The exhaustion and absence of drive that numerous cancer patients face toward the end of life have been perceived as inevitable results of their diminishing physical condition and significant weight reduction. However, new findings from Washington University School of Medicine in St. Louis contest this long-standing belief, revealing instead that these behavioral alterations originate from specific inflammation-detecting neurons in the brain.
In a study published on April 11 in Science, the researchers noted a direct link between cancer-associated inflammation and the loss of motivation often observed in advanced cancer. By examining mice afflicted with cancer-induced cachexia, a condition commonly associated with the illness that causes muscle wastage and weight loss, they uncovered a previously unidentified pathway in the brain. This pathway detects inflammation and actively dampens dopamine — a crucial element of motivation — leading to disinterest and lack of initiative.
Inhibiting the pathway reinstated motivation, even as cancer progression and weight deterioration persisted. This suggests that apathy can be addressed independently of the disease itself.
“The ramifications of this study are significant,” remarked the principal author, Adam Kepecs, PhD, a neuroscience and psychiatry professor at WashU Medicine. “We’ve revealed a specific brain mechanism through which inflammation promotes apathy in cancer, and we successfully restored typical motivation in mice with cachexia, despite the continued inflammation as cancer advanced.”
Approximately 70% of advanced cancer patients endure cachexia. Beyond physical deterioration, these individuals frequently encounter intense fatigue, disinterest, and a lack of motivation that negatively impacts their overall quality of life.
To determine if these psychological symptoms are merely side effects stemming from physical decline or if they originate from separate biological processes, the research team — which includes Marco Pignatelli, MD, an assistant professor of psychiatry at WashU Medicine, and Tobias Janowitz, MD, PhD, an associate professor at Cold Spring Harbor Laboratory — utilized a well-established mouse model of cancer cachexia. They specifically concentrated on behavioral symptoms, which had not been previously explored, and mapped the brain areas involved.
The researchers discovered that a structure in the brainstem, which governs essential functions such as respiration and heart rate, serves as a detector for inflammatory signals in the bloodstream, particularly a molecule known as interleukin-6 (IL-6), which is increased in cancer cachexia. When IL-6 levels elevate, neurons in this area of the brainstem send a signal via a defined pathway that inhibits dopamine release in a region of the brain known as the nucleus accumbens, which plays a vital role in motivation and reward. The ensuing decrease in dopamine resulted in reduced motivation in the mice to engage in activities.
To test whether manipulating this response could alleviate the lack of motivation and apathy, Kepecs and his colleagues attempted two distinct methods: they enhanced dopamine levels and inhibited inflammation-sensitive neurons in the brainstem. Both strategies either eliminated or diminished apathy in the mice. Treating the mice with an IL-6 antibody, akin to an existing FDA-approved medication for rheumatoid arthritis, also reinstated the animal’s motivation, indicating a potential therapeutic option for the psychological symptoms linked with advanced cancer.
“What’s extraordinary is that motivation was restored even in end-stage disease,” remarked Pignatelli. “This implies we might be able to enhance quality of life by targeting the brain circuitry.”
For acute conditions, such as infections, this inflammation-induced reduction in motivation might be beneficial, aiding the body to conserve energy to combat the illness, explained Kepecs. However, in chronic cases like cachexia, prolonged apathy — such as diminished enthusiasm to eat, move, or socialize — can become detrimental, exacerbating health issues and diminishing quality of life. Given that IL-6 — the inflammatory molecule driving this effect — is increased in various other ailments and the brain regions involved are crucial for motivation, this same circuit likely plays a role in apathy across a spectrum of chronic diseases.
“This offers us a new perspective on apathy in advanced cancer,” stated Kepecs. “It’s not merely a byproduct of physical deterioration but a direct reaction to inflammation in the brain. This means we could potentially target the underlying biology to enhance motivation and quality of life — even when the cancer itself is no longer amenable to treatment.”
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. A neuroimmune circuit mediates cancer cachexia-associated apathy. Science. April 11, 2025. DOI: 10.1126/science.adm8857
This investigation was supported by the National Institute of Child Health and Human Development of the National Institutes of Health (NIH) grant P50 HD103525, Deutsche Forschungsgemeinschaft grant DFG -STA 1544, LaCaixa, the Mark Foundation for Cancer Research grant 20-028-EDV, the Simons Foundation, Cancer Grand Challenges, NIH grant 1OT2CA278690-01, CRUK: 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, a WUSTL BJC investigator award and NIH grant DP1 MH14002. The content solely reflects the authors’ views and does not necessarily represent the official opinions of the NIH.
About Washington University School of Medicine
WashU Medicine is a prominent entity in academic medicine, encompassing biomedical research, patient care, and educational initiatives with a faculty of 2,900 individuals. Its National Institutes of Health (NIH) research funding portfolio ranks second among U.S. medical schools and has increased by 56% over the last seven years. In conjunction with institutional investment, WashU Medicine allocates well over $1 billion annually to innovative basic and clinical research and training. Its faculty practice consistently ranks within the top five nationally, with over 1,900 faculty physicians practicing across 130 locations, also serving as the medical teams for Barnes-Jewish and St. Louis Children’s hospitals under BJC HealthCare. WashU Medicine boasts a rich history in MD/PhD education, having recently dedicated $100 million to scholarship programs and curriculum revitalization for its medical students, and is home to outstanding training programs across every medical subspecialty, as well as in physical therapy, occupational therapy, and audiology and communications sciences.
Originally published on the WashU Medicine website
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