Progestogens' effects and mechanisms for object recognition memory across the lifespan

Abstract

This review explores the effects of female reproductive hormones, estrogens and progestogens, with a focus on progesterone and allopregnanolone, on object memory. Progesterone and its metabolites, in particular allopregnanolone, exert various effects on both cognitive and non-mnemonic functions in females. The well-known object recognition task is a valuable experimental paradigm that can be used to determine the effects and mechanisms of progestogens for mnemonic effects across the lifespan, which will be discussed herein. In this task there is little test-decay when different objects are used as targets and baseline valance for objects is controlled. This allows repeated testing, within-subjects designs, and longitudinal assessments, which aid understanding of changes in hormonal milieu. Objects are not aversive or food-based, which are hormone-sensitive factors. This review focuses on published data from our laboratory, and others, using the object recognition task in rodents to assess the role and mechanisms of progestogens throughout the lifespan. Improvements in object recognition performance of rodents are often associated with higher hormone levels in the hippocampus and prefrontal cortex during natural cycles, with hormone replacement following ovariectomy in young animals, or with aging. The capacity for reversal of age- and reproductive senescence-related decline in cognitive performance, and changes in neural plasticity that may be dissociated from peripheral effects with such decline, are discussed. The focus here will be on the effects of brain-derived factors, such as the neurosteroid, allopregnanolone, and other hormones, for enhancing object recognition across the lifespan.

Keywords: Aging; Allopregnanolone; Hippocampus; Hormones; Neurosteroid; Progesterone.

Figure 1

Mean % of time spent with the novel object (± SEM) as a function of the total time spent investigating objects during the testing phase. The portion of bars showing performance above chance are in white and below chance are in gray. Data depicted on the left side are from rats with typical ovarian function across the estrous cycle (diestrous, proestrous, and estrous phases), and during early (week 1) and late (week 3) pregnancy, and two days (PPD2) and 14 days (PPD14) postpartum. Data depicted in the middle are from young adult rats that had typical ovarian function before they were ovariectomized (OVX, surgical ovarian decline) and replaced back with oil vehicle placebo or estradiol (E₂;09 mg/kg, which produces proestrous-like levels of circulating E₂) and progesterone (P₄; 4 mg/kg, which produces proestrous-like levels of circulating P₄). Data depicted on the left side are from rats with decline in ovarian function with aging: mid-aged (12-14 months old) administered placebo vehicle, E₂, P₄, or E₂+P₄ immediately after training and aged (15-18 month old) rats administered placebo vehicle or conjugated equine estrogens (CEE; 0.625 mg/kg). All placebo or hormone treatments were administered via subcutaneous injections immediately after the training phase. All rats were tested four hours after training. There were 8-12 rats per experimental group.

Figure 2

Mean % of time spent with novel object (± SEM) of wild type mice and estrogen receptor β knockout (βERKO) mice administered placebo vehicle, progesterone (P₄; 4 mg/kg), dihydroprogesterone (DHP; 4 mg/kg), or allopregnanolone (3α,5α-THP; THP; 4 mg/kg). There were 8-13 mice per group. All injections were subcutaneous and administered immediately after the training trial.* over line indicates significant effect of genotype revealed by Analyses of Variance (F_1,82= 5.18) and Fisher's LSD post hoc testing for group differences (p=0.02). * over individual bars indicates significant effect of hormone condition revealed by analyses of variance (F_3,82= 2.60) and Fisher's LSD post hoc testing for group differences (p=0.05).