Investigators Study Orexins' Role in Resilience to Stress

Chronic stress, whether it is from illness, interpersonal relationships, or other social stressors, can have a significant influence on the brain and body. Yet, only some individuals develop illness in response to chronic stress, such as anxiety, depression, and post-traumatic stress disorder (PTSD).

Why do some of us get stressed out while others seem to roll with life’s punches? That is the big question in the field of stress neurobiology, and to get closer to the answer, researchers at The Children’s Hospital of Philadelphia are exploring peptides called orexins as potential mediators of resilience or vulnerability to the effects of stress.

“If we could understand better the brain mechanisms that lead to vulnerability to stress, then we could either prevent the effects of stress from happening or help treat individuals who are sick and even try to identify them before they get sick,” said Seema Bhatnagar, PhD, an associate professor in the CHOP Research Institute’s Division of Stress Neurobiology.

Scientists first described orexins about 17 years ago and found that these neurochemicals are important for arousal, sleep, vigilance, and feeding. Orexins are made in the hypothalamus, but they have widespread projections to other areas of the brain. Growing evidence suggests that orexins play a role in people’s ability to be alert and respond to stressful stimulus.

In a new research project recently funded by The National Institute of Mental Health, Dr. Bhatnagar’s study team will use a model of repeated social defeat in young adult male rats in which two distinct subpopulations emerge with different coping strategies. When exposed for a week to a larger, more aggressive rat that is territorial, some animals that show anxiety and depressive-type behaviors will give up quickly and assume a defeat posture. Others are more active in resisting the defeat and appear more resilient. Based on the researchers’ preliminary data, it appears that the resilient population exhibits lower orexin expression.

“If we’re correct that orexins are important in vulnerability and resilience, you could imagine developing drugs that inhibit orexin release could be used in a situation of chronic stress or trauma to decrease arousal and maybe prevent the effects of stress from happening,” Dr. Bhatnagar said.

The study team will use an emerging technology called DREADDs (designer receptors exclusively activated or inhibited by designer drugs) to modulate orexin release. These viral vectors have mutated receptors that are either stimulatory or inhibitory, and they are injected into the brain where they enter orexin cells. The researchers can target the viral vectors through a drug administered peripherally to stimulate or inhibit the population of orexin cells. They will observe if this shifts the animals’ phenotype during periods of stress. Can vulnerable animals become more resilient and vice versa? In other experiments, the investigators also will look at which key brain regions are facilitating the effects that they are seeing in the resilient and vulnerable animals.

While many other neurochemicals are being studied for their potential role in mediating stress resilience or vulnerability, the CHOP researchers’ exploratory research is novel because it is the first to center on orexins. The early data they gathered on orexins came from a study supported by the Defense Advanced Research Projects Agency, which focused on preclinical studies examining neural substrates of arousal and on clinical studies with military service members with PTSD through collaborations with the Philadelphia VA Medical Center. Dr. Bhatnagar also is a co-primary investigator of National Institutes of Health-funded study on adolescent stress that eventually could provide insights into the specific involvement of orexins.

“There’s very clear literature that stress in early life has long-lasting impact for producing depression and anxiety,” Dr. Bhatnagar said. “We don’t know if the orexin system is important in mediating resilience or vulnerability to early life stress as it develops across the lifespan. We hope to gather enough data to expand our research to look at the pediatric and adolescent periods.”