Early stress confers lifelong vulnerability causing alterations in a specific brain region

June 15, 2017
Credit: George Hodan/public domain

Early life stress encodes lifelong susceptibility to stress through long-lasting transcriptional programming in a brain reward region implicated in mood and depression, according to a study conducted at the Icahn School of Medicine 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 material is activated. Such regulation derives, in part, from the function of transcription factors—specialized 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 increases the risk for depression and other psychiatric syndromes, but the neurobiology linking the two has remained elusive until now.

"Our work identifies a molecular basis for stress during a sensitive developmental window that programs 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 behavioral 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 orthodenticle 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 10-20) had suppressed Otx2 in the VTA. While Otx2 levels ultimately recovered by adulthood, 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 behavior 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 behavior for mice stressed during the sensitive time period.

To test the prediction that Otx2 was actually responsible 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 depression-like behavior, 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 understood 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 development.

"This mouse paradigm will be useful for understanding the molecular correlates of increased risk of depression resulting from stress and could pave the way to look for such sensitive windows in human studies," says Eric J. 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."

Explore further: Molecular 'on switch' could point to treatments for pediatric brain tumor

More information: C.J. Peña el al., "Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2," Science (2017). science.sciencemag.org/cgi/doi … 1126/science.aan4491

Related Stories

Molecular 'on switch' could point to treatments for pediatric brain tumor

February 24, 2017
Massachusetts General Hospital (MGH) researchers have identified a mechanism that controls the expression of genes regulating the growth of the most aggressive form of medulloblastoma, the most common pediatric brain tumor. ...

Antidepressants induce resilience and reverse susceptibility

February 2, 2017
When they work, antidepressant medications may take weeks or months to alleviate symptoms of depression. Progress in developing new and more effective antidepressant treatments has been limited, though a new study published ...

Changes in a single gene's action can control addiction and depression-related behaviors

November 10, 2014
Regulation of a single, specific gene in a brain region related to drug addiction and depression is sufficient to reduce drug and stress responses, according to a study conducted at the Icahn School of Medicine at Mount Sinai ...

Early childhood stress affects brain's response to rewards

October 19, 2015
A Duke University-led study has pinpointed how early childhood stress affects the adult brain's response to rewards. Their findings suggest a possible pathway by which childhood stress may increase risk of depression and ...

Early supplementation may help offset early-life stress on the adult brain

October 26, 2016
Early-life stress has been shown to impair learning and memory in later life, but new research, published online in The FASEB Journal, suggests that improved nutrition may help offset the negative effects of this stress. ...

Brain protein influences how the brain manages stress; suggests new model of depression

November 12, 2014
The brain's ability to effectively deal with stress or to lack that ability and be more susceptible to depression, depends on a single protein type in each person's brain, according to a study conducted at the Icahn School ...

Recommended for you

Distractions diminish ability to remember, but important facts stick, psychologists report

August 24, 2017
"In a world of computers and iPhones, it's rare that we're fully focused," said Alan Castel, a UCLA professor of psychology.

Children with fragile X syndrome have a bias toward threatening emotion

August 23, 2017
Anxiety occurs at high rates in children with fragile X syndrome (FXS), the most common form of inherited intellectual disability. Children with co-occurring anxiety tend to fare worse, but it can be hard to identify in infants. ...

So-called "bright girl effect" does not last into adulthood

August 23, 2017
The notion that young females limit their own progress based on what they believe about their intelligence—called the "bright girl effect"—does not persist into adulthood, according to new research from Case Western Reserve ...

High moral reasoning associated with increased activity in the human brain's reward system

August 22, 2017
Individuals who have a high level of moral reasoning show increased activity in the brain's frontostriatal reward system, both during periods of rest and while performing a sequential risk taking and decision making task ...

Like adults, children show bias in attributing mental states to others

August 22, 2017
Young children are more likely to attribute mental states to characters that belong to the same group as them relative to characters that belong to an outside group, according to findings published in Psychological Science, ...

Yoga and meditation improve mind-body health and stress resilience

August 22, 2017
Many people report positive health effects from practicing yoga and meditation, and experience both mental and physical benefits from these practices. However, we still have much to learn about how exactly these practices ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

johnqsmith
not rated yet Jun 25, 2017
Maybe it's only me, but I think the explanations given in this article concerning behavior can be presented with more clarity. What I got is that epigenetic changes because of earlier life experiences may set the stage for behavioral traits (such as depression) that are learned later in life, with the potency of these later life experiences being enhanced because of the earlier conditioning. And this later learning perhaps even effecting the DNA genome. Maybe I got it wrong, but I do believe that the writer should decide beforehand what the key message of the story is and writing it down clearly.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.