II. Cognitive performance of middle-aged female rats is influenced by capacity to metabolize progesterone in the prefrontal cortex and hippocampus

Abstract

Cognitive decline can occur with aging; however, some individuals experience less cognitive decline than do others. Secretion of ovarian hormones is reduced post-menopause and may contribute to cognitive function. The extent to which hormonal effects may be parsed out from other age-related factors to influence cognition is of interest. Middle aged (12-month-old) female rats that were retired breeders were categorized as maintaining or declining reproductive function based upon their estrous cyclicity (regular 4-5 day cycles), fertility (> 60 % successful pregnancy) and fecundity (> 10 pups/litter). Performance in object recognition, Y-maze, water maze, inhibitory avoidance, and contextual/cued fear conditioning was evaluated. Estradiol, progesterone (P4), dihydroprogesterone, and 5α-pregnan-3α-ol-20-one (3α,5α-THP) were assessed in medial prefrontal cortex (mPFC) and hippocampus: corticosterone was assessed in plasma. Rats maintaining reproductive function performed significantly better on the object recognition, Y-maze, water maze, inhibitory avoidance, and cued fear conditioning tasks, than did rats with declining reproductive function. Steroid concentrations varied greatly within groups. Higher levels of P4 in mPFC and hippocampus were associated with better Y-maze performance. In mPFC, higher levels of P4 were associated with poorer inhibitory avoidance performance: greater levels of 3α,5α-THP were associated with better object memory. Neither estradiol, nor corticosterone, levels significantly contributed to cognitive performance. Thus, the capacity for cortico-limbic P4 utilization may influence cognitive performance in aging.

Bisphenol A, bisphenol F and bisphenol S affect differently 5α-reductase expression and dopamine–serotonin systems in the prefrontal cortex of juvenile female rats

“…Besides dihydrotestosterone (DHT) synthesis, 5α-R is the rate-limiting enzyme in the biosynthesis of 3α,5α-reduced neurosteroids (3α,5α-NS), such as allopregnanolone (AlloP). 3α,5α-NS modulate emotional responses and cognitive function (Frye, 2009;Paris et al, 2011b), which are mediated in part by the PFC (Davidson, 2002;Paris et al, 2011b). With this in mind and the finding that short-term exposure to BPA affects 5α-R levels in the PFC of adult female rats (Castro et al, 2013b), we believe that this enzyme might be a potential target for BPA-mediated effects in the female perinatal brain.…”

Ovariectomy increases the age-induced hyperphosphorylation of Tau at hippocampal CA1

“…For instance, reference and working memory in middle-age rats deteriorate since 12 months old, coinciding with the onset of alterations in the estrous cycle (Paris et al 2011;Markowska 1999). Consistent with this, Frick et al (2000) reported that in mice the onset of age-related impairment in spatial navigation occurs at the age of 17 months in females.…”

“…For instance, the deterioration of associative learning, evaluated by the ALT, appears earlier than observed in the Morris water maze by Markowska (1999) in which a good spatial ability is required. Similarly, rats maintaining reproductive functions have shown to spend more time exploring the novel arm of the Y-maze than rats with declining reproductive function (Paris et al 2011). Interestingly, Y-maze is a learning task that, similar to ALT, is integrated at cortex and hippocampus (Dillon et al 2008;Wagner et al 2007).…”

Age Increase of Estrogen Receptor-α (ERα) in Cortical Astrocytes Impairs Neurotrophic Support in Male and Female Rats

“…With the heterochronic in vitro astrocyte model (20), Lewis et al (26) showed impaired E2-dependent neurotrophic support of astrocytes from acyclic 10-month vs 3-month cycling rats. The importance of resolving the effects of acyclicity from age is indicated by impairments of spatial learning in irregular cyclers relative to regular cyclers in rats of the same age (27). We found that astrocytic ER␣ increased with age and with ovarian senescence, which we specifically link to increased GFAP and to impaired E2-dependent neurotrophic activity.…”

“…Thus, astrocyte response to E2 is sensitive to ovarian changes that are not a strict function of chronological age. The close relationship of astrocyte neurotrophic support to synaptic functions could be a mechanism in the impaired learning of irregularly cycling middle-aged rats relative to regular cyclers of the same age (27). We argue below for a role of elevated E2-P4 in astrocyte E2 desensitization.…”