration time during the five trials of the NO/NL task (C). Preference for the novel object during trial 5 (novel object test), and for a familiar object in a novel location vs. the old location, were unaffected by T or DHT supplementation, as were total exploration time during the five trials of the NO/NL task.

Figure 4.

Average swim velocity (A) and learning during the hidden and visible trials of reference-memory water maze training as measured by escape latency (B) and total distance moved (C). Also shown are memory retention during the first (D), second (E), and third and final probe trials (F) of the reference-memory Morris water maze. Mice in all groups showed significant performance improvement over the training sessions during both visible and hidden training according to all measures. However, performance was unaffected by either T or DHT supplementation. In contrast, mice that received T supplementation achieved significant spatial bias in the third probe trial, whereas placebo- and DHT-treated mice did not. No significant preference for the target quadrant of the maze was observed during either the first or second probe trials for any group. *P < 0.05, a priori planned contrast.

Figure 5.

Roto-rod performance. Although there was significant performance improvement over the nine training trails for all groups, there was no effect of either T or DHT supplementation.

Figure 6.

Passive avoidance (PA) training performance (A) and memory performance (B), 24 h following training. Neither T nor DHT supplementation affected training performance as measured by the number of trials to criterion (A). In contrast, compared with either T- or placebo-treated mice, mice that received DHT supplementation showed significantly elevated latencies to enter the dark chamber (PA test latency) 24 h after training, indicating improved passive avoidance memory (B). In contrast, performance was not improved in T-treated mice compared with placebo-treated mice. Each data point in the figure (B) represents the actual PA test latency for each mouse. *P < 0.05 by Mann-Whitney U-test following Kruskall-Wallis test.