Research published by Dr. Joyce Yau et al. in the Journal of Neuroscience earlier this year examined whether negative effects of cortisol on memory could be blocked using antagonists for brain receptors for cortisol.
The researchers noted that local brain amplification of glucocorticoids (cortisol) by 11beta-hydroxysteriod dehydrogenase type 1 (11beta-HSD1) is “pivotal” in age-related memory loss.
Cortisol acts by binding to cell receptors. In their research, Yau and colleagues found that when levels of cortisol are low, a particular cortisol receptor is bound. However, at higher concentrations, cortisol has a spillover effect and binds a second receptor. Binding to this second receptor activates cellular processes in the brain that cause memory impairment.
The receptors studied were the high-affinity mineralocorticoid receptor (MR) and low-affinity glucocorticoid receptor (GR). As models for memory impairment, they used aged C57BL/6J mice as controls. Also studied were 11beta-HSD1-deficient mice (-/-), which ordinarily show no age-related memory deficits. Mouse memory was tested with a spatial memory task, a Y maze.
The mice were treated with intracerebral infusions of spironolactone, an MR antagonist or RU486, a GR antagonist.
The aged control mice showed impaired ability to navigate a Y maze. Their performance was unaffected (still impaired) by treatment with an MR antagonist, but performance improved when the GR antagonist was administered.
The aged, 11beta-HSD1-deficient mice had no impairment with the Y maze task. Their spatial memory became impaired, however, when given the MR antagonist, but was not affected with the GR antagonist.
The researchers showed that hippocampal mRNA levels for GR and MR were not significantly altered with either antagonist in either type of mouse, nor were blood levels of cortisol affected by the GR or MR blockade.
Conclusions were that 11beta-HSD1-deficient, aging mice, had lower cerebral concentrations of glucocorticoids (cortisol) , which activated the MR and enhanced memory, while in aging C57BL/6J controls the increased glucocorticoids saturated MRs and activated GRs causing memory impairment, which was reversed by treatment with a GR antagonist.
I would like to think that this means a solution to the memory deficits that accompany aging, are close at hand. However, training in scientific research tells me that actual in-pharmacy solutions may not occur next week/month/year. So I did some digging on cortisol and the aging brain and found the following details and links somewhat helpful. Read on for a shorter term potential therapy for too much cortisol on the brain.
Memory declines with aging. One factor that negatively affects memory is stress. While stress, in some cases, actually aids in establishing memory, continued stress can have a cumulative and negative effect on the brain and in particular, the hippocampus region of the brain, the memory bank. Research by Robert M. Sapolsky has shown that sustained stress damages the hippocampus, the area of the brain important to learning and memory.
The culprits of this damage are known to be glucocorticoids, steroid hormones secreted by the adrenal glands in response to stress. Glucocorticoids are more commonly called corticosteroids or, more simply, cortisol. Details on cortisol are available from Wikipedia.
When we are suddenly startled or alerted by a noise, or other surprise, the adrenal glands release adrenalin. If the threat isn’t immediately resolved or is elevated, the adrenals then release cortisol. Cortisol acts in part, to divert glucose from the brain, to the muscles.
Think about it: Einstein probably did not pen the theory of relativity in response to screams from the backyard.
When something really frightens us, the impulse is to RUN. When surprised, we JUMP first, breathe and think later. Persons in severe crisis may appear befuddled or unable to respond. When cortisol redirects blood glucose away from the brain and to the muscles, it supports the impulse to run, but negatively affects the ability to think and to store memories in the hippocampus.
In a study, rats were subjected to electric shock as a stressor, then asked to go through a maze that they had previously seen. If the rats were shocked 4 hours or 2 minutes before being sent into the maze, they were successful at navigating the maze. But if the shock was administered 30 minutes before the maze was presented, the rats could not successfully navigate the maze. The 30 minute timepoint correlates with the known peak for blood levels of cortisol after stress.
Somehow, all this information has made me feel worse, not better. However, digging a bit deeper into Sapolsky’s research revealed an article on reversing the effect of glucocorticoid toxicity on the hippocampus. By providing the brain some fuel!
All very interesting and enlightening work! Please take a look…and remember to write and let us know how it’s going.
Yau, J., Noble, J., & Seckl, J. (2011). 11 -Hydroxysteroid Dehydrogenase Type 1 Deficiency Prevents Memory Deficits with Aging by Switching from Glucocorticoid Receptor to Mineralocorticoid Receptor-Mediated Cognitive Control Journal of Neuroscience, 31 (11), 4188-4193 DOI: 10.1523/JNEUROSCI.6145-10.2011
Kari Kenefick
