Differential effects of acute progesterone administration on spatial and object memory in middle-aged and aged female C57BL/6 mice

Abstract

The present study examined the effects of acute progesterone administration on hippocampal-dependent memory consolidation in ovariectomized middle-aged (16 months old) and aged (22 months old) female mice. Spatial memory was tested in a 2-day Morris water-maze task and object memory was tested using an object recognition task with 24- and 48-h delays. Immediately after water-maze training, mice received i.p. injections of vehicle, or 5.0, 10.0, or 20.0 mg/kg of water-soluble progesterone. Twenty-four hours later, retention of the platform location was tested. No overnight forgetting of the platform location was observed in middle-aged vehicle-treated mice. Acute progesterone administration had no effect on spatial memory in middle-aged mice. However, aged vehicle-treated mice demonstrated impaired memory for the platform location on Day 2 relative to Day 1. Twenty mg/kg, but not 5 or 10 mg/kg, progesterone reversed these deficits, suggesting that 20 mg/kg progesterone can improve spatial memory in aged females. In the object recognition task, mice explored two identical objects and then immediately received vehicle or progesterone injections. In middle-aged mice, 10 and 20 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24-h, but all doses were ineffective after 48-h. In aged mice, 10 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24 h, whereas both 5 and 10 mg/kg progesterone enhanced memory after 48 h. Together, these results indicate that acute progesterone differentially enhances hippocampal-dependent memory in middle-aged and aged females.

Figure 1

Effects of post-training progesterone injection on water maze performance in middle-aged (A & C) and aged (B & D) females. For all graphs, each point represents the group mean for each trial. Error bars represent ± standard error of the mean (SEM). The filled arrow represents the progesterone injection immediately after training trial 8. (A) Spatial memory consolidation in middle-aged mice. Swim distance in all middle-aged groups decreased over the eight training trials on Day 1. The groups did not differ on trial 8 of Day 1, suggesting that all groups performed similarly during the last trial before training. None of the groups demonstrated significant overnight forgetting after 24 hours, as evidenced by no significant increase in swim distance between trial 8 of Day 1 and trial 1 of Day 2. There were no differences among groups across the 4 testing trials of Day 2, likely due to a lack of forgetting after 24 hours. (B). Spatial memory consolidation in aged mice. Swim distance in all aged groups decreased over the eight training trials on Day 1. The groups did not differ in trial 8 of Day 1, suggesting similar performance during the last training trial. During the first trial of Day 2, swim distances in the vehicle, 5 mg/kg, and 10 mg/kg groups were significantly higher than during trial 8 of Day 1 (148%, 112%, and 84%, respectively). In contrast, the 35% increase in swim distance exhibited by the 20 mg/kg group was not significant, suggesting that this dose of progesterone can enhance spatial memory consolidation in aged female mice. Swim speeds were not affected by progesterone in either the middle-aged (C) or aged (D) mice. Within an age, swim speeds decreased similarly during Day 1 and were significantly faster on the 1^st trial of Day 2 relative to the last trial of Day 1. Further, swim speeds decreased similarly in all groups over the four testing trials on Day 2, suggesting that alterations in swimming ability did not contribute to the differences observed in swim distance.

Figure 2

Change in performance from trial 8 of Day 1 to trial 1 of Day 2in middle-aged (A) and aged (B) females. (A) There were no significant differences in swim distance from Day 1 to Day 2 in any of the middle-aged groups. Among aged females, (B), vehicle-treated mice demonstrated significantly increased swim distances on the first trial of Day 2 relative to the last trial of Day 1. The 20 mg/kg dose of progesterone, but not 5 or 10 mg/kg progesterone, prevented this decline in performance.

Figure 3

Effects of post-training progesterone injection on novel object memory consolidation in middle-aged (A & C) and aged (B & D) females. For all graphs, error bars represent ± SEM and * = p < 0.05 relative to chance (dotted line at 15 s). (A) In middle-aged females both 10 mg/kg and 20 mg/kg progesterone increased the time spent with the novel object relative to chance at the 24 hour delay. In contrast, progesterone in middle-aged females (C) did not affect time spent with the novel object at the 48 hour delay, relative to chance. In aged females, ten mg/kg significantly increased the time spent with the novel object relative to chance after 24 hours (B). After the 48 hour delay (D), both 5 and 10 mg/kg doses increased the time that aged females spent with the novel object, relative to chance.