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. 2020 Mar:113:104550.
doi: 10.1016/j.psyneuen.2019.104550. Epub 2019 Dec 19.

Testosterone replacement causes dose-dependent improvements in spatial memory among aged male rats

Eliza C B Jaeger  1 , L Erin Miller  2 , Emily C Goins  3 , Chloe E Super  4 , Christina U Chyr  5 , John W Lower  6 , Lauren S Honican  7 , Daryl E Morrison  8 , Rajan A Ramdev  9 , Mark D Spritzer  10
Affiliations

Testosterone replacement causes dose-dependent improvements in spatial memory among aged male rats

Eliza C B Jaeger et al. Psychoneuroendocrinology. 2020 Mar.

Abstract

Testosterone has been shown to have dose-dependent effects on spatial memory in males, but the effects of aging upon this relationship remain unclear. Additionally, the mechanism by which testosterone regulates memory is unknown, but may involve changes in brain-derived neurotrophic factor (BDNF) within specific brain regions. We tested the effects of age and testosterone on spatial memory among male rats using two spatial memory tasks: an object-location memory task (OLMT) and the radial-arm maze (RAM). Castration had minimal effect on performance on the RAM, but young rats (2 months) performed significantly fewer working memory errors than aged rats (20 months), and aged rats performed significantly fewer reference memory errors. Both age and castration impaired performance on the OLMT, with only the young rats with intact gonads successfully performing the task. Subsequent experiments involved daily injections of either drug vehicle or one of four doses of testosterone propionate (0.125, 0.250, 0.500, and 1.00 mg/rat) given to castrated aged males. On the RAM, a low physiological dose (0.125 mg) and high doses (0.500-1.000 mg) of testosterone improved working memory, while an intermediate dose (0.250 mg) did not. On the OLMT, only the 0.250 mg T group showed a significant increase in exploration ratios from the exposure trials to the testing trials, indicating that this group remembered the position of the objects. Brain tissue (prefrontal cortex, hippocampus, and striatum) was collected from all subjects to assay BDNF. We found no evidence that testosterone influenced BDNF, indicating that it is unlikely that testosterone regulates spatial memory through changes in BDNF levels.

Keywords: Aging; BDNF; Object location memory; Radial arm maze; Spatial memory; Testosterone.

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Conflict of interest statement

Declaration of Competing Interest None.

Figures

Fig. 1.
Fig. 1.
Performance by Young (2 months old) and Old (20 months old) male rats that were either castrated (GDX) or sham castrated (Sham) during 25 days of testing in an 8-arm radial maze (n = 10–12/group). Entry rates and memory errors (mean ± SEM) are divided into 5-day blocks in the left-hand graphs and averaged across blocks in the right-hand graphs. Letters designate groups that differed significantly from each other within blocks (p < 0.05). (A) Arm entry rate increased significantly over the testing blocks (p < 0.0005), and Young rats entered arms at a significantly faster rate than Old rats (*p < 0.0005). There was no effect of castration on arm entry rate. (B) Rats performed significantly fewer WMEs on later testing blocks (p = 0.037), and Young rats performed significantly fewer WMEs than Old rats (*p < 0.0005). There was no main effect of castration, but on the final testing block (days 21–25), the Old/GDX group performed significantly more WMEs than all of the other groups. (C) There was no effect of block or castration on RMEs, but the Old rats performed significantly fewer RMEs than the Young rats (*p < 0.0005). (D) Rats performed significantly fewer WREs on later testing blocks (p = 0.003), and Young rats performed significantly fewer WREs than Old rats (*p < 0.0005). There was no main effect of castration for WREs, but on the final testing block the Old/Sham group performed at a level intermediate between the Old/GDX group and the Young groups.
Fig. 2.
Fig. 2.
Performance by male rats injected daily with sesame oil (Sham and GDX) or one of four doses of testosterone propionate during 25 days of testing in an 8-arm radial maze (n = 12/group). All rats in the GDX and testosterone-injected groups were bilaterally castrated, and the Sham group underwent sham castrations. Entry rates and memory errors (mean ± SEM) are divided into 5-day blocks in the left-hand graphs and averaged across blocks in the right-hand graphs. Letters designate groups that differed significantly from each other within blocks (p < 0.05). (A) Arm entry rate increased significantly over the testing blocks (p < 0.0005), but there were no effects of treatment on arm entry rates. (B) Treatment had a significant effect on WMEs (p = 0.017), with the 0.500 mg T group performing the fewest WMEs and the Oil GDX and Sham GDX groups performing the most WMEs. There was no effect of testing block on WMEs. (C) There was no main effect of block or treatment on RMEs, but during the second block of testing (days 6–10) the 1.000 mg T group performed fewer RMEs than the Oil GDX and Sham GDX groups. (D) Treatment had a significant effect on WREs (p = 0.005), with the 0.500 mg T and 1.000 mg T groups performing the fewest WREs and the Oil GDX and Sham GDX groups performing the most WMEs overall. A significant effect of treatment on WREs was also observed during the final block of testing, with differences between groups comparable to the effect of treatment averaged across blocks.
Fig. 3.
Fig. 3.
Behavioral data (mean ± SEM) for Young (2 months old) and Old (20 months old) male rats that were either castrated (GDX) or sham castrated (Sham) during habituation and testing on the OLMT (n = 9–11/group). (A) Over the four days of habituation to the open field prior to testing, all groups showed a significant decrease in the distance traveled (p < 0.0005). Old rats had significantly shorter path lengths than young rats overall (p < 0.0005), and the effect of age was significant within each day except day 3 of habituation. Letters designate groups that differed significantly from each other within blocks (p < 0.05). (B) During OLMT testing, the total exploration time for both objects was significantly greater during the exposure trials than during the testing trials (p < 0.0005) and the young rats engaged in significantly more exploration of the two objects than did the old rats (*p < 0.0005). (C) During OLMT testing, Young rats had a significantly higher exploration ratios than old rats during the testing trials (*p = 0.007). Only the Young/Sham group showed a significant increase in exploration ratios from the exposure trials to the testing trials (#p < 0.0005) and was the only group to have a mean exploration ratio during the testing trials that was significantly greater than the chance level of 0.5, indicated by the dashed line (p = 0.001).
Fig. 4.
Fig. 4.
Behavioral data (mean ± SEM) for male rats injected daily with sesame oil (Sham and GDX) or one of four doses of testosterone propionate during habituation and testing on the OLMT (n = 9–13/group). All rats in the GDX and testosterone-injected groups were bilaterally castrated, and the Sham group underwent sham castrations. (A) Over the four days of habituation to the open field prior to testing, all groups showed a significant decrease in the distance traveled (p < 0.0005). There was no effect of treatment on path length during habituation. (B) During OLMT testing, the total exploration time for both objects was significantly greater during the exposure trials than during the testing trials (p < 0.0005), but there was no significant differences between the groups for total time exploring the objects. (C) During OLMT testing, only the 0.250 mg T group showed a significant increase in exploration ratios from the exposure trials to the testing trials (*p < 0.05). None of the groups showed exploration ratios during the testing trials that were significantly greater than the chance level of 0.5, indicated by the dashed line.
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