Retinal ganglion cell loss and gliosis in the retinofugal projection following intravitreal exposure to amyloid-beta.

Pathological accumulations of amyloid-beta (Aß) peptide are found in retina early in Alzheimer's disease, yet its effects on retinal neuronal structure remain unknown. To investigate this, we injected fibrillized Aß1-42 protein into the eye of adult C57BL/6 J mice and analyzed the retina, optic nerve (ON), and the superior colliculus (SC), the primary retinal target in mice. We found that retinal Aß exposure stimulated microglial activation and retinal ganglion cell (RGC) loss as early as 1-week post-injection. Pathology was not limited to the retina, but propagated into other areas of the central nervous system. Microgliosis spread throughout the retinal projection (retina, ON, and SC), with multiplex protein quantitation demonstrating an increase in endogenously produced Aß in the ON and SC corresponding to the injected retinas. Surprisingly, this pathology spread to the opposite side, with unilateral Aß eye injections driving increased Aß levels, neuroinflammation, and RGC death in the opposite, un-injected retinal projection. As Aß-mediated microglial activation has been shown to propagate Aß pathology, we also investigated the role of the Aß-binding microglial scavenger receptor CD36 in this pathology. Transgenic mice lacking the CD36 receptor were resistant to Aß-induced inflammation and RGC death up to 2 weeks following exposure. These results indicate that Aß pathology drives regional neuropathology in the retina and does not remain isolated to the affected eye, but spreads throughout the nervous system. Further, CD36 may serve as a promising target to prevent Aß-mediated inflammatory damage.

Nodes of Ranvier in Glaucoma.

Retinal ganglion cell axons of the DBA/2J mouse model of glaucoma, a model characterized by extensive neuroinflammation, preserve synaptic contacts with their subcortical targets for a time after onset of anterograde axonal transport deficits, axon terminal hypertrophy, and cytoskeletal alterations. Though retrograde axonal transport is still evident in these axons, it is unknown if they retain their ability to transmit visual information to the brain. Using a combination of in vivo multiunit electrophysiology, neuronal tract tracing, multichannel immunofluorescence, and transmission electron microscopy, we report that eye-brain signaling deficits precede transport loss and axonal degeneration in the DBA/2J retinal projection. These deficits are accompanied by node of Ranvier pathology - consisting of increased node length and redistribution of the voltage-gated sodium channel Nav1.6 that parallel changes seen early in multiple sclerosis (MS) axonopathy. Further, with age, axon caliber and neurofilament density increase without corresponding changes in myelin thickness. In contrast to these findings in DBA/2J mice, node pathologies were not observed in the induced microbead occlusion model of glaucoma - a model that lacks pre-existing inflammation. After one week of systemic treatment with fingolimod, an immunosuppressant therapy for relapsing-remitting MS, DBA/2J mice showed a substantial reduction in node pathology and mild effects on axon morphology. These data suggest that neurophysiological deficits in the DBA/2J may be due to defects in intact axons and targeting node pathology may be a promising intervention for some types of glaucoma.

Population coding strategies and involvement of the superior colliculus in the tactile orienting behavior of naked mole-rats.

Even simple behaviors of vertebrates are typically generated by the concerted action of large numbers of brain cells. However, the mechanisms by which groups of neurons work together as functional populations to guide behavior remain largely unknown. One of the major model systems for exploring these mechanisms has been mammalian visuomotor behavior. We describe here experiments that establish a new model system for analyzing the sensory control of behavior by neuronal populations using a mammalian somatosensory response: orientation to touch cues in a rodent. We found that the CNS mechanisms used to direct these orientation responses to touch can be delineated from behavioral experiments. In this study we demonstrate that the superior colliculus, a component of the vertebrate midbrain most often thought of as a visual structure, is an essential component of the naked mole-rat's unique tactile orienting behavior. Furthermore, the information processing that underlies this behavior displays striking parallels with that used for visual orientation at anatomical and computational levels.