Understanding Cognitive Inflexibility in Depression

Chronic stress contributes to a range of mental health disorders, including major depressive disorder (MDD). At the core of these issues lies a critical function: cognitive flexibility. To better understand how stress can lead to cognitive inflexibility and pave the way for improved therapeutic options, John Mantsch, PhD, Florence J. Williams Professor and Chair of pharmacology and toxicology at the Medical College of Wisconsin (MCW) has been awarded a five-year $3.5M R01 grant from the National Institutes of Health (NIH).

The grant will fund a pioneering study titled “Chronic stress-induced REDD1 expression in prefrontal cortex and cognitive inflexibility,” led by Dr. Mantsch in collaboration with Marquette University. The research aims to uncover how chronic stress alters brain function at a cellular level and leads to cognitive rigidity—a key deficit in individuals with MDD.

The Value of Flexible Thinking

Cognitive flexibility is the ability to adapt behavior in response to changing environments. This function is essential for daily life. When impaired, it manifests as ruminative thinking, poor problem-solving and difficulty regulating emotions—challenges frequently seen in individuals with depression. The study seeks to identify the brain mechanisms that contribute to these deficits and how stress exacerbates them.

Researchers will focus on the prefrontal cortex (PFC), a brain region integral to rational decision-making and behavioral control. Stress is known to disrupt PFC function, but the exact pathways and mechanisms behind these changes remain unclear. The research team will investigate the role of a protein called REDD1, which has been found in elevated levels in individuals with MDD and may hold the key to understanding stress-related cognitive dysfunction.

A Collaborative, Multidisciplinary Approach

The study brings together a multidisciplinary team from MCW and Marquette University, combining expertise in behavioral science, systems neuroscience and molecular biology. Matt Hearing, PhD, associate professor of biomedical sciences in the Marquette University College of Health Sciences, a long-time collaborator of Dr. Mantsch, will play a key role in the project. By leveraging complementary skills, the team aims to examine how stress-induced changes in cellular structures like dendritic spines impact broader neural circuits and behavior.

“Our project is an example of how collaborative science can allow you to do more work and do it better,” says Dr. Mantsch. “Instead of just relying on what you have, you bring in the people who have what you need to solve the problem.”

Implications for Mental Health Treatment

Previous studies have shown sex-based differences in how chronic stress affects brain function, with male rodents appearing more susceptible to stress-induced cognitive deficits than females. The research team aims to explore these differences further and inform potential sex-specific therapeutic strategies.

Dr. Mantsch acknowledges that while animal models cannot fully replicate human depression, they provide valuable insights.

“There’s a big leap between rodent models and human conditions, but the behavioral and structural parallels are compelling,” he says. “This alignment has been a priority for the National Institute of Mental Health, and it’s one reason this project received enthusiastic support.”

The study has significant implications for the future of mental health treatment. REDD1 also appears to play a role in how promising treatments like ketamine and psychedelics work to alleviate depression. While these treatments have shown rapid antidepressant effects, they are not without limitations. Dr. Mantsch believes that understanding the pathways involved can inform the development of more precise therapies.

“Ketamine obviously has been put out there as a bit of a wonder drug, but it has its limitations,” Dr. Mantsch says. “The more we know about how it signals to produce changes in brain function that can address depression, the better. The goal is to target what ketamine does while eliminating its less desirable attributes.”

Beyond the Lab

Dr. Mantsch’s dedication to improving mental health outcomes extends beyond the laboratory. In Milwaukee, he collaborates with community partners to address health disparities, particularly in underserved populations. This dual focus on basic science and community health underscores his holistic approach to tackling mental health challenges.

Ultimately, this project represents a significant step forward in understanding the neural underpinnings of depression and cognitive deficits. By investigating how chronic stress alters the brain, Dr. Mantsch and his team aim to pave the way for new, more effective therapeutic strategies.

“Science doesn’t exist in a vacuum,” he says. “Our research institutions have a responsibility to not only advance knowledge but also ensure it translates into real-world impact. Whether it’s through drug development or public health initiatives, the ultimate goal is to improve lives.”