Epigenetics Update

March 22, 2013 · Posted in Risk Factors 

molecular structure

In the BNN we have previously written about the role of epigenetics in the onset and course of bipolar disorder. Epigenetics refers to the idea that events and substances in the environment can affect the structure of DNA by adding chemicals (often methyl or acetyl groups) onto DNA and histones (structures around which DNA is wound) in such a way that the DNA is more or less likely to be transcribed and activated to produce new proteins. Thus our DNA is shaped not only by the genetic inheritance we receive from our parents, but also by events in the environment (which do not alter the sequence of DNA but can influence how easily the DNA gets turned on to produce proteins in our bodies.)

Researcher David Sweatt published a review article on epigenetics and memory in the journal Neuropsychopharmacology in 2012.  In it he examined research on rodents who show epigenetic changes after repeatedly being exposed to stimuli such as a fear-inducing environment or cocaine.

Sweatt made two main points abut the mechanisms by which the environment influences gene expression. The first is about the effects that histone deacetylase (HDAC) inhibitors can have on epigenetics. Contextual fear conditioning (when a rodent experiences danger in a particular place and begins to associate fear with that particular physical environment) can be augmented by histone deacetylase (HDAC) inhibitors, which include sodium butyrate and valproate. In rodents who have been given cocaine and whose interest in cocaine is associated with the physical environment they were in while receiving the cocaine, Marcelle Wood reported that extinction of this context-dependent cocaine-induced place preference could also be enhanced with an HDAC inhibitor.

Sweatt’s second point was that DNA methylation is necessary for long-term memory, and traumatic learning like that of the rodent avoiding the place it encountered danger can actually be erased using zebularine, an inhibitor of DNA methylation.

Editor’s Note:  Zebularine can also reverse other lifelong responses to neonatal trauma such as decreases in brain-derived neurotrophic factor (BDNF), a neuroprotective factor necessary for long-term memory, in the prefrontal cortex. Zebularine can also block the long-lasting increases in motor activity in response to repeated cocaine use, i.e. cocaine sensitization. Thus, it looks like much of what one learns or responds to in the environment is coded at the level of epigenetics when DNA or histones are methylated and/or acetylated (among other chemical modifications).

Amazingly, some of these epigenetic marks on our DNA and histones can even be transmitted to the next generation!

At a recent conference, researcher Johannes Bohacek reported that in an experiment in which rat pups were repeatedly separated from their mothers for 3 hours at a time and the mothers were exposed to unpredictable stressors, not only were the pups more stressed as adults, but when the males were mated with females who had not been exposed to stress as pups, the father’s stress alone produced epigenetic effects in the next 3 generations. Surprisingly, with each generation, the sex of the offspring affected alternated.  Males in the first generation showed more floating in a swim stress paradigm (indicating they gave up trying to swim, an indirect measure of depression) while females in the second generation were affected, and then males were again affected in the third generation. Social interaction deficits also crossed generations.

Also at the conference, Eric Nestler showed that the depression- and anxiety-like behavioral effects of defeat stress (which occurs when a small rodent is repeatedly exposed to the threat of a larger rodent defending its territory) could be transmitted (presumably via sperm) to a second and third generation.

Researcher Jasmine Hurd, likewise, reported that some of the behavioral effects of tetrahydrocannabinol (marijuana) could be transmitted to the next generation.

Moral of the story: Not only do we get our unalterable genetic inheritance from our mother and father, but some of what our parents learned or experienced could be passed on to us and perhaps to subsequent generations by epigenetic mechanisms, i.e. ones that do not change the genes or DNA sequences, but can change how easily our inherited genes get turned on or off and thus affect our behavior. The wistful admonition to “choose your parents well” may be more meaningful than we ever realized, since catastrophic stressors they experienced may in some instances affect us. Note of caution–it is clear that the genes we inherit do not deterministically dictate our traits or life course, and epigenetic influences are likely to have even more subtle effects on our behavior and to be further modified by other environmental influences.



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