Wireless activation of dopamine neurons for rapid regulation of depression-related behaviors by upconversion optogenetics

Rapid regulation of depression-related behavior is crucial to help patients recover social functions and improve their life quality, however, it is still challenging for present medication therapy which always takes several weeks or even months to efficiently relieve depression. In this work, to rapid and safe regulation of depressive-like behavior in chronic stress induced depression modeled mice, we developed an upconversion nanoparticle (UCNPs)-doped hydrogel to remotely activate dopamine neurons in ventral tegmental area of mouse brain. The hydrogel transformed transcranial near infrared light to visible blue light, that can wirelessly activate the channel-rhodopsin transgene expressed dopamine neurons from the scalp outside, and then project to nucleus accumben to significantly relieve mouse depressive behaviors. Moreover, the UCNPs hydrogel could be easily removed after treatments without any nanoparticle’s residue, greatly avoiding brain tissue-damages. Tissue staining experiments revealed that cell nucleus density around the UCNP-injection tissue sites increased by 57 %, whereas it was only 8 % in the hydrogel group, indicating a significant inflammation for the UCNP-injection. Overall, this novel upconversion optogenetics hydrogel provides more efficient and safe treatment strategies for brain diseases. • A UCNPs hydrogel was developed to wirelessly activate dopamine neurons in ventral tegmental area . • The UCNPs hydrogel exhibited excellent phototransduction and biocompatibility. • The transcranial NIR light irradiation repeatedly activated dopamine neurons over a period of 7 days to reverse depressive behaviors. • The implanted UCNPs hydrogel can be removed after treatment significantly reduced long-term damage to brain tissues.