Adaptive changes of the ground squirrel retina during hibernation

National Eye Institute

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Abstract

Axonal injury and subsequent neuronal cell death are the pathological underpinnings of many neurological disorders, including acute neural injuries to the spinal cord or optic nerve, and chronic neurological diseases such as multiple sclerosis and glaucoma. In this project, we observed a striking neuroprotective phenomenon in hibernating GS with in-depth anatomical and physiological characterization. We found that retinal ganglion cells survive axonal crush during hibernation and remain throughout the duration of hibernation - a remarkable example of neural protection as well as an ideal starting point for regeneration. We hope to link metabolic adaptation in hibernation with immunometabolic regulation and neuroprotection, highlighting a potential therapeutic strategy for neural injury and degeneration. Modeling human retinal ganglion cell (RGC) and optic nerve diseases in non-human primates is ideal, but has practical limitations. In addition, many visual degenerative disorders are age-related, making their study in primate models prohibitively slow. Thus, mice and rats are commonly used to model RGC injuries. However, as nocturnal mammals, these rodents have retinal structures that differ significantly from primate; for example, they possess less than one tenth of the RGCs found in the primate retina (60,000 vs 1,000,000). We demonstrate the diurnal GS as a surrogate model that offers an agreeable tradeoff between the limitations of both commonly used rodent models and nonhuman primates. 1) We showed that the number and distribution of RGCs in the GS retina is much closer to that of primates than other rodent models. The GS retina possesses 600,000 RGCs, with the highest density along the visual streak; there can be as many as four layers of RGCs, there, as in the central primate retina. 2) We also reported that GS and primate retinas share a similar interlocking pattern between RGC axons and astrocyte processes in the retina nerve fiber layer, which is lacking in mice and rats. 3) The GS has an elongated optic nerve head, which allowed us to we develop a partial optic nerve crush (pONC) model, so we could precisely control the extent of injury and spare a portion of the retina as an ideal internal control. 4) We developed procedures to perform ONC in hibernating GS without interrupting hibernation, providing the necessary foundation to study injury responses in hibernating animals. In active GS, the time course of cell death after ONC mirrors that seen in rat and mouse: approximately 80% of cells are lost 14d post-ONC in active GS, whereas torpid GS exhibited virtually no RGC loss. Importantly, these RGCs were not merely dead cell bodies yet to be cleared. Multielectrode array (MEA) recordings of spontaneous RGC activity in active GSs revealed a marked decline in spiking-cell densities in injured nasal retinas in comparison to their uninjured temporal counterparts. Nevertheless, RGCs were still active after ONC in torpid GS, and densities of spiking RGCs were similar to those of uninjured retinas, supporting the notion that such RGCs are exempt from degeneration post-ONC. In addition, we found that axon degeneration, including proximal and distal (Wallerian) degeneration, was also significantly alleviated in torpid GS. While it is possible that lower body temperature may slow RGC death and clearance (i.e. via a Q10 effect), it is unlikely to account for the torpor-associated survival completely: RGC death was largely absent at 21 days and even 6 weeks post-injury in torpid GS; furthermore, some torpid GS occasionally woke from hibernation after ONC, and these animals suffered RGC death despite remaining in the cold room. Moreover, torpid GS went through multiple rounds of interbout arousal after ONC, during which their body temperature rose to 37 C, yet did not cumulatively elicit RGC death. Taken together, these observations indicate that torpor bestows GS with temperature-independent mechanisms that protect RGCs from axonal injury-induced neuronal death. We are exploring the mechanism of this form of neuroprotection.