Insufficient Oligodendrocyte Turnover in Optic Nerve Contributes to Age-Related Axon Loss and Visual Deficits.

Age-related decline in visual functions is a prevalent health problem among elderly people, and no effective therapies are available up-to-date. Axon degeneration and myelin loss in optic nerves (ONs) are age-dependent and become evident in middle-aged (13-18 months) and old (20-22 months) mice of either sex compared with adult mice (3-8 months), accompanied by functional deficits. Oligodendrocyte (OL) turnover is actively going on in adult ONs. However, the longitudinal change and functional significance of OL turnover in aging ONs remain largely unknown. Here, using cell-lineage labeling and tracing, we reported that oligodendrogenesis displayed an age-dependent decrease in aging ONs. To understand whether active OL turnover is required for maintaining axons and visual function, we conditionally deleted the transcription factor Olig2 in the oligodendrocyte precursor cells of young mice. Genetically dampening OL turnover by Olig2 ablation resulted in accelerated axon loss and retinal degeneration, and subsequently impaired ON signal transmission, suggesting that OL turnover is an important mechanism to sustain axon survival and visual function. To test whether enhancing oligodendrogenesis can prevent age-related visual deficits, 12-month-old mice were treated with clemastine, a pro-myelination drug, or induced deletion of the muscarinic receptor 1 in oligodendrocyte precursor cells. The clemastine treatment or muscarinic receptor 1 deletion significantly increased new OL generation in the aged ONs and consequently preserved visual function and retinal integrity. Together, our data indicate that dynamic OL turnover in ONs is required for axon survival and visual function, and enhancing new OL generation represents a potential approach to reversing age-related declines of visual function.SIGNIFICANCE STATEMENT Oligodendrocyte (OL) turnover has been reported in adult optic nerves (ONs), but the longitudinal change and functional significance of OL turnover during aging remain largely unknown. Using cell-lineage tracing and oligodendroglia-specific manipulation, this study reported that OL generation was active in adult ONs and the efficiency decreased in an age-dependent manner. Genetically dampening OL generation by Olig2 ablation resulted in significant axon loss and retinal degeneration, along with delayed visual signal transmission. Conversely, pro-myelination approaches significantly increased new myelin generation in aging ONs, and consequently preserved retinal integrity and visual function. Our findings indicate that promoting OL generation might be a promising strategy to preserve visual function from age-related decline.

Establishment of an acute extraocular muscle injury model in cats.

AIM: To describe an acute extraocular muscle injury model in cats. METHODS: Seventy-two cats were randomly divided into 6 groups (12 cats per group). Cats' left lateral recti were clamped using a surgical needle holder with a clamping strength of 2 (Groups A and D), 4 (Groups B and E) and 6 kg (Groups C and F). The right lateral recti were treated as controls. On the 4th and 7th days, hematoxylin eosin (HE) staining, immunohistochemical staining for proliferating cell nuclear antigen (PCNA), muscle force measurements and ocular alignment changes were performed to evaluate the extent of injuries. RESULTS: The morphological changes were graded as mild, moderate or severe by HE staining in all experiment groups. PCNA immunohistochemical staining indicated repairment of muscle fibers in the damaged area. On the 4th and 7th days after clamping, the injured lateral muscle exhibited an elevated threshold for electric stimulation. The muscle forces among groups 2, 4 and 6 kg injury at 4d (Groups A, B and C) were statistically significant (P<0.05), but no significant differences were noted among groups 2, 4 and 6 kg injury at 7d (Groups D, E and F) (P>0.05), respectively. In addition, medial deviation in ocular alignment was also present to various degrees in all groups. CONCLUSION: A cat model of acute extraocular muscle injury can be established by rectus clamping. Different clamping strengths can make different degrees of muscle injury. This model may help the future study in the acute extraocular muscle injury.