Sunday, September 7, 2014

Transgenerational inheritance of fear

A new semester has begun and I have no extra time to update this blog, so just a short entry today.  This paper was just too cool to pass up.  It was published earlier this year in Nature Neuroscience by Dias and Ressler.  They conducted a series of experiments which showed that learned fear can be passed on from generation to generation in the sperm DNA.  That’s Lamarckian evolution for all you evolution nerds out there.  A learned behavior that is inherited genetically -- totally crazy!

The DNA sequence itself isn’t changing, but instead the expression of genes is altered, so different amounts of proteins are being made.  This process is known as epigenetics (which I’ve discussed before with regard to histone modifications).  One way to change DNA expression is by methylating cytosines (the “C” in DNA sequences).  The methyl group (CH3) makes it harder for proteins to bind to the DNA and transcribe the genes into mRNA and subsequently into protein.  The general rule of thumb is: more methylation --> less gene expression, less methylation --> more gene expression.  This is a common way our cells regulate gene expression, and what’s really interesting is that many external influences can affect DNA methylation, like traumatic life experiences, smoking, exercise, environmental toxins, etc. 
Cytosine getting methylated (note the H3C addition on the the molecule on the right)

It is conceivable that DNA methylation patterns can be inherited through generations, so changes in gene expression that affected your great grandparents could still be maintained in your cells.  Most of these types of studies focus on changes that occur to the mom during pregnancy.  For example, lets say that researchers expose a pregnant mouse to a toxin that may affect DNA methylation.  The next generation (the F1 generation) is also being exposed in utero to the same toxin.  The eggs or sperm progenitor cells are also developing in the embryo, so the next next generation (F2) may also be exposed to the toxin.  Thus, if you see DNA methylation changes in the F1 and F2 offspring, this isn’t really so surprising since these cells were all exposed at the same time as the mom (F0 generation).  In order to really prove that DNA methylation patterns can be inherited across generations (transgenerationallly), you need to expose the parents to a stimulus before conception, before the F1 and F2 generation even exist, which is what they did in this paper.

The authors chose to initiate changes to gene expression by conducting odor conditioning in mice.  They paired a particular odor with a mild foot shock and conditioned F0 males to be afraid of the odor.  Then these males mated with na├»ve females (never exposed to the odor).  The F1 offspring showed excessive fear to the conditioned odor, even though they had never encountered it before.  It was their fathers who had been shocked, not them.  The authors found there were more cells in the olfactory region of their brains that expressed the olfactory receptor for the conditioned odor.  Furthermore, their dad’s sperm and their own sperm were less methylated in the gene that encodes for that particular odor receptor, so the offspring of F1 were also affected.

F0 dad learns fear for odor --> decreased methylation for receptor gene --> F1 offspring inherit methylation changes --> express more of the receptor --> increased sensitivity to odor --> F1 sperm have same decreased methylation --> sensitivity for odor passed on to F2 generation  

Grandpa (F0) had a bad experience with an odor and now his grandkids will be more afraid and sensitive to that odor.  And it’s all genetic.  The authors did a series of experiments to show that it isn’t behaviorally based (grandpa isn’t telling the grandkids about his horrible experience with this smell).  For instance, they took the sperm from the F0 mice and took it to a different mouse facility and did in vitro fertilization, so the father was nowhere near his offspring or the mother.  The F1 mice from in vitro fertilization were just as super sensitive to the odor.

This is nuts!