Dose-dependent effects of testosterone on spatial learning strategies and brain-derived neurotrophic factor in male rats

Abstract

Studies suggest that males outperform females on some spatial tasks. This may be due to the effects of sex steroids on spatial strategy preferences. Past experiments with male rats have demonstrated that low doses of testosterone bias them toward a response strategy, whereas high doses of testosterone bias them toward a place strategy. We investigated the effect of different testosterone doses on the ability of male rats to effectively employ these two spatial learning strategies. Furthermore, we quantified concentrations of brain-derived neurotrophic factor (pro-, mature-, and total BDNF) in the prefrontal cortex, hippocampus, and striatum. All rats were bilaterally castrated and assigned to one of three daily injection doses of testosterone propionate (0.125, 0.250, or 0.500 mg/rat) or a control injection of the drug vehicle. Using a plus-maze protocol, we found that a lower testosterone dose (0.125 mg) significantly improved rats' performance on a response task, whereas a higher testosterone dose (0.500 mg) significantly improved rats' performance on a place task. In addition, we found that a low dose of testosterone (0.125 mg) increased total BDNF in the striatum, while a high dose (0.500 mg) increased total BDNF in the hippocampus. Taken altogether, these results suggest that high and low levels of testosterone enhance performance on place and response spatial tasks, respectively, and this effect is associated with changes in BDNF levels within relevant brain regions.

Keywords: BDNF; Place strategy; Rat; Response strategy; Spatial memory; Testosterone.

Fig 1.

Behavioral testing for plus-maze protocol. Rats were trained to complete 100 trials on either the (A) place task or (B) response task. For the place task, rats were trained to locate food in one baited arm that was consistent for all trials involving the rat. For the response task, rats were trained to locate food in one baited goal arm that was consistently in the same direction (e.g., to right) for all of the trials involving that rat.

Fig 2.

Mean trials to criterion (±SEM) for rats receiving daily oil or testosterone injections. Criterion was reached after the rat made 9 out of 10 choices turning in the correct direction. (A) Among rats tested on the place task, there was a significant effect of treatment on the number of trials to criterion (p = 0.001, with the 0.500 mg T group performing better than all other groups. (B) Among rats tested on the response task, there was also a significant effect of treatment on the number of trials to criterion (p = 0.004), with the 0.125 mg T group performing better than all other groups. Letters designate groups that differed significantly from each other (p < 0.05).

Fig 2.

Mean trials to criterion (±SEM) for rats receiving daily oil or testosterone injections. Criterion was reached after the rat made 9 out of 10 choices turning in the correct direction. (A) Among rats tested on the place task, there was a significant effect of treatment on the number of trials to criterion (p = 0.001, with the 0.500 mg T group performing better than all other groups. (B) Among rats tested on the response task, there was also a significant effect of treatment on the number of trials to criterion (p = 0.004), with the 0.125 mg T group performing better than all other groups. Letters designate groups that differed significantly from each other (p < 0.05).

Fig 3.

Mean number of correct arm choices (±SEM) during training over every 10-trial block for rats receiving daily oil or testosterone injections. (A) Among rats tested on the place task, there was a significant block effect, a significant treatment effect, and a significant interaction between block and treatment (all p < 0.0005). Analyses within blocks revealed that there were significant differences between treatment groups for most of the blocks (*all p < 0.05). (B) Among rats tested on the response task, there was a significant block effect and a significant treatment effect (both p < 0.002), but no significant interaction effect. However, analyses within blocks revealed that there were significant differences between treatment groups during only blocks 1 and 3 (*all p < 0.05).

Fig 4.

Mean (±SEM) cortical, hippocampal, and striatal concentrations of (A) proBDNF, (B) mBDNF, and (C) total BDNF for rats injected with oil or testosterone that completed the place task. For all three cases, hippocampal levels were significantly greater than cortical and striatal levels (all p <0.0005). Letters designate groups that differed significantly from each other within each brain region (all p < 0.05).

Fig 4.

Mean (±SEM) cortical, hippocampal, and striatal concentrations of (A) proBDNF, (B) mBDNF, and (C) total BDNF for rats injected with oil or testosterone that completed the place task. For all three cases, hippocampal levels were significantly greater than cortical and striatal levels (all p <0.0005). Letters designate groups that differed significantly from each other within each brain region (all p < 0.05).

Fig 5.

Mean (±SEM) cortical, hippocampal, and striatal concentrations of (A) proBDNF, (B) mBDNF, and (C) total BDNF for rats injected with oil or testosterone that completed the response task. For all three cases, hippocampal levels were significantly greater than cortical and striatal levels (all p <0.0005). Letters designate groups that differed significantly from each other within each brain region (all p < 0.05).

Fig 5.

Mean (±SEM) cortical, hippocampal, and striatal concentrations of (A) proBDNF, (B) mBDNF, and (C) total BDNF for rats injected with oil or testosterone that completed the response task. For all three cases, hippocampal levels were significantly greater than cortical and striatal levels (all p <0.0005). Letters designate groups that differed significantly from each other within each brain region (all p < 0.05).