Novel neuroscience research targets social loss therapy

Effectively managing social stressors and trauma leads to healthier individuals and healthier communities. Some people are “wired” to handle stress, while others could use some help. KU School of Pharmacy Associate Professor of Pharmacology & Toxicology Adam Smith is uniquely exploring the brain science of social stress. Smith and his graduate student researchers are looking for ways that pharmacology can intersect with neurobiology with a goal of finding potential therapies that can help people better navigate stress.

Research of this type takes time, says Smith. Some of his research is at the basic science level that could take 10-15 years to better understand the components and adapt it for clinical use. Some of his group’s discovery is closer to novel therapeutic development that could see a 5-10 year timeline before a clinical treatment phase.

Smith’s research is primarily being funded by the National Institutes of Health. Since 2019, he has secured more than $5 million from NIH to investigate the complex relationship between social stress, the brain and social networks. The focus of that research is with prairie voles, in part because they are socially monogamous—choosing partners for life. They have similar social structures to humans and their reactions to social stressors can inform human behavior.

Like in humans, prairie voles have chemical reactions in their brain cells as they respond to different stimulus, or in Smith’s research, social stressors. “A neuron communicates through chemical signals,” says Smith. “These chemicals are ions that have a positive or negative charge. A predominate ion is calcium, and researchers have developed methods to tag calcium events in cells with a fluorescent protein so that anytime a neuron is active, it essentially glows—it gives a discharge of fluorescent light.”

That light can be monitored and recorded in real time with in vivo devices. This can show how a vole’s brain responds to events, such as a partner being removed, or neurochemical agent being introduced, such as neurotransmitters like dopamine or oxytocin-based suppressants. One device is a miniature microscope tiny enough to be attached to the head of a prairie vole. It has a fiberoptic cable that connects to a receiver that can capture live response images from the brain. By better understanding how the brain responds to broad and specific inputs, researchers are moving toward therapies that could help humans more effectively cope with loneliness, loss and trauma.

Oxytocin is a hormone and neuropeptide released naturally in response to stress. Smith’s research with male and female prairie voles introduced therapeutic treatments of oxytocin. In females, but not males, the oxytocin treatments proved to be very effective in promoting more typical social engagement after a stress experience.

“As we understand the biology of stress systems, we get to understand the potential for therapeutic targets going forward,” Smith said. “There are currently no FDA-approved drugs available for any sort of treatment through the oxytocin system, as it relates to mental health. Knowing that this system is key to regulating social anxiety in our animal model could open a whole new class of therapeutics towards anxiety management and anxiety disorder treatments in humans.”

Most of the research around social loss or trauma has been in the field of human psychology. Limited research has been approached from the neuroscience of grief. Smith says technology such as functional magnetic resonance imaging (fMRI), often used to plan brain surgeries in humans, is informing his research.

By using fMRI with prairie vole subjects whose partners had been taken away, Smith’s team was able to detect increased blood flow or hyperactivity in certain parts of the brain. With additional testing, they found the hyperactivity “was associated with an increase of dopamine in that brain region.

“We've been trying to associate this increased activity to the experience in humans. In human research literature, this symptom of grief is called yearning. It is highly associated to the activity of these same motivation centers of the brain. We've been looking at how the dopamine system is influencing this whole process, and this is giving us a novel mechanism that we've never studied, suggesting that the motivation that we experience during separation from others is actually driven through this dopamine signal in these brain areas that are responsible for emotional pain and motivation.”

Smith says there are less than 10 labs in the U.S. studying animal models of social loss. He’s excited about the possibilities of improving human mental health through these experiments and possibly even physical health.

“If you’re 50 years or older and lose a spouse, literature suggests you’re in a high-risk pool for heart attack, stroke, immune specific infections and certain cancers,” says Smith. “You don’t want to numb the world to the loss of a loved one, but for individuals who carry that loss and are struggling to resolve that pain, they can stay at a high risk for these health conditions.”

Dopamine is a “tricky thing to modulate in the brain,” according to Smith, “so with some of this targeted research, we’re going to have to couple that with pharmacology to start to see if therapy would produce benefits or have side effects or potential risks.

“Until we started doing this work, there were no targets of neurochemical systems in the brain to even look at. We're among the first to start showing all this. We’re at the beginning steps of having a better understanding of the science that we can then convert into potential therapy.”

The School of Pharmacy is well known for its skill in drug development having helped formulate and deliver more than two dozen FDA-approved drug products in collaboration with pharmaceutical companies. With some help from the prairie vole, Smith is hoping to add to that tradition while improving the mental and physical health of humans.