For the first time, researchers have been able to study in a controlled environment the long term effects of early-life stress on the developing brain.
While research has previously indicated that brain development is governed by more than just genetics, a team of researchers from universities and medical centers across the globe, including from the department of psychiatry at the School of Medicine, was able to verify this directly by exposing macaque monkeys to stress early in their lives and monitoring their brain development with brain scans into late adulthood. They found that the animals’ brain structure had been altered — mirroring effects that were historically thought to be genetic — to look more like the brains of human patients with depression. The study was published in Frontiers in Behavioral Neuroscience on Oct. 6.
“Early-life stress sets the stage for the way the brain develops,” said Jeremy Coplan, professor of psychiatry at SUNY Downstate Medical Center and lead author of the paper.
Twelve macaque monkeys were exposed to stress by being fed on a “variable foraging demand” schedule, in which mothers of infant macaques had plentiful amounts of food for two weeks followed by scarce amounts of food for the next two. That pattern was continued for four months. While there was always enough food available for the macaques — and their weights remained the same as a separate control group fed regularly — the mothers would have to work harder to find food in a simulated foraging environment, preventing them from spending time with their infants. After infancy, the variable foraging demand schedule was replaced with a continuous one — identical to the demand schedule of the control macaques.
When the infant macaques reached adulthood, the investigators scanned their brains with an MRI and found that the monkeys’ left amygdalar volumes, on average, were greater than that of the control group. The amygdala is a primary player in emotional reactions and memory formation.
But not all monkeys responded to early-life stress similarly. Those who had the shorter version of serotonin transport genes — which have been linked to increased rates of depression in humans — and were on the variable foraging demand schedule had greater amygdalar volumes than both macaques with the longer version of the gene who were placed in the treatment group and those in the control group. This suggests that genes only partially govern brain structure, while environmental factors can influence the expression of those genes, said Joan Kaufman, professor of psychiatry at the School of Medicine and co-author of the study.
“We’re learning not just that variation in genes is important to understanding individual differences in outcome, but we’re also starting to learn how experience affects gene expression through epigenetic changes,” she said.
The researchers, hoping to see if early life stress affects responses to perceived threats, also found behavioral differences in how the macaques from different foraging groups responded to an “intruder” — a researcher walking into the room and making eye contact with them. Those with larger amygdalas and the shorter serotonin transport gene acted more timidly towards the perceived threat than did their neurotypical peers, who acted aggressively.
In fact, Coplan said, some research suggests that while most areas of the brain atrophy under stress, the amydala — integral in fear response — creates more connections.
The study supports earlier research indicating that early-life stress in humans can affect brain development, specifically studies which considered stressors like mistreatment, having a chronically depressed caretaker and being raised in an institution. But this study is the first in which researchers have been able to exercise complete control of subjects’ experiences throughout the entirety of their lives. Additionally, because the macaques were a part of the study for their whole lives, the researchers were able to collect much more data than many other studies, measuring chemical and cellular responses to early life stress as well.
Arie Kaffman, a research scientist in psychiatry at the medical school and a study co-author, said this study was important because it gave researchers the chance to examine a model for human response to early-life stress through a primate analog in a controlled environment.
“What’s really exciting about this growing research is that we used to think of genetic effects as being fixed, and what the research is highlighting is that there is a plasticity in brain development, and there is a genomic plasticity,” Kaufmann said. “It’s turned our thinking about some of these things upside down. We used to think that if you need to change something that affects brain development, it has to be drugs or biological, but we are now learning experience can alter [brain development].”
Coplan said that he intends to publish the results of a neurogenesis examination, in which he found that increased amygdalar volumes correlated with decreased neurogenesis — the creation of new brain cells — in the monkeys’ hippocampi, a brain structure critical to the formation of memory. Coplan said he believes this is because neurogenesis for memory formation is a calorically intensive process, and if food is scare or foraging is dangerous, the brain may adapt by not building as many neurons.
He added that this same trait in humans is a maladaptation because, while many may undergo serious stress in early life, it is unlikely they will face food shortages later on.
“The next step is to really understand the cellular and molecular mechanism that is responsible for the increase in the size of the amygdala,” Kaffman said. “The amygdala is such an important hub in terms of modifying the fearful response.”
It has previously been found that adults with depression who were exposed to stressed early in life are less likely to respond to evidence-based treatment, and their depression may have a different biological cause than others’. Antidepressants, namely Prozac, have been shown to combat this sort of depression and also to promote neurogenesis.
According to the Centers for Disease Control and Prevention, about 6.7 percent of American adults suffer from depression in any given year.