According to a new study from the Icahn School of Medicine at Mount Sinai in New York, stress experienced early in the critical development of a mouse sets it up for an extra sensitivity to stressors due to genetic changes in the part of the brain responsible for mood.
The study, published in the journal Science, centered on how a gene’s action changes due to certain regulatory molecules versus inherited DNA alone, a field of study called epigenetics. These molecules control the timing, placement, and degree of gene activation and are determined by a number of factors.
One way gene activation can be determined is by transcription factors. Transcription factors are specialized proteins that adhere to DNA sequences and can influence the expression of said DNA.
Although previous studies have made the connection between stress early on in life and certain mood conditions, such as depression, later in life the precise neurobiological mechanism has not been discovered 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,” said Dr. Catherine Peña, lead researcher on the study. “We discovered that disrupting maternal care of mice produces changes in levels of hundreds of genes in the ventral tegmental area (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,” she added.
The main regulator of this particular transcription factor is orthodenticle homeobox 2 (Otx2). The scientists on the study found that when mice pups were stressed during a specific age, between 10 and 20 days old, Otx2 was suppressed in the VTA. After the initial event, Otx2 levels eventually returned to normal but the period of suppression already started a chain reaction of gene changes that continued as the mouse aged. The researchers say this shows that childhood stress can disrupt development if it occurs at a particularly critical time.
However, this effect only becomes apparent after a second stressor occurs during adulthood. Only then does the mouse who experienced the Otx2 suppression during the critical period fall prey to depression-type behavior in adulthood.
Before the second stressor, all the adult mice, that is the ones who developed normally and those who had Otx2 suppressed, behaved normally during the study.
In order to fully test the role of Otx2 in stress susceptibility, scientists created viral tools to increase or decrease the molecule levels. This way they found that the suppression alone, even without an actual stressor, was enough to create the depression effect later in life.
“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,” said 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.”
Still, little is known about the periods of childhood development when adversity or stress may or may not be critical to brain development or in particular to the mood-regulating VAT region, say the scientists.
Yet, this study is the first of its kind in utilizing genome-wide instruments to determine how exactly an early stressor can alter VTA development and give new data about emotional evolution.
“This mouse paradigm will be useful for understanding 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 J. Nestler, M.D., Ph.D., 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.”
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