Genes 2 Brains 2 Mind 2 Me

In Robert Sapolsky’s book, “Why Zebras Don’t Get Ulcers“, he details a biological feedback system wherein psychological stress leads to the release of glucocorticoids that have beneficial effects in the near-term but negative effects (e.g. ulcers, depression, etc.) in the long-term.  The key to getting the near-term benefits and avoiding the long-term costs – is to be able to turn OFF the flow of glucocorticoids.  This is normally dependent on circuitry involving the frontal cortex and hippocampus, that allow individuals to reset their expectations and acknowledge that everything is OK again.  Here’s the catch (i.e. mother nature’s ironic sense of humor). These very glucocorticoids can initiate a kind of reorganization or ‘shrinkage’ to the hippocampus  – and this can disable, or undermine the ability of the hippocampus to turn OFF the flow of glucocorticoids.  Yes, that’s right, the very switch that turns OFF glucocorticoid flow is disabled by exposure to glucocorticoids!  Can you imagine what happens when that switch (hippocampus) get progressively more disabled?  Your ability to turn OFF glucocorticoids gets progressively worse and the negative effects of stress become more and more difficult to cope with.

Sounds depressing.  Indeed it is, and there are many findings of reduced hippocampal volume in various depressive illnesses.  The complex problem at hand, then, is how to reverse the runaway-train-like (depression leads to glucocorticoids which leads to smaller hippocampus which leads to more depression) effects of stress and depression?

One new avenue of research has been focused on the ability of the hippocampus to normally produce new cells – neurogenesis – throughout life.  Might such cells be useful in reversing hippocampal remodeling (shrinkage)?  If so, what molecules or genes might be targeted to drive this process in a treatment setting?

The recent paper by Joffe and colleagues, “Brain derived neurotrophic factor Val66Met polymorphism, the five factor model of personality and hippocampal volume: Implications for depressive illness” [doi: 10.1002/hbm.20592] offers some key insights.  They examined 467 healthy participants of the Brain Resource International Database (a personalized medicine company with a focus on brain health) using personality tests, structural brain imaging and genotyping for an A-to-G variation (valine-to-methionine) polymorphism in the BDNF gene.  They report that lower volume of the hippocampus was associated with higher scores of neuroticism (worriers) – but, this negative relationship was not found in all people – just those who carry the A- or methionine-allele.  Thus, those individuals who carry the G/G (valine/valine) genotype of BDNF may be somewhat more protected from the negative (hippocampal remodeling) effects of psychological stress.  Interestingly, the BDNF gene seems to play a role in brain repair!  So perhaps this neuro-biochemical pathway can be explored to further therapeutic benefit.  Exciting!!

By the way, the reason zebras don’t get ulcers, is because their life revolves around a lot of short term stressors (mainly hungry lions) where the glucocorticoid-stress system works wonderfully to keep them alive.  Its only homo sapiens who has enough long-term memory to sit around in front of the TV and incessantly fret about the mortgage, the neighbors, the 401K etc., who have the capacity to bring down all the negative, toxic effects of chronic glucocorticoids exposure upon themselves. My 23andMe profile shows that I am a G/G valine/valine … does this mean I’m free to worry more?  Now I’m worried.  More on BDNF here.