Adenosine signaling in the habenula: a depression-myocardial infarction nexus.

Depression has been closely associated with an elevated risk of myocardial infarction, yet the underlying mechanistic link remains unclear. Adenosine, a neuromodulator implicated in both depression and cardiovascular diseases, is believed to play a critical role in this connection. Here, we present a highly sensitive adenosine-responsive nanosensor capable of in vivo imaging of adenosine levels in the brain. Using this nanosensor, we identified a marked elevation of adenosine levels in the habenula of mouse models exhibiting both depressive-like behavior and myocardial infarction. Mechanistically, we found that accumulated adenosine activates microglia, leading to the release of pro-inflammatory cytokines and subsequent neuroinflammation. This neuroinflammatory response appears to trigger peripheral inflammation, ultimately activating the JAK1-STAT1-RIPK1-caspase-8 signaling pathway in cardiomyocytes and exacerbating myocardial injury. Importantly, treatment with the antidepressant fluoxetine significantly reduced adenosine accumulation in the brain, as detected by the nanosensor, and simultaneously alleviated myocardial damage. This innovative approach to imaging adenosine in the brain offers fresh insights into the relationship between depression and myocardial infarction.