The fatigue and lack of motivation that many cancer patients experience at the end of their lives are considered an inevitable consequence of their physical health and extreme weight loss. But new Washington University School of Medicine’s new study in St. Louis challenges long-standing hypothesis, rather that these behavioral changes stem from specific inflammatory neurons in the brain.
The researchers reported in a study published on April 11 that they identified a direct link between cancer-related inflammation and loss of motivational features in advanced cancers. Using cancer-associated Cashicia to study mice, a typical disease that leads to muscle waste and weight loss, they discovered previously unknown pathways in the brain. This pathway feels inflammation and actively inhibits dopamine (the main driving force of motivation), resulting in apathy and loss of drive.
Even if cancer and weight loss persist, the blocking pathways restore motivation. This suggests that apathy can be treated separately from the disease itself.
“The implications of this study are profound,” said Adam Kepecs, PhD, professor of neuroscience and psychiatry, the study’s lead author. “We have discovered a direct brain mechanism where inflammation causes apathy in cancer to cause apathy, although we are able to recover the normal motivation of mice with cachexia as the cancer progresses.”
About 70% of patients with advanced cancer experience cachexia. In addition to physical decline, patients often suffer from severe fatigue, indifference and lack of motivation, which affect their overall quality of life.
To understand whether these psychological symptoms are side effects due to physical deterioration or are derived from different biological mechanisms, including Marco Pignatelli, MD, Assistant Professor of Psychiatry at Washu Medicine and Tobias Janowitz, MD, MD, MD, associate professor of Cold Spring Spring Harbour Laboratory, became Cancer cancaria cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia cancacia. They specifically target behavioral symptoms that have not been studied before and mapped the brain regions involved.
They found that the structure in the brain stem is part of the brain that controls important functions such as breathing and heart rate, and it is a sensor of inflammatory signals in the blood, especially a molecule called interleukin-6 (IL-6), which is elevated in cancer cachexia. When IL-6 levels rise, neurons in the brainstem region transmit signals through defined pathways that inhibit the release of dopamine release in the brain, which is key to motivation and reward. The resulting dopamine decrease effect is to reduce the motivation of the mice to exert their own activities.
To see if this response can treat lack of motivation and apathy, Kepecs and his colleagues tried two different approaches: They raise dopamine levels and block inflammatory neurons in the brainstem. Both methods eliminate or reduce the indifference in mice. The inflammatory disease also restores the animal’s motivation by treating mice with IL-6 antibodies similar to existing FDA-approved drugs for rheumatoid arthritis, and this finding suggests a potential treatment for psychological symptoms associated with advanced cancer.
“It is worth noting that even in later stages of illness, motivation is restored,” Pignatelli said. “This suggests that we can improve quality of life by targeting the brain circuit.”
Kepecs explains that for acute diseases, such as infections, this inflammatory-driven reduction in motivation may be adaptive and helps the body save energy to fight the disease. However, in chronic diseases such as cachexia, prolonged apathy (including reducing motivation for eating, moving, or socializing) can become harmful, and deteriorate health and quality of life. Because IL-6 (the inflammatory molecule that drives this effect) is elevated under many other conditions and the brain region involved is at the core of motivation, the same circuit can lead to apathy for multiple chronic diseases.
“This provides us with a new way to understand apathy in advanced cancer,” Kepecs said. “This is not only a by-product of physical decline, but a direct response to brain inflammation. This means we can potentially target potential biology to improve motivation and quality of life, even if the cancer itself is no longer treatable.”
Zhu XA, Starosta S, Ferrer M, Hou J, Chevy Q, Lucantonio F, Muñoz-Castañeda R, Zhang F, Zang K, Zhao X, Fiocchi FR, Bergstrom M, Siebels AA, Upin T, Wulf M, Evans S, Kravitz AV, Osten P, Janowitz T, Pignatelli M, Kepecs A. Neuroimmune circuit mediates cancer cache-related apathy. science. April 11, 2025. DOI: 10.1126/science.adm8857
This study was awarded by the National Institute of Child Health and Human Development (NIH), Forschungsgemeinschaft Grant DFG -STA 1544, Lacaixa, Mark Mark Mark Cancem for for Mark Cance CGCATF-2021/ 100019, and NIH/National Cancer Institute grant R37CA286477-01A1, Cancer Center Support grant 5P30CA045508, NIMH grant MH130610, the Taylor Family Institute for Innovative Psychiatric Research, the Hope Center Pilot Grant, the McDonnell Center for Systems Neuroscience Small Grant, and the NARSAD Young Investigator Grant 27102 and P&S Fund, Wustl BJC Investigator Award and NIH Grant DP1 MH14002. Content is only the author’s responsibility and does not necessarily represent the official view of NIH.
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