Fear of cherry blossom

There has been a rash of headlines about mice inheriting memories, for example: Phobias may be memories passed down from ancestors; Fearful memories haunt mouse descendants; Memories pass between generations; Fear of a smell can be passed down several generations; Mice inherit the memories of their grandfathers; Fear can be inherited through sperm. This contrasts with the title of the paper that is being discussed: Parental olfactory experience influences behavior and neural structure in subsequent generations. You will notice that the paper title does not mention either ‘memory’ or ‘inheritance’. How you react to this research depends on how you understand memory and inheritance.



Male mice are trained to fear a particular odour; their children and grandchildren also avoid that smell. Whatever is happening is ‘epigenetic’, that is it is not a permanent change to the DNA code. It is a change in how that code is used. This is inheritance in a broad meaning of the word but should not be confused with a permanent change to the DNA. Epigenetics is a fairly new field and there are many puzzles still to be solved. It is a way for cells in the body to differ (like heart cells differ from skin cells) and for cells to adapt to particular environmental challenges. The mechanisms of epigenetics are ways to increase or decrease the production of a protein and/or to change the way it is prepared for use. All this has absolutely nothing to do with inheritance. But… sometimes these changes are passed on to offspring, because of the material in the egg cell and/or because of faults in clearing all of the epigenetic markers in the egg and the sperm. (In this case, it appear to be the sperm marker was not being cleared.) But this is a new field and there are probably a host of little quirks in the system that have no come to light. In this study the researchers found that the gene for a particular odour receptor was given an epigenetic marker that increased that gene’s use and as a result increased the strength of the brain’s representation of that odour and the behavior association with it. It is not clear to me whether the behavior (aversion) is the same but just stronger or whether the aversion is a new component of the behavior.



It is not just epigenetics that is not well understood. The effect of fear on memory is also a bit vague. Episodic memories are stored in the cortex by the hippocampus. But memories that are fearful also involve the amygdala. Just exactly how the amygdala changes the recall of the memory is not clear. Nor is it clear exactly how memories associated with odours are handled. It is not clear how the odour receptor fields and odour perception are modified to respond to differing environments.



So I have a number of questions. These may be answered in the original paper but I have not been able to read the original. The questions are not answered in the abstract nor in other reviews of the paper. How do mice react to strong unusual smells in the absence of fear conditioning? If they react with aversion then the increase in receptors could explain the increase in aversion. Can the mice be conditioned to some other behavior-odour association, rather than fear, and pass it on to offspring? If this only works for fear conditioning then they may be dealing with a distinct type of memory and not ordinary memories. For how many generation is the effect present and does its strength diminish slower that other cases of epigenetic inheritance? If it is a robust effect over generations than it is probably protected by a special mechanism – like a ‘do not erase’ tag for epigenetic markers to do with fear and/or smell? If the effect is being protected it may be a quirk of epigenetics that needs to be investigated. It might be an advantageous adaption to block the erasing mechanism to prepare offspring for the local environment under certain conditions. Why does it only get passed on in sperm? Is this an indication of a general difference in the erasing of epigenetic markers in the two sexes?



I have a general rule to not trust individual papers, especially those with unexpected results. I don’t assume they are wrong; I wait for other scientists to add confirmation or suspicion. I know nothing about the detail of these experiments (wish their were open access) and that is another reason for reluctance. But I have no reason to reject the results either and they are very interesting results, even if they are not results about ‘inheriting’ ‘memories’ as we usually use those words.



Here is the abstract of Dias & Ressler; Parental olfactory experience influences behavior and neural structure in subsequent generations. Nature Neuroscience (2014) 17, 89-96 doi:10.1038/nn.3594.




Using olfactory molecular specificity, we examined the inheritance of parental traumatic exposure, a phenomenon that has been frequently observed, but not understood. We subjected F0 mice to odor fear conditioning before conception and found that subsequently conceived F1 and F2 generations had an increased behavioral sensitivity to the F0-conditioned odor, but not to other odors. When an odor (acetophenone) that activates a known odorant receptor (Olfr151) was used to condition F0 mice, the behavioral sensitivity of the F1 and F2 generations to acetophenone was complemented by an enhanced neuroanatomical representation of the Olfr151 pathway. Bisulfite sequencing of sperm DNA from conditioned F0 males and F1 naive offspring revealed CpG hypomethylation in the Olfr151 gene. In addition, in vitro fertilization, F2 inheritance and cross-fostering revealed that these transgenerational effects are inherited via parental gametes. Our findings provide a framework for addressing how environmental information may be inherited transgenerationally at behavioral, neuroanatomical and epigenetic levels.


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