Spatiotemporally Resolved Imaging of Adenosine in the Mouse Brain Links Depression and Inflammation

Depression disrupts central nervous system function and may further elevate the risk of systemic diseases by triggering inflammatory responses. However, the precise mechanisms underlying its role in driving inflammation remain elusive. Adenosine (Ado), a critical molecule in depression, exhibits abnormal concentration changes that are closely associated with neuroinflammation. Thus, precise imaging of adenosine in the whole brain is essential for unraveling the mechanisms linking depression and inflammatory responses. However, current biosensors face limitations in whole-brain adenosine imaging. To address this limitation, a fluorescent nanoprobe with high spatiotemporal resolution was developed. The nanoprobe incorporates a targeting unit consisting of ferrocene-containing aptamers and phospholipid vesicles, ensuring excellent blood-brain barrier (BBB) penetration and high specificity for adenosine detection. Additionally, the nanoprobe features a near-infrared (NIR)-activated light-switching unit, enabling precise and real-time imaging of adenosine dynamics. The results revealed that adenosine activates the A_2A receptor (A_2AR) and downstream extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, inducing the secretion of proinflammatory cytokines by microglia and driving neuroinflammation. Elevated levels of inflammatory cytokines in the blood of depressed mice further suggest that depression may exacerbate systemic disease risk via peripheral inflammation. In summary, this nanoprobe not only achieves high spatiotemporal resolution imaging of adenosine in the brain but also serves as a powerful tool for elucidating the inflammatory mechanisms linking depression to systemic diseases.