Experiencing stress in early life could prime your brain with a lifelong susceptibility to stress and depression by altering gene expression in the brain’s reward pathways, a new study found.

Image credits Bhakti Iyata.

It’s the gift that keeps on giving — even though you’d rather it stop. We are, of course, talking about stress. A new study from the Icahn School of Medicine at Mount Sinai reports that early-life stress may hard-wire a susceptibility to stress, mood fluctuations and even depression in the brain.

The study focused at how epigenetics can alter our ability to cope with stress. Epigenetics is basically our body’s way of fine-tuning DNA — by employing various molecules to regulate where, when, and how much certain genes are activated/expressed, our bodies can prompt pretty significant changes to what a gene does without changing the data is encodes. Epigenetic changes are handled in part by specialized proteins called transcription factors. These bind to specific sequences in our DNA and either promote or inhibit the expression of a gene.

We knew from previous studies that epigenetics play an important part in the way our brains develop. We also knew that early life stress increases the risk of subsequent depression and other syndromes — but why this happens, or if epigenetics plays a part, remained unanswered questions.

“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, and lead investigator of the study.

“We discovered that disrupting maternal care of mice produces changes in levels of hundreds of genes in the VTA [ventral tegmental area] 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.”

The team found that the transcription factor orthodenticle homeobox 2 (Otx2) acts as a sort of master regulator for these genetic changes. They showed how baby mice stressed in a sensitive period (between the 10th and 20th after birth) had suppressed Otx2 in their VTA. Its levels would recover by the time the rats reached adulthood, but that initial suppression period was enough to set epigenetic changes in motion which lasted well into adulthood. So stress in early life can disrupt the way a brain develops, at least as far as gene programming governed by Otx2 is concerned.

Sleeper stress

The full effect of these changes only becomes apparent as the adult mice experienced additional stress. While all mice behaved normally, to begin with, those who experienced stress early on were more likely to succumb to depression-associated behavior as adults after experiencing social stress.

Finally, the team developed a viral treatment to check whether Otx2 was indeed responsible for the changes. The viral vectors would either increase or decrease Otx2 levels in mice’s brains, and the team reports that a suppression of Otx2 in early life was “necessary and sufficient” for mice to show greater susceptibility to stress as adults. Not only does the protein alter our brains’ ability to deal with stress in the long run, but in the short term as well.

“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.”

This is the first study to use genetic data to understand how early development alters the development of the VTA and show how crucial it is for our ability to cope with stress and manage our emotions throughout life. However, more research needs to be done to pinpoint exactly which age intervals are key here.

The full paper “Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2” has been published in the journal Science.

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