Abstract
Purpose :
Retinal ganglion cells (RGC) are vulnerable to damage in diseases and injuries that cause blindness and cannot repair themselves. One promising approach is to reapply developmental mechanisms that form visual circuits, to promote repair. During development, target-derived cues and neural activity are required in both, the RGCs and target cells, to connect RGC axons with their synaptic partners in the brain. While many studies have identified events occurring in the RGCs to promote repair, far less is known about the role of target cells in RGC axon regeneration. Here we are testing a novel idea that post-synaptic target cells in the retinofugal pathway can be leveraged to promote regeneration of visual circuits.
Methods :
We performed a distal injury to sever the optic tract of adult mice anterior to the pre-tectum. We increased neural activity broadly in the distal optic pathway using a chemogenetic approach; injury-only animals served as controls. To identify the specific contribution of target cells, we used synaptotagmin17::cre (Syt17::Cre) mice to precisely activate cells in the nucleus of the optic tract (NOT), a subcortical visual target. We used the rabies viral tracing system to identify inputs to cre-labeled cells in the NOT. We assessed RGC degeneration through immunohistochemistry, and axon regeneration through intravitreal injection of fluorophore-conjugated cholera-toxin subunit β.
Results :
We observed significant regeneration of RGC axons (p=0.0007, Mann-Whitney, n=10) in the group that received increased neural activity, with significant regeneration within pre-tectum targets. We confirmed that cre-labeled cells in the NOT are bonafide retinorecipient cells. We also observed significant regeneration of RGC axons (p=0.03, Mann Whitney, n=7) in Syt17::Cre mice in which only the retinorecipient target cells were activated.
Conclusions :
Our data shows that increasing electrical activity of neurons in the distal optic pathway can promote regeneration of RGC axons, and that specific activation of retinorecipient targets is sufficient to promote RGC axon regeneration in a distal injury model. These results suggest that target-derived cues are important to promote robust, accurate rewiring of injured visual circuits. These experiments will address the role of post-synaptic cells in CNS repair and have widespread relevance for treating blinding diseases, stroke and traumatic brain injury.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.