Progestogens' (e.g., progesterone and its neuroactive metabolite, allopregnanolone), cognitive effects and mechanisms among males are not well-understood. We hypothesized if progestogen's effects on cognitive performance are through its metabolite allopregnanolone, and not actions via binding to traditional progestin receptors (PRs), then progesterone administration would enhance performance in tasks mediated by the hippocampus and cortex, coincident with increasing allopregnanolone concentrations, brain derived neurotrophic factor (BDNF) and/or muscimol binding of PR knock out (PRKO) and wild-type PR replete mice. Experiment 1: Progesterone (4 mg/kg, subcutaneously (SC; n = 12/grp), or oil vehicle control, was administered to gonadally-intact adult male mice PRKO mice and their wild-type counterparts and cognitive behaviors in object recognition, T-maze and water maze was examined. Progesterone, compared to vehicle, when administered post-training increased time investigating novel objects by the PRKO and wild-type mice in the object recognition task. In the T-maze task, progesterone administration to wild-type and PRKO mice had significantly greater number of spontaneous alternations compared to their vehicle-administered counterparts. In the water maze task, PRKO mice administered vehicle spent significantly fewer seconds in the quadrant associated with the escape platform on testing compared to all other groups. Experiment 2: Progesterone administered to wild-type and PRKO mice increased plasma progesterone and allopregnanolone levels (n = 5/group). PRKO mice had higher allopregnanolone levels in plasma and hippocampus, but not cortex, when administered progesterone and compared to wild-type mice. Experiment 3: Assessment of PR binding revealed progesterone administered wild-type mice had significantly greater levels of PRs in the hippocampus and cortex, compared to all other groups (n = 5/group). Wild-type mice administered progesterone, but not vehicle, had increased BDNF levels in the hippocampus, but not the cortex, compared to PRKOs. Wild-type as well as PRKO mice administered progesterone experienced significant increases in maximal GABAA agonist, muscimol, binding in hippocampus and cortex, compared to their vehicle-administered counterparts. Thus, adult male mice can be responsive to progesterone for cognitive performance, and such effects may be independent of PRs trophic actions of BDNF levels in the hippocampus and/or increases in GABAA activity in the hippocampus and cortex.
The clinical literature and recent studies in our laboratory using rodent models demonstrate that there are individual differences in androgens’ pleiotropic effects across the lifespan that need to be better understood. The question to address that challenges the field is that levels of androgens (current and/or prior) may not drive differing responses to androgens. The clinical example of Post-finasteride Syndrome, in which side-effects persist long after treatment is discontinued, supports investigations of this novel question relating to long-term effects of androgen manipulations, independent of existing levels of androgens.
One Health is a principle that takes into account the interactions of humans, animals, the surrounding environment, and how they affect each other. In order to examine this concept in an experimental paradigm, the effects and benefits of wild Alaskan blueberries were compared to those from the continental United States (Lower-48 states) in human and animal studies. Blueberries have been hailed as a superfood for years now due to their high antioxidant levels and the positive effects they have on cardiovascular health and overall health and well-being. We hypothesize that although they are both beneficial, wild Alaskan blueberries have a greater positive effect on health and well-being than those from the lower 48. First, teachers and staff at the Anne Wien Elementary School in Fairbanks Alaska were provided with Alaskan and Lower-48 blueberries and asked to log the effects each coded sample had on their mental and physical health compared to a 5-day control period without blueberries. There was a significant stepwise positive effect of respondents reporting higher self-ratings of well-being overall. Alaskan blueberries significantly improved self-ratings of well-being compared to those from Lower-48 blueberries, albeit those blueberries did improve well-being compared to no blueberries. This experiment was replicated at a control site contemporaneously. The following year it was also replicated by participating teachers and staff at William S. Hackett Middle School in Albany, New York, as well as a control site. Further, lab rats, whose diets were supplemented with with Alaskan blueberries, performed better in exploratory and cognitive tests than did rats whose diets were supplemented with Lower-48 blueberries (who, similar to the previous trials, performed better than rats whose diets had not been supplemented at all). These findings suggest that blueberries have an overall positive effect on self-rated wellness in people and cognitive performance in lab rats and that Alaskan blueberries have a particularly greater and more beneficial effect. Whether this is due to greater antioxidant effects associated with higher altitude or fewer endocrine-disrupting contaminants in Alaska compared to the Lower-48 States is unknown and subject to ongoing investigation.
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