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Early life stress encodes lifelong susceptibility
to stress through long-lasting transcriptional
programming in a brain reward region impli-
cated in mood and depression, according to a
study conducted at the Icahn School of Med-
icine at Mount Sinai and published June 15 in
the journal Science.
The Mount Sinai study focuses on epigenetics,
the study of changes in the action of genes caused
not by changes in DNA code we inherit from our
parents, but instead by molecules that regulate
when, where, and to what degree our genetic ma-
terial is activated.
Such regulation derives, in part, from the func-
tion of transcription factors---specialised proteins
that bind to specific DNA sequences in our genes
and either encourage or shut down the expression
of a given gene.
Previous studies in humans and animals have
suggested that early life stress increases the risk for
depression and other psychiatric syndromes, but the
neurobiology linking the two has remained elusive
"Our work identifies a molecular basis for stress
during a sensitive developmental window that pro-
grams a mouse's response to stress in adulthood," says
Catherine Peña, PhD, lead investigator of the study.
"We discovered that disrupting maternal care of
mice produces changes in levels of hundreds of genes
in the VTA that primes this brain region to be in a
depression-like state, even before we detect behav-
ioural changes. Essentially, this brain region encodes
a lifelong, latent susceptibility to depression that is
revealed only after encountering additional stress."
Specifically, Mount Sinai investigators identified
a role for the developmental transcription factor or-
thodenticle homeobox 2 (Otx2) as a master regulator
of these enduring gene changes. The research team
showed that baby mice that were stressed in a sensitive
period (from postnatal day ten-20) had suppressed
Otx2 in the VTA.
While Otx2 levels ultimately recovered by adult-
hood, the suppression had already set in motion gene
alterations that lasted into adulthood, indicating that
early life stress disrupts age-specific developmental
programming orchestrated by Otx2.
Furthermore, the mice stressed during the early-life
sensitive time period were more likely to succumb
to depression-like behaviour in adulthood, but only
after additional adult stress. All mice acted normally
before additional adult social stress, but a "second hit"
of stress was more likely to trigger depression-like
behaviour for mice stressed during the sensitive time
To test the prediction that Otx2 was actually re-
sponsible for the stress sensitivity, the research team
developed viral tools that were used to either increase
or decrease Otx2 levels. They found that suppression
of Otx2 early in life was both necessary and sufficient
for increased susceptibility to adult stress.
"We anticipated that we would only be able to
ameliorate or mimic the effects of early life stress
by changing Otx2 levels during the early sensitive
period." says Dr Peña.
"This was true for long-lasting effects on depres-
sion-like behaviour, but somewhat to our surprise we
could also change stress sensitivity for short amounts
of time by manipulating Otx2 in adulthood."
While early-life critical periods have been un-
derstood for processes such as language learning,
little is known about whether there are sensitive
periods in childhood when stress and adversity
most impacts brain development and particularly
emotion-regulation systems. This study is the first
to use genome-wide tools to understand how early
life stress alters development of the VTA, providing
new evidence for sensitive windows in emotion de-
"This mouse paradigm will be useful for under-
standing the molecular correlates of increased risk of
depression resulting from early life stress and could
pave the way to look for such sensitive windows in
human studies," says Eric Nestler, MD, PhD, Nash
Family Professor of Neuroscience and Director of the
Friedman Brain Institute at Mount Sinai and senior
investigator of the study.
"The ultimate translational goal of this research is
to aid treatment discoveries relevant to individuals
who experienced childhood stress and trauma." (The
Mount Sinai Hospital / Mount Sinai School of Medicine)
Previous studies have suggested that early life
stress increases the risk for depression and other
psychiatric syndromes, but the neurobiology linking
the two has remained elusive until now.
Early stress confers lifelong vulnerability
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