Zhu, Xiaoyue Aelita, Starosta, Sarah, Ferrer, Miriam, Hou, Junxiao, Chevy, Quentin, Lucantonio, Federica, Muñoz-Castañeda, Rodrigo, Zhang, Fengrui, Zang, Kaikai, Zhao, Xiang, Fiocchi, Francesca R, Bergstrom, Mason, Siebels, Aubrey A, Upin, Thomas, Wulf, Michael, Evans, Sarah, Kravitz, Alexxai V, Osten, Pavel, Janowitz, Tobias, Pignatelli, Marco, Kepecs, Adam (April 2025) A neuroimmune circuit mediates cancer cachexia-associated apathy. Science, 388 (6743). eadm8857. ISSN 0036-8075
Abstract
Cachexia, a severe wasting syndrome associated with inflammatory conditions, often leads to multiorgan failure and death. Patients with cachexia experience extreme fatigue, apathy, and clinical depression, yet the biological mechanisms underlying these behavioral symptoms and their relationship to the disease remain unclear. In a mouse cancer model, cachexia specifically induced increased effort-sensitivity, apathy-like symptoms through a cytokine-sensing brainstem-to-basal ganglia circuit. This neural circuit detects elevated interleukin-6 (IL-6) at cachexia onset and translates inflammatory signals into decreased mesolimbic dopamine, thereby increasing effort sensitivity. We alleviated these apathy-like symptoms by targeting key circuit nodes: administering an anti-IL-6 antibody treatment, ablating cytokine sensing in the brainstem, and optogenetically or pharmacologically boosting mesolimbic dopamine. Our findings uncovered a central neural circuit that senses systemic inflammation and orchestrates behavioral changes, providing mechanistic insights into the connection between chronic inflammation and depressive symptoms.
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