I’m still coming down from the high of watching some of the world’s best athletes in the 2022 Winter Olympics. Halfpipe snowboarder Kaishu Hirano of Japan set a new world record for the highest amplitude a snowboarder has soared out of a 22-foot snowboard halfpipe! And Swedish speed skater Nils van der Poel achieved a new Olympic record for 5000m and 10,000m speed skating!

While enormously entertaining for sports fans worldwide, these daring athletes perform these feats at great risk to their short- and long-term health. The most recent example is gold medal-winning American snowboarder Chloe Kim reporting that she sustained a concussion during her third run of this year’s games.

Kim’s injury is not uncommon – approximately 3.8 million concussions occur in just the United States alone from sports-related injuries. Ramesh Raghupathi, PhD, a professor in Drexel’s College of Medicine, who has studied concussions and other forms of traumatic brain injuries for decades, was recently senior author on a research letter that reveals new insights into why females are more at-risk for depression than males are after a concussion – and offers a new lead in developing treatment regimens to prevent depression that can occur after a traumatic brain injury.  

When the head makes sudden impact or is quickly shaken, a resulting traumatic brain injury may occur as the brain hits the surrounding skull, causing cell damage and dangerous chemical alterations. This partly explains why many studies show a link between concussion and depression. A concussion from a sports-related injury can raise the risk of depressive-like symptoms, a history of concussions can put someone at more than three times the risk of developing depression and depression is a risk factor for needing longer time to heal after concussion. But many questions remain about why females are more at risk and what mechanism causes this depression-like behavior.

In the latest study in the Journal of Neuroscience Research, using swim and maze tests, Raghupathi and colleagues found that female rats with past adolescent traumatic brain injury were more likely to develop depression-like behavior in adulthood than their male counterparts. They also found that this behavior – recorded six weeks after the injury – took place during the estrus phase of the reproductive cycle, which takes place after estrogen and progesterone hormone levels drop in the body and suggests a depression-like phenotype. 

The team took this knowledge a step further, blocking estrogen and progesterone receptors with a dose of the drugs tamoxifen and mifepristone, during the proestrus phase when these hormones would otherwise be at their highest levels.

The result? The team was able to prevent depression-like behaviors that previously occur only in specific phases of the reproductive cycle – right after the increase in estrogen and progesterone.

“Hormones play a critical role in regulating depression after a traumatic brain injury,” said Raghupathi. “Therapies that target these hormones may help alleviate or even prevent depression for millions of women and girls suffering from a history of these brain injuries.”

Previous rat studies on traumatic brain injury and depression tracked subjects for just two weeks after the injury. This current study instead goes further – tracking up to five to six weeks after injury to record behavioral changes that take longer to develop.

Raghupathi said the team witnessed these behavioral changes in female rats once they reached adulthood, necessitating the need for longer-term studies than those previously done.

The authors also note that they did not observe any lesions, alterations in tissue or changes at the cellular level in both male and female rats, and say this model helps find behavior changes that are impossible to catch with imaging techniques. Male rats did not exhibit any change in behaviors following the injury, but the authors suggest that might be due to milder injuries than in other previous studies.

Studying rats presents a unique challenge, as a menstrual cycle lasts for roughly 30 days and a rat’s is compacted across just five days. Additionally, testosterone levels fluctuate in male rats, but in female rats multiple hormones all have different timing of when they peak and drop.

The authors report that it’s a combination of injury and hormones in this estrous period that causes the behavior change—not the injury alone or the reproductive cycle alone. This knowledge should inform the next steps in research, such as studies on the individual influence of estrogen and progesterone and the interaction of hormones and neurotransmitter signals in inducing depression-like behaviors following a traumatic brain injury.

“If male and female rats experience the same injury – we find the male rats are more resistant,” said Raghupathi. “Regulating hormones during the proestrus phase may open up opportunities for more targeted treatment after a traumatic brain injury rather than the current prolonged prescribing of anti-depressants.”

Media interested in an interview with Raghupathi should contact Greg Richter at 215-895-2614 or gdr33@drexel.edu.

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