The fatigue and lack of motivation that many cancer patients experience near the end of life have been seen as the unavoidable consequences of their declining physical health and extreme weight loss. But new research from Washington University School of Medicine in St. Louis challenges that long-held assumption, showing instead that these behavioral changes stem from specific inflammation-sensing neurons in the brain.
In a study published April 11 in Science, the researchers report that they identified a direct connection between cancer-related inflammation and the loss of motivation characteristic of advanced cancer. Studying mice with cancer-linked cachexia, a condition typical of the disease that leads to muscle wasting and weight loss, they discovered a previously unrecognized pathway in the brain. This pathway senses inflammation and actively suppresses dopamine — a key driver of motivation — resulting in apathy and loss of drive.
Blocking the pathway restored motivation, even though the cancer and weight loss continued. This indicates that apathy can be treated separately from the disease itself.
“The implications of the research are profound,” said the study’s lead author, Adam Kepecs, PhD, a professor of neuroscience and of psychiatry at WashU Medicine. “We’ve uncovered a direct brain mechanism through which inflammation drives apathy in cancer, and we were able to restore normal motivation in mice with cachexia, despite ongoing inflammation as cancer progressed.”
About 70% of patients with advanced cancer experience cachexia. In addition to physical decline, patients often suffer from severe fatigue, apathy and a lack of motivation that affect their overall quality of life.
To understand whether these psychological symptoms are side effects that emerge from physical deterioration or whether they arise from distinct biological mechanisms, the research team, including Marco Pignatelli, MD, an assistant professor of psychiatry at WashU Medicine, and Tobias Janowitz, MD, PhD, an associate professor at Cold Spring Harbor Laboratory, turned to a well-validated mouse model of cancer cachexia. They focused specifically on behavioral symptoms, which had not previously been investigated, and mapped the brain regions involved.
They discovered that a structure in the brainstem, a part of the brain that controls vital functions such as breathing and heart rate, acts as a sensor for inflammatory signals in the bloodstream, particularly a molecule called interleukin-6 (IL-6), which is elevated in cancer cachexia. When IL-6 levels rise, neurons in this region of the brainstem transmit a signal through a defined pathway that suppresses dopamine release in a part of the brain called the nucleus accumbens, which is key for motivation and reward. The resulting drop in dopamine had the effect of making the mice less motivated to exert themselves to complete activities.