A whiff of fear down the generations

Last week saw
a lot of media
interest around a US study published in Nature Neuroscience reporting
the transgenerational effects of fear-conditioning in mice (see BioNews 733).

The paper (1), by Dr Brian Dias and Professor Kerry Ressler from Emory University, Georgia, is
important for two reasons. It addresses constitutional fearfulness that is relevant
to phobias, anxiety and post-traumatic stress disorders, plus the controversial
subject of transmission of the 'memory' of ancestral experience (literally
shocking in this case) down the generations. The study adds to the growing
evidence from animal experiments for a phenomenon that we can broadly term
transgenerational responses (TGR). However, this was a particularly 'clean',
well-controlled experiment with surprising results - not only did the fearful
behaviour manifest in offspring and grand-offspring, but they also inherited
the associated structural changes in their nervous system.

The starting
point was to fear-condition adult male mice by giving them a mild electric
shock to the footpad at the same time as presenting a very specific odour (acetophenone)
that they had never experienced before. As expected, these mice soon exhibited
alarm when just presented with that specific smell, and also showed the
expected increase in the specific odorant receptors and olfactory sensory
neurons in the pathway from nose to brain.

So specific
are these odorant receptors (each coded by their own gene) that the researchers
could use a 'control' odour and they could even distinguish the associated
neurological changes with this from those associated with acetophenone. Here we
have a system where the causal link between exposure and response (increased
sensitivity to acetophenone, but not the control odour) was understood at the
cellular and molecular-genetic level. This is very different from TGR
experiments on, for example, ancestral high fat diet and tendency to diabetes down
the generations, where the causal pathways between exposure and response are still
poorly understood.

Dias and
Ressler wanted to test whether the hypersensitivity to acetophenone was
biologically (rather than socially) transmitted down the male line to
grandsons, and so went to extreme lengths to ensure there was no chance of the
offspring learning to fear the smell from their parents. It may be that wild
mice learn to fear the smell of fox urine from their parents' reaction as well
as by other routes of transmission. Remarkably, the sons and grandsons of the
acetophenone-conditioned males had an increased sensitivity to this odour even
though they had never smelt it before, and furthermore they had also inherited
the associated neurological changes.

Next, they
looked at the sperm DNA of the fear-conditioned mice to check the Olfr 151 gene which codes for the
specific odorant receptor for acetophenone. They found an epigenetic change:
reduced methylation at one particular DNA site in the Olfr 151 gene. This is suggestive, but not proof, that the
transmission of the increased sensitivity to acetophenone to their sons is
through an epigenetic signal carried in the sperm. Such an epigenetic mechanism
does not change the DNA sequence, but can lead to enduring changes in gene
activity that in turn can change the structure or workings of the organism.

How
frightened were the offspring and grand-offspring mice when this strange new
odour was presented? We don't know. Only the sensitivity to acetophenone was actually
measured, and assessing fearfulness per
se is less easy to do. But that does not detract from the importance of
this clear demonstration of TGR, free of confounding transmission through
social imitation and learning.

Is it
relevant to wild mice and humans? I think so. This experiment is not entirely
removed from real life. Some way of forewarning the next generation of an olfactory
danger signal may well have evolved in mice, and experiments over the last
decade have shown, in line with common belief, that smell is important in human
fear. Researchers in the Netherlands have demonstrated
that, irrespective of confirmatory or contradictory audiovisual information,
olfactory fear signals produced by senders induced fear in receivers outside of
conscious access (2).

Studies have
demonstrated the phenomenon, but not yet the mechanism of TGR in humans (3). For
example, research in Sweden showed that the paternal grandparents' food supply
at particular times in their childhood was associated with longevity in the
grandchildren. Despite the elegant mouse experiment described above, it is
important to emphasise that TGRs are not confined to 'inheritance of acquired
characteristics' with the same feature in each generation. A Bristol study
showed that men who started smoking cigarettes before their puberty are more
likely to have future sons with obesity in adolescence compared to those who
started smoking later, yet those smoking fathers were thin. It is also worth
remembering that TGRs can be for better or worse.

It
is high time TGR is taken seriously in epidemiology, both as a potential
contributor to human constitutional variation in basic human biological
research and in public health research. I suspect we will not understand the
rise in neuropsychiatric disorders or obesity, diabetes and metabolic
disruptions generally without taking a multigenerational approach.