Experiencing stress leads to a suite of rapid physiological changes, and over time, the body can acclimate to the stress, eventually changing an individual's baseline brain state. To improve understanding of the changes in the brain and body during acclimation to stress using a mouse model, the U.S. National Institutes of Health's National Institute of General Medical Sciences has awarded a five-year, $2 million grant to Grayson Sipe, assistant professor of biology in the Penn State Eberly College of Science.
"We tend to think of the body's normal resting state as a sort of baseline that it returns to after day-to-day experiences like eating, exercising, sleeping or short-term experiences like getting sick," said Sipe, who is also an assistant professor of biomedical engineering in the College of Engineering. "But when life changes dramatically - when you move to a new area or you're getting used to your leg being in a cast - or otherwise gets stressful, that baseline might shift to a new normal once you acclimate, a process called allostasis. In our research, we are broadly interested in how the brain and the rest of the body acclimate to stress, including how that new allostasis is established and how one's sense of control over the situation might influence how well they acclimate to stress. This also has implications for new baselines that might emerge with addiction and stress disorders."
Sipe, who specializes in neurobiology, is particularly interested in studying brain cells called astrocytes. Although neurons, the primary messengers in the brain, are more commonly studied, astrocytes are dynamic partners with neurons and are critical in maintaining a healthy brain. Sipe said astrocytes have more recently been implicated in changing brain states across behaviors, but not much is known about how they operate in this context.
"One of the interesting things about astrocytes is that they communicate with so many other elements in the brain, including neurons, blood vessels, immune cells and neuromodulators," he said. "We want to move beyond thinking about brain states as being isolated in the brain. We want to see how much of these changes are being coordinated across the body."
Sipe and his team will use a mouse-model system to study astrocytes as mice experience the mild stress of acclimating to a new environment. The team will look at a wide range of other changes in the brain and body during this acclimation period, including the rate that signals are sent from the brain to the organs, hormone circulation, cardiovascular dynamics, changes to signaling and microorganisms in the gut, and several measures of behavior.
"It's not just the brain that communicates with the organs and limbs, but the rest of the body also shares information back with the brain, like when your gut tells you you're hungry," Sipe said. "We plan to investigate this bi-directional communication during stress to have a truly comprehensive understanding of the acclimation process."
Sipe said that many organs have cells that are genetically similar to astrocytes, and although they have different shapes and other characteristics, they may play an important role in communication with the brain and synchronizing the whole body during stress acclimation. Because these cells are constantly in motion as an animal moves, Sipe is working with Tao Zhou, assistant professor of engineering science and mechanics in the Penn State College of Engineering, to develop a new way to consistently monitor the activity of these astrocyte-like cells around the gut.
"Ultimately, we hope to gain a more wholistic understanding of how the brain and body work together to deal with stress," Sipe said. "If we can identify cells or signaling pathways responsible for changing states under stress, we might be able to target those with drugs, for example for treatment of addiction or stress disorders. We're also interested in why some people respond better to stress than others. Improving our understanding of how the body acclimates to stress - and how and why that might differ among individuals - might also eventually have implications for personalized medicine."
Sipe and his lab are also interested in the psychological component to stress acclimation. As the mice adapt to their new environment, they can choose to run on a mouse-sized treadmill, and the researchers can provide a corresponding visual stimulus - like visuals of running down a hallway - through virtual reality.
"This exercise and virtual environment provide enrichment to the animal, but what happens when the visuals don't respond the way you expect?" he said "For example, if the room stands still while you are running, like a glitch in the matrix? We predict that having a sense of control over your environment will improve the process of acclimating to stress."
If this prediction holds true, Sipe said this could have implications for humans as well. For example, if a healthcare provider is sharing a difficult diagnosis with a patient, they may have better outcomes if they are provided a sense of control, or a choice. Although this has been shown in a variety of medical contexts, the underlying physiological mechanisms are poorly understood.
"This work could inform how we provided diagnoses in a way that gives people the feeling of autonomy," he said. "Other interventions could even be done with virtual reality, such as how virtual reality is used to help some individuals with phobias. This is all very early work, but we hope to get a much better understanding of how the whole body responds to stress and the role of astrocytes and psychology, which one day may impact how we as humans deal with our frequently stressful environments."
