Closed‐Loop Control of Cerebral ATP Transients by an Optogenetic Nanosensor for Alleviation of Depressive‐Like Symptoms

ABSTRACT Adenosine 5′‐triphosphate (ATP), as a signaling molecule, has been used to modulate neurobiological processes associated with depression. However, its detailed dose‐effects relationship on depressive‐like behaviors is unclear because in situ monitoring and on‐demand control of ATP release still remain challenging. In this work, a transcranial near‐infrared (NIR) optogenetic approach based on upconversion nanoprobes was developed to precisely and selectively monitor ATP dynamics in real time, while cell‐autonomous releasing ATP from astrocytes by optogenetic stimulation in the mouse brain. We used the nanoprobe to measure temporally distinct and functionally heterogeneous ATP transients associated with motor control in mouse medial prefrontal cortex, and reported an effective concentration window of ATP‐based alleviation of depressive‐like symptoms ranging from 65 to 105 µ m for the first time. Transcriptomic analysis revealed that maintaining ATP within this homeostatic window restored the expression of neuroprotective receptors, whereas excessive ATP (>105 µ m ) triggered neuroinflammation‐mediated immune pathways, leading to the recurrence of depressive‐like symptoms. This work provides a powerful tool to reveal how the precise release of neuromodulators alters the functions of their target circuits through the combination of nanophotonics with neurobiology.