Life-long burden

Scientists have known for some time that people who experience early childhood adversity are more prone to developing health and behavioral issues in adulthood, but the brain mechanisms behind these disparities are not well understood.

In new research published in the Proceedings of the National Academy of Sciences, a team of University of New Mexico School of Medicine researchers describe how adverse childhood experiences appear to disrupt activity across multiple brain networks when threats are encountered later in life.

“The big question we're looking at is really the neural underpinnings of mental health vulnerabilities in adulthood that come after early life adverse experiences,” said Taylor Uselman, a doctoral student who processed and analyzed brain imaging data and served as lead author on the paper.

“Many studies have seen that adverse childhood experiences, like neglect and abuse, can lead to many different physical and mental health outcomes later in life, like addiction, depression and anxiety.”

The UNM study, conducted in mice by Uselman, Elaine Bearer, MD, PhD, Distinguished Professor of Pathology, and Russell E. Jacobs, PhD, an affiliate faculty member in Pathology and professor at the University of Southern California, found that early life adversity predisposed them to an exaggerated response to threats later in life.

Brain scans showed hyper-activation of the amygdala and the locus coeruleus – brain regions involved in processing fear – when the mice were exposed to a threat as adults, he said. There was also greater activity in other areas of the brain that modulate the brain and body’s stress response using neurotransmitters like dopamine, noradrenaline and serotonin.

The study compared mice that had been subjected to adversity in infancy with those that had normal upbringings. The mothers of mice in the first group were deprived of sufficient nesting materials while raising their pups, triggering anxious behavior that interfered with their ability to properly nurture their offspring.

When those mice reached adulthood, they were exposed to a predator threat – the odor of fox urine – which predictably triggered a strong fear response. Normally raised mice were also fearful following the exposure, Uselman said.

All of the mice were then injected with manganese, a metallic element, before undergoing MRI scans while under sedation. The manganese molecules were taken up by active neurons in the mouse brains, with the densest accumulations highlighting the most active brain regions on the scans, he said. The use of manganese as a contrast agent in MRI studies is a research technique developed in part by Jacobs and Bearer.

“We coupled this brain-wide imaging with advanced computational analysis to get more detailed information,” Uselman said. “This bridges a major gap. These types of studies are not feasible in humans, and in mice, researchers often only look at one or two brain regions at a time. We wanted to look at every brain region in mice over a series of experiences to fill in missing information that is not possible to study for human conditions.”

Although both sets of mice showed a fear response to the predator threat, those that had experienced early life adversity displayed abnormal brain activity, compared with the normally raised mice, Uselman said.

Nine days after the acute threat, the mice with abnormal upbringings still showed heightened neural activity in various areas of the brain; the locus coeruleus, the posterior amygdala, the hippocampus and different parts of the hypothalamus.

“These results reveal functional imbalances that arise between multiple brain systems after early life adversity,” Uselman said.

Mouse brains differ from human brains in many respects, and scientists are cautious about extrapolating the findings in mice to people, he added, but there is considerable similarity across species, particularly in deeper brain regions that make up the ‘reptilian’ brain.

“You see a lot of these deeper brain regions that are activated, and these neuro-regulatory systems are highly conserved across different species,” Uselman said. “The systems that seem to be disrupted due to a threatening experience and early life adversity are also very similar from mice to humans.”

More research is needed, Uselman said, but the study results suggest that there are certain time points during neural development when the brain is most sensitive to traumatic experiences.

“If you could identify that in humans, you would know whether these people might be vulnerable to threat and use that as a diagnostic marker,” he said.

That, in turn, could lead to potential interventions and treatments.

“If we understand what regions are sensitized to threat, we can also potentially treat them in a way that even if they were exposed to a threat or some fearful experience, they would not develop depression or anxiety or PTSD.”