Studies in animals have shown that
stressful experiences can be passed
onto offspring, often in the form of
a general anxious or stress-sensitive
phenotype. A new study now shows
that highly specific experiences can
also be inherited by subsequent generations,
in terms of behaviour and
anatomy, and that this transmission
occurs through parental gametes.
Dias and Ressler trained male
mice (F0 mice) to associate mild footshocks
with one of two odours: acetophenone
(Ace) or propanol (Prop).
The mice subsequently mated with
females, and the resulting F1-Ace and
F1-Prop male offspring underwent an
odour-potentiated startle test to assess
their sensitivity to the two odours.
This test revealed that F1-Ace males
displayed, on average, higher sensitivity
to Ace (but not to Prop) than
control mice, and that F1-Prop mice
showed higher sensitivity to Prop (but
not to Ace). Thus, mice whose fathers
had undergone a painful experience
associated with a particular odour
were more sensitive to that odour,
even though they had never been
exposed to it themselves.
Ace is detected by M71 odorant
receptors on neurons in the olfactory
bulb and main olfactory epithelium
(MOE). F1-Ace males had larger
M71-specific glomeruli in the olfactory
bulb and a greater number of
M71 receptor-expressing olfactory
sensory neurons in the MOE compared
with control males. These
anatomical changes might underlie
the behavioural effects; however, the
two could not be directly correlated
because they were assessed in different
sets of animals.
Interestingly, the male offspring of
F1-Ace males and F1-Prop males (that
is, F2 males) also showed increased
sensitivity to Ace and Prop, respectively.
Moreover, like their fathers,
F2-Ace males had larger M71-specific
glomeruli. These findings suggest that
a specific olfactory experience had
been transmitted down two generations.
A crucial experiment provided
evidence that this transmission
occurred via the gametes: when sperm
from F0-Ace males and F0-Prop
males was used for in vitro fertilization
of eggs from naive females, the
offspring of F0-Ace males had larger
M71-specific glomeruli than did the
offspring of F0-Prop males.
The authors nevertheless examined
whether social transmission — for
example, through altered maternal
behaviour — might also play a part.
Here, they trained female mice to
associate Ace with footshocks. The
male offspring of these mice showed
increased sensitivity to Ace and had
enlarged M71-specific olfactory glomeruli,
even if they had been fostered
by control females. Conversely, the
offspring of control mothers had no
increased sensitivity to Ace, even
if they had been fostered by Ace
mothers. These findings indicated
that the transmission of the olfactory
sensitivity to Ace was not socially
mediated and can also occur through
the maternal line.
The authors reasoned that if
F0-Ace mice transmit their olfactory
experience through gametes, then
DNA in sperm of F0-Ace males
might show epigenetic changes in
the gene encoding the M71 receptor
(Olfr151). Indeed, Olfr151 was hypomethylated
in both F0-Ace sperm
(compared with F0-Prop sperm) and
F1-Ace sperm. Interestingly, however,
there was no Olfr151 hypomethylation
in neurons in the MOE of
F1-Ace and F2-Ace males.
This study is ground-breaking in
that it shows that a specific sensory
and/or learning experience can be
transmitted — via the gametes — to
the offspring, where it manifests as
a specific behavioural sensitivity.
Arguably, it raises more questions
than it answers. For example, not all
F1-Ace and F1-Prop offspring showed
enhanced sensitivity to the relevant
odour, and methylation in Olfr151 was
found in the gene itself rather than in
a promoter region. Perhaps the greatest
mystery is how an olfactory experience
that is encoded in the brain can
be transmitted to the gametes — an
exciting challenge for future studies.
Leonie Welberg
EPIGENETICS
A lingering smell?
ORIGINAL RESEARCH PAPER Dias, B. G. &
Ressler, K. J. Parental olfactory experience
influences behavior and neural structure in
subsequent generations. Nature Neurosci. http://
dx.doi.org/10.1038/nn.3594 (2013)
mice whose
fathers had
undergone
a painful
experience
associated
with a
particular
odour were
more sensitive
to that odour,
even though
they had
never been
exposed to it
themselves
J. Vallis/NPG
RESEARCH HIGHLIGHTS
NATURE REVIEWS | NEUROSCIENCE	 VOLUME 15 | JANUARY 2014
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