Mapping the Brain Toward Better Treatments for Depression

Believe it or not, stress can be good and motivating. However, when regularly experienced over a lengthier period of time, chronic stress can rewire the brain and negatively change how someone perceives and responds to his or her environment. 

The neurobiology of stress and its effects on the brain is at the core of the Lemos Laboratory led by Julia Lemos, PhD, an assistant professor in the Department of Neuroscience at the University of Minnesota Medical School and member of the University’s Medical Discovery Team on Addiction. In April, Dr. Lemos received a five-year, $1.6 million grant from the National Institute of Mental Health to dig into the scientific idea that chronic stress can make someone more vulnerable to different diseases, including addiction, anxiety and depression.

“You might not necessarily die from depression, but your ability to work, function and contribute productively to society is greatly diminished over a very long period of time,” she said. “When you think of the years that it takes you out of commission, depression is actually one of the most costly and highest disease burdens of all the diseases in the world, according to the World Health Organization.”

Current, first-line treatments for depression, known as SSRIs or selective serotonin reuptake inhibitors, only benefit about half of patients with depression, according to Dr. Lemos. Developing a holistic view of the brain’s state in those with depression may be the key in finding new treatments or therapies—an approach, blending neuroscience and mental health, that she hopes will prove useful.

The Study

Using four different mouse groups—a male and female control group and a male and female experimental group—Dr. Lemos will explore how the concept of “uncertainty” changes the brain state of each group.

“One of the things that we found that is most distressing across the animal kingdom up to humans is uncertainty—just look at how COVID-19 has impacted our lives for that very reason,” Dr. Lemos said. “If you know that every day a siren is going to go off at 6 a.m., that might be really stressful the first couple of days it happens, but then eventually you habituate and go on with your life. But, if every day, you don’t know what’s going to happen, then that’s pretty stressful.”

Dr. Lemos says the experimental mouse groups will be “unpredictably annoyed” over a period of six weeks and experience random acts like wet bedding, lights staying on all night or short periods of restraint—all happening without notice. After six weeks, all four groups will be exposed to rewarding stimuli (like high-fat, sweet foods) as well as neutral stimuli and aversive stimuli (like predator odors). 

“Then, we see how their brain responded using a technique that helps us look at the whole brain. We will be able to see the areas of the brain that light up in response to these different stimuli, and then we can see how that’s different between the control groups and the chronically stressed (experimental) groups,” Dr. Lemos said.

She predicts that the experimental groups will be more responsive and active to negative stimuli and less responsive toward rewarding stimuli—mimicking the brain state of depression.

“The idea is to identify those circuits within the whole brain that are particularly affected by stress,” Dr. Lemos said. “Once you understand how the brain is changed in response to chronic stress, then you can see whether pharmacological therapy or behavior therapy reverses it back to a normal brain state. But first, we want to understand what gets messed up as a result of chronic stress.”

The Impact

Unlike other neurological disorders, mental illnesses don’t show their presence through tumors or dying brain cells. Because of that, Dr. Lemos says scientists have started researching the brain as a roadmap, rather than seeing it as a collection of “compartments.” 

“If you think of the brain as a roadmap, with other neurological conditions, you can see when the bridge is out or something’s been blown up,” she said. “In mental health disorders, it’s more of a rewiring of your brain, so some pathways (or roads) get amplified or diminished when they shouldn’t be. That’s the shift in mental health—to look at the map of the whole brain and see how it’s altered after stress.”

For those with depression, she predicts that some SSRI users may respond to the drug because they do have an issue with their serotonin system.

“But, it could be that in another portion of people, what’s wrong for them is that their reward and motivational circuitry is messed up, and they would benefit from a different type of therapy,” Dr. Lemos said. “That’s why we’re looking at the whole brain. The idea is that, if you reverse the whole brain state back to a normal condition, that might actually be more effective for those people.”

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