Cognition in aged rhesus monkeys: effect of DHEA and correlation with steroidogenic gene expression

Abstract

Estradiol supplementation has been shown to enhance cognitive performance in old ovariectomized rhesus macaques (Macaca mulatta). To determine if similar benefits could be achieved in perimenopausal animals using alternative hormonal supplements, we administered dehydroepiandrosterone (DHEA) to old ovary-intact female rhesus macaques for ∼2.5 months. Using computerized touch screen memory tasks, including delayed response (DR) and delayed matching-to-sample (DMS), we observed improved performance with time in all of the animals but failed to detect a significant effect of DHEA. On the other hand, gene expression profiling disclosed a significant correlation between cognitive performance and the expression of several steroidogenic and steroid-responsive genes. The DR performance was positively correlated with hippocampal expression of AKR1C3 and STAR and negatively correlated with the expression of SDRD5A1. A positive correlation was also found between DMS performance and prefrontal cortical expression of AKR1C3 and a negative correlation with STAR, as well as a negative correlation with the hippocampal expression of HSD11B1 and NR3C1. Taken together, the results suggest that steroidogenic gene regulation within the brain may help to maintain cognitive function during the perimenopausal transition period, despite a decline in sex-steroid levels in the circulation.

Keywords: Cognition; cortisol; cortisone; dehydroepiandrosterone; estradiol; hippocampus; hormone therapy; menopause; perimenopause; prefrontal cortex.

Figure 1

Cognitive tests. In the DR task, animals were shown a red square on either the left or right side of a touch screen in the stimulus presentation phase (a) and, after a delay, were required to select the square on the same side during the query phase (b). In the DMS task, monkeys were shown a picture at the center of a touch screen in the stimulus presentation phase (c) and, after a delay, were required to select the previously shown image in the query phase (d). Correct responses resulted in a small palatable food reward.

Figure 2

Schematic of the cognitive testing protocol. Animals completed one Baseline testing battery, and then underwent additional testing batteries one week, one month, and two months after the start of DHEA supplementation. They subsequently completed three more testing batteries without DHEA supplementation, and then an additional final testing battery while on DHEA supplementation.

Figure 3

Baseline cognitive performance in aged female rhesus macaques in the DR (a) and DMS (b) tasks, with variable delays. As expected cognitive performance decreased as delay intervals increased, with performance at a delay of 15 seconds being considered a true measure of memory in the DR task and performance a delay of 120 seconds a true measure of memory in the DMS task. Each bar represents the mean of 8 animals and the vertical lines represent SEMs. Values with different letters were significantly different (P < 0.01), except for the difference in DMS performance at 60-sec and 120-sec delays (P < 0.05; ANOVA followed by the Newman-Keuls test).

Figure 4

DR and DMS performance in aged female rhesus macaques treated with DHEA relative to untreated baseline. Performance is presented as scores starting at the 2-month time point after the start of each testing phase (ON and OFF), relative to the baseline of each testing phase. This manipulation of the data corrected for the practice effect observed that resulted in higher scores as the study progressed. No significant effect of treatment was observed in DR (a) performance nor in DMS (b) performance.

Figure 5

Correlation of cognitive performance with steroidogenic and steroid-related gene expression in the hippocampus (HPC) and prefrontal cortex (PFC) of aged female rhesus macaques. Animals were ranked by their score in the final Off-DHEA battery on the 15-second delay in the delayed response (DR) task and the 60-second delay in the delayed matching-to-sample (DMS) task. These ranks were then correlated with relative gene expression using Kendall’s τ b. Only significant correlations are presented. See Table 1, and text for details of the statistical analysis definition of gene names.