High serum androstenedione levels correlate with impaired memory in the surgically menopausal rat: a replication and new findings.

After natural menopause in women, androstenedione becomes the primary hormone secreted by the residual follicle-depleted ovaries. In two independent studies, in rodents that had undergone ovarian follicular depletion, we found that higher endogenous serum androstenedione levels correlated with increased working memory errors. This led to the hypothesis that higher androstenedione levels impair memory. The current study directly tested this hypothesis, examining the cognitive effects of exogenous androstenedione administration in rodents. Middle-aged ovariectomised rats received vehicle or one of two doses of androstenedione. Rats were tested on a spatial working and reference memory maze battery including the water-radial arm maze, Morris water maze (MM) and delay match-to-sample task. Androstenedione at the highest dose impaired reference memory as well as the ability to maintain performance as memory demand was elevated. This was true for both high temporal demand memory retention of one item of spatial information, as well as the ability to handle multiple items of spatial working memory information. We measured glutamic acid decarboxylase (GAD) protein in multiple brain regions to determine whether the gamma-aminobutyric acid (GABA) system relates to androstenedione-induced memory impairments. Results showed that higher entorhinal cortex GAD levels were correlated with worse MM performance, irrespective of androstenedione treatment. These findings suggest that androstenedione, the main hormone produced by the follicle-depleted ovary, is detrimental to working memory, reference memory and memory retention. Furthermore, while spatial reference memory performance might be related to the GABAergic system, it does not appear to be altered with androstenedione administration, at least at the doses used in the current study.

Differential effects of duration of sleep fragmentation on spatial learning and synaptic plasticity in pubertal mice.

STUDY OBJECTIVE: To examine the differential effects of acute and chronic sleep fragmentation (SF) on spatial learning and memory, and hippocampal long-term potentiation (LTP) in pubertal mice. METHODS: Two studies were performed during which adolescent C57/Bl6 mice were subjected to acute-SF 24h a day × 3 days or chronic-SF for 12h a day × 2 weeks using a programmable rotating lever that provides tactile stimulus with controls housed in similar cages. Spatial learning and memory was examined using the Morris water maze, and long-term potentiation (LTP) was evaluated after stimulation of Schaffer collaterals in CA1 hippocampus post SF. Actigraphy was used during the period of SF to monitor rest-activity patterns. Electroencephalographic (EEG) recordings were acquired for analysis of vigilance state patterns and delta-power. Serum corticosterone was measured to assess stress levels. RESULTS: Acute-SF via tactile stimulation negatively impacted spatial learning, as well as LTP maintenance, compared to controls with no tactile stimulation. While actigraphy showed significantly increased motor activity during SF in both groups, EEG data indicated that overall sleep efficiency did not differ between baseline and SF days, but significant increases in number of wakeful bouts and decreases in average NREM and REM bout lengths were seen during lights-on. Acute sleep fragmentation did not impact corticosterone levels. CONCLUSIONS: The current results indicate that, during development in pubertal mice, acute-SF for 24h a day × 3 days negatively impacted spatial learning and synaptic plasticity. Further studies are needed to determine if any inherent long-term homeostatic mechanisms in the adolescent brain afford greater resistance to the deleterious effects of chronic-SF.