The heritability of fears

Cyborg © EEG

As many of you know, one of my favorite topics here on the blog is epigenetic inheritance, i.e. the mechanisms that regulate changes in gene expression that can be passed from one generation to the next. Epigenetics has revolutionized the way we look at genetic inheritance: Darwin had taught us that the only way the environment can shape the genome of a species is through natural selection. While this is certainly still true, today we also know that:

1) Most of the mutations we see in a population have reached fixation through random drift -- the constant reshuffling from one generation to the next -- not selection.

2) The environment can induce changes in one generation that may indeed be passed on to the next generation not through actual changes in the DNA but, rather, in the way the DNA is "packaged" inside the cell nucleus (for a great explanation on how this work, see my colleague Karissa Sanbomatsu's TED talk).

 In a Nature Neuroscience paper [1], authors Dias and Ressler explored the following premise in a mouse model:

"An important, but often ignored, factor that influences adult nervous systems is exposure of parents to salient environmental stimuli before the conception of their offspring. Such information transfer would be an efficient way for parents to ‘inform’ their offspring about the importance of specific environmental features that they are likely to encounter in their future environments. However, this would necessitate the transgenerational inheritance of environmental information via the germ line by offspring not even conceived at the time."

The researchers used olfactory fear as the stimulus mostly because it's one of the best understood mechanisms, both at the neurological and the molecular biology levels. Of course, a caveat would be that humans, besides being very different from mouse models, they've evolutionarily replaced olfactory stimuli with visual ones.

The researchers used odor-naive male mice and targeted an odorant receptor (M71) whose expression in the olfactory sensory neurons has been shown to be activated by acetophenone. It is important to note that the experiment did not induce any change in the actual DNA of the mice. What they did, instead, was use acetophenone to activate the receptor so it would be expressed inside these special neurons.

As I explained in older posts, DNA is wrapped around "spools" called histones. Cells produce proteins and activate receptors depending on what genes are on the outer surface of the "histone yarn", while hidden parts of the DNA remain unexpressed (as if that gene didn't exist). A molecule like acetophenone can induce changes inside olfactory sensory neurons that cause the histones to move and expose the gene that encodes the M71 odorant receptor. Once this happens, the receptor is "activated."

 Since the mice are initially odor naive, their M71 receptor is inactivated (the gene is not expressed) prior to the exposure to acetophenone. After the receptor activation, these male mice were mated with odor naive females. So, genetically speaking, the offsprings had no reason to have the M71 receptor activated, since neither parent had it activated at birth. Yet the offsprings of the mice stimulated with acetophenone, despite not being previously exposed to any of the odors with which they were tested, were able to detect acetophenone at lower concentrations than the offsprings of mice stimulated with another molecule (propanole).

Not all offsprings were behaviorally tested. Some of the offsprings were kept naive to any exposure so that their neuroanatomy could be tested separately without risking the results to be affected by the behavioral tests. When they looked at the offsprings of the acetophenone exposed mice, the researchers found an increase in the M71 glomerular area together with a significant increase in the numbers of M71-activated olfactory sensory neurons in the main olfactory epithelium.

So, how these epigenetic changes get inherited? To address the question, Dias and Ressler examined the sperm of the acetophenone exposed mice. This part of the paper gets a little technical, but the interesting idea is that they did find molecular changes in the sperm DNA around the Olfr151 gene, which encodes the M71 receptor. They found that the 3' end of Olfr151 was significantly less methylated in the acetophenone induce mice. At the same time, they

"did not observe any histone-mediated epigenetic signatures around the M71 locus when chromatin was immunoprecipitated with antibodies that recognize histone modifications that either permit or repress to transcription."

The authors conclude:

"In summary, we have begun to explore an under-appreciated influence on adult behavior—ancestral experience before conception. From a translational perspective, our results allow us to appreciate how the experiences of a parent, before even conceiving offspring, markedly influence both structure and function in the nervous system of subsequent generations. Such a phenomenon may contribute to the etiology and potential intergenerational transmission of risk for neuropsychiatric disorders, such as phobias, anxiety and post-traumatic stress disorder."

[1] Dias, B., & Ressler, K. (2013). Parental olfactory experience influences behavior and neural structure in subsequent generations Nature Neuroscience, 17 (1), 89-96 DOI: 10.1038/nn.3594




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