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
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA.
Neuroscience Graduate Program, Washington University School of Medicine, St. Louis, MO, USA.
Science. 2025 Apr 11;388(6743):eadm8857. doi: 10.1126/science.adm8857.
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.
恶病质是一种与炎症性疾病相关的严重消瘦综合征，常导致多器官功能衰竭和死亡。恶病质患者会经历极度疲劳、冷漠和临床抑郁，然而这些行为症状背后的生物学机制及其与疾病的关系仍不清楚。在小鼠癌症模型中，恶病质通过细胞因子感知脑干至基底神经节回路特异性地导致努力敏感性增加和类似冷漠的症状。这个神经回路在恶病质发作时检测到白细胞介素-6（IL-6）升高，并将炎症信号转化为中脑边缘多巴胺减少，从而增加努力敏感性。我们通过靶向关键回路节点缓解了这些类似冷漠的症状：给予抗IL-6抗体治疗、消除脑干中的细胞因子感知，以及用光遗传学或药理学方法增强中脑边缘多巴胺。我们的研究结果揭示了一个感知全身炎症并协调行为变化的中枢神经回路，为慢性炎症与抑郁症状之间的联系提供了机制性见解。
