More Brain Genes are Altered by Early-life Stress Than by a Head Injury

brain injury

When researchers began investigating whether early-life stress compounded the consequences of a childhood head injury on health and behavior later in life, they discovered something unexpected. Stress changed the activation level of many more genes in the brain than a head injury did in an animal research model.

Head injuries are known to be prevalent in young children, particularly from falls, and have been linked to mood disorders and social issues later in life. Adverse childhood experiences are also prevalent and can increase the risk of disease, mental illness, and substance abuse in adulthood.

“But we don’t know how those two things can interact. We wanted to understand whether experiencing a traumatic brain injury in the context of early life stress circumstances could modulate the response to the brain injury. And using an animal model allows us to really get into the mechanisms through which these two things might be impacting brain development as it’s occurring,”

said senior study author Kathryn Lenz, associate professor of psychology at The Ohio State University.

Don’t Underestimate Stress

The potential for early life stress to have long-term health effects may not be fully understood, according to this initial set of rat experiments, according to Lenz.

“We found many, many, many more genes were differentially expressed as a result of our early life stress manipulation than our traumatic brain injury manipulation. Stress is really powerful, and we shouldn’t understate the impact of early life stress on the developing brain. I think it tends to get dismissed, but it’s an incredibly important public health topic,”

Lenz said.

The research was presented in a poster Nov. 12, 2023 at Neuroscience 2023, the annual meeting of the Society for Neuroscience.

Hippocampal Gene Expression

In order to simulate the effects of adverse childhood experiences, which can include a range of potentially traumatic events, researchers temporarily separated newborn rats from their mothers on a daily basis for 14 days.

Stressed and non-stressed rats were given either a concussion-like head injury under anesthesia or no head injury on day 15, when rats are developmentally equal to toddlers. Three situations were compared to uninjured, non-stressed rats: stress alone, head injury alone, and stress combined with head injury.

Using single-nuclei RNA sequencing, first author Michaela Breach, a graduate student in Lenz’s lab, investigated the changes in gene expression in the hippocampal region of the animals’ brains later in the juvenile period.

Plasticity and Oxytocin

Stress alone and stress combined with traumatic brain injury (TBI) produced a few notable consequences. Both circumstances activated pathways in excitatory and inhibitory neurons linked with plasticity, which is the brain’s ability to adjust to all types of changes — mostly to improve flexibility, but sometimes when the changes are maladaptive, resulting in detrimental results.

“This may suggest that the brain is being opened up to a new period of vulnerability or is actively changing during this period of time when it could program later life deficits,”

Breach said.

Both settings had an influence on oxytocin signaling, a hormone associated with maternal behavior and social bonding. Stress alone and in combination with TBI stimulated this oxytocin pathway, while brain injury alone blocked it.

“Both stress and TBI are linked to abnormal social behavior, but we’re finding these differing effects with the oxytocin signaling. That demonstrates that the effect of stress might modulate how TBI is changing the brain since the combination treatment was different from TBI on its own. Oxytocin is involved in the response to stress and repair, so that may mean it could be an interesting modulator for us to pursue in the future,”

Breach added.

Risk-taking Behavior

Only rats that had suffered early-life stress were more likely to enter a wide-open space, which is a place where rodents usually feel vulnerable to predators, according to behavior tests conducted on adult rats.

“Overall, that suggests they might be taking more risks later in life, which is consistent with human data showing that early life stress can increase the risk for certain conditions like ADHD, which can be characterized by risk-taking behavior or substance use disorders,”

Breach said.

Lenz stated that additional proof of the need to address traumatic childhood experiences comes from behavior data that shows the negative effects of early-life stress.

“Things like social support and enrichment can buffer the effects of early-life stress — that has been shown in animal models and in people. I don’t think it can be over-emphasized how damaging early-life stressors can be if they’re not dealt with,”

she said.

The research was supported by Ohio State’s Chronic Brain Injury Institute, the Brain Injury Association of America, and a National Science Foundation Graduate Research Fellowship.