Learning about resilience to stress

Some people with chronic stress are more likely to develop anxiety disorders, post-traumatic stress disorder, or depression, while others are more resilient. Why is that? This is a question that Seema Bhatnagar, professor of anesthesiology and critical care in the Perelman School of Medicine, is trying to understand through animal models in the Bhatnagar Lab of Stress Neurobiology.

“What in the brain are the mechanisms through which some individuals stay resilient to stress or become more vulnerable?” Bhatnagar asks.

This summer, she had assistance in this work from second-year students Daniella Oyenuga and Eshu Venkataswamy, as part of the Penn Undergraduate Research Mentoring program. Each PURM student receives a $5,000 award from the Center for Undergraduate Research & Fellowships for the 10-week program. Bhatnagar says PURM benefits students by exposing them to high-quality research experiences at Penn, and the energy and curiosity of undergraduate students also benefits the host lab because students ask questions that can influence future research.

Oyenuga, who is from Canada and plans to major in psychology or neuroscience, says she was drawn to the resilience part of the project, wanting to know why some people come out stronger from a situation than others. She says it was interesting to learn about resiliency from a neurobiological standpoint, considering she had previously looked at it through a psychological lens.

Venkataswamy, a sociology and finance major from Athens, Pennsylvania, was already working with the Bhatnagar Lab in the spring semester. He saw this project listed through CURF and reached out, wanting an introduction to research and to stay in Philadelphia for the summer.

Bhatnagar says, “We’re a basic science lab. We’re trying to find new substrates in the brain that can tell us about individuals going through stress.” She says there is no single gene or molecule that predicts resilience, that multiple genes and circuits are involved. 

The ultimate goals, Bhatnagar says, are to identify ways to promote resilience to life stressors based on neurobiological findings and to identify blood biomarkers that indicate whether a person will be vulnerable to the effects of stress, which could help them get treatment soon after trauma. To accomplish this, she studies what is happening in the brains of rats who are active and resist aggressors compared to those who are passive and give up, and says the latter show behaviors that she thinks are important in understanding anxiety and depression in humans.

This summer, Venkataswamy worked on a study in which rats were exposed to social stress through aggression from another animal. Some animals respond to such stress through active coping and resist being defeated by the aggressor, whereas other animals are passive and submit quickly. The passive animals also show behaviors reminiscent of anxiety and depression. 

The Bhatnagar lab has identified receptors in the brain that promote resilience and others that underlie vulnerability. Venkataswamy looked at the role of the brain’s orexin receptors in regulating those behavioral responses.

“If you experience a traumatic event, that’s the receptor that will make it so the memory of that is really exaggerated,” Venkataswamy says. Researchers were trying to figure out what would happen if they blocked the receptor’s activity and how it would affect passive coping to social stress.

Whereas Venkataswamy studied social aggression, Oyenuga looked at responses to mild cognitive stress. Bhatnagar says when someone is re-exposed to something that will not harm them, it is important to reduce their response, a process called habituation. But she says in humans, “It goes awry sometimes. People with PTSD are not able to just reduce their responses to stimuli when others go, ‘I know what that is.’”

Oyenuga analyzed rats’ ability to habituate to repeated mild, cognitive stress and assessed neuron activity in brain regions important for habituation. She explains that the CRISPR technique was used to downregulate a molecule that regulates the S1PR3 gene, which promotes resilience through anti-inflammatory effects in the brain. These were compared to wild type brains, meaning nothing happened to them. 

She says the rats were exposed to stress for 30 minutes each day for five days, and researchers took blood to see if the rats habituated after five days. Oyenuga says if stress hormone levels decreased from day one to day five, that indicates habituation, which indicates resilience to stress.

Bhatnagar says that, while deleting the gene made rats more vulnerable in the social defeat model that Venkataswamy worked on, animals with the gene deletion habituated just fine, though there were differences in brain activity. These findings suggest that resilience can be achieved through different neural mechanisms depending on the stressor. Anti-inflammatory effects of S1PR3 are important for resilience to social stress but may not be as important in mild, cognitive stress.

“Resilience and vulnerability are not traits of individuals; they’re dependent on the environment, on the past experiences of the individual, and on the stressful situation,” Bhatnagar says. “Just because we’re resilient under one situation doesn't mean we’re resilient in all areas of our lives. That’s certainly true of humans. Our goal is to understand how the brain changes with stressful and traumatic experiences so we can promote resilience to such experiences.”