Herein, for the first time, we proposed a precise and minimally invasive neuromodulation strategy for the treatment of PD using upconversion optogenetics.
We applied the 6-OHDA-induced PD animal model, in which blue-light sensitive pAAV-hSyn-hChR2(H134R)-mCherry was expressed in the globus pallidus externus (GPe) brain region, followed by in situ injection of upconversion nanoparticles (UCNPs). Near-infrared (NIR) light was delivered through a fiber fixed on the skull, allowing UCNPs to convert NIR light into blue light. The experiment was divided into four groups: Control group, PD group, PD + NIR with UCNPs group, and PD + NIR without UCNPs group. Open field and rotarod tests were conducted to measure the motor abilities and coordination of PD mice. The invasiveness of conventional optogenetics and upconversion optogenetics on tissues was assessed using immunohistochemistry and immunofluorescence methods. Additionally, we employed a small animal imaging system and inductively coupled plasma-optical emission spectrometry to explore the in vivo efficiency and stability of upconversion optogenetics. Biosafety assessments of upconversion optogenetics were performed using H&E staining and blood biochemical indicators.
Under excitation by NIR light, UCNPs emitted intense blue fluorescence, peaking at 473 nm, which them suitable for activating ChR2. Upconversion optogenetics, combining UCNPs and optogenetics, could precisely activate GPe neurons. A significant impairment in the motor performance of PD mice was observed, characterized by reduced moving distance, average velocity, and increased immobility time, as well as decreased time on rod, compared to the Control group. However, each of these motor indicators was successfully improved in the NIR with UCNPs group, while those in the NIR without UCNPs group showed no enhancement in motor ability. Meanwhile, upconversion optogenetics demonstrated excellent therapeutic efficacy comparable to conventional methods, significantly avoiding brain injury caused by optical fiber implantation. This precise and minimally invasive neuromodulation technique could sustain its effects for several weeks and also demonstrates excellent biocompatibility. Additionally, upconversion optogenetics could be extended to control various neural activities, including activation of the nigrostriatal pathway and modulation of feeding behavior in living mice, showcasing the versatility of the proposed method.
Our study presents a precise and minimally invasive neuromodulation strategy for PD treatment, with potential therapeutic applications in various neurological disorders.
Neuromodulation technologies have broad applications in the treatment of brain disorders. The precise and minimally invasive neuromodulation technique applied in this study offers a novel approach for the treatment of PD. Compared to TMS and tES, it offers advantages in precise neuromodulation, making it suitable for rehabilitation therapies. When combined with exercise therapy, it may yield improved rehabilitation outcomes.
upconversion optogenetics
Parkinson’s disease
