Candidate pathways for retina to scleral signaling in refractive eye growth.

The global prevalence of myopia, or nearsightedness, has increased at an alarming rate over the last few decades. An eye is myopic if incoming light focuses prior to reaching the retinal photoreceptors, which indicates a mismatch in its shape and optical power. This mismatch commonly results from excessive axial elongation. Important drivers of the myopia epidemic include environmental factors, genetic factors, and their interactions, e.g., genetic factors influencing the effects of environmental factors. One factor often hypothesized to be a driver of the myopia epidemic is environmental light, which has changed drastically and rapidly on a global scale. In support of this, it is well established that eye size is regulated by a homeostatic process that incorporates visual cues (emmetropization). This process allows the eye to detect and minimize refractive errors quite accurately and locally over time by modulating the rate of elongation of the eye via remodeling its outermost coat, the sclera. Critically, emmetropization is not dependent on post-retinal processing. Thus, visual cues appear to influence axial elongation through a retina-to-sclera, or retinoscleral, signaling cascade, capable of transmitting information from the innermost layer of the eye to the outermost layer. Despite significant global research interest, the specifics of retinoscleral signaling pathways remain elusive. While a few pharmacological treatments have proven to be effective in slowing axial elongation (most notably topical atropine), the mechanisms behind these treatments are still not fully understood. Additionally, several retinal neuromodulators, neurotransmitters, and other small molecules have been found to influence axial length and/or refractive error or be influenced by myopigenic cues, yet little progress has been made explaining how the signal that originates in the retina crosses the highly vascular choroid to affect the sclera. Here, we compile and synthesize the evidence surrounding three of the major candidate pathways receiving significant research attention - dopamine, retinoic acid, and adenosine. All three candidates have both correlational and causal evidence backing their involvement in axial elongation and have been implicated by multiple independent research groups across diverse species. Two hypothesized mechanisms are presented for how a retina-originating signal crosses the choroid - via 1) all-trans retinoic acid or 2) choroidal blood flow influencing scleral oxygenation. Evidence of crosstalk between the pathways is discussed in the context of these two mechanisms.

ON than OFF pathway disruption leads to greater deficits in visual function and retinal dopamine signaling.

The visual system uses ON and OFF pathways to signal luminance increments and decrements. Increasing evidence suggests that ON and OFF pathways have different signaling properties and serve specialized visual functions. However, it is still unclear the contribution of ON and OFF pathways to visual behavior. Therefore, we examined the effects on optomotor response and the retinal dopamine system in nob mice with ON pathway dysfunction and Vsx1-/- mice with partial OFF pathway dysfunction. Spatial frequency and contrast sensitivity thresholds were determined, and values were compared to age-matched wild-type controls. Retinas were collected immediately after visual testing to measure levels of dopamine and its metabolite, DOPAC. At 4 weeks of age, we found that nob mice had significantly reduced spatial frequency (19%) and contrast sensitivity (60%) thresholds compared to wild-type mice. Vsx1-/- mice also exhibited reductions in optomotor responses (3% in spatial frequency; 18% in contrast sensitivity) at 4 weeks, although these changes were significantly smaller than those found in nob mice. Furthermore, nob mice had significantly lower DOPAC levels (53%) and dopamine turnover (41%) compared to controls while Vsx1-/- mice displayed a transient increase in DOPAC levels at 4 weeks of age (55%). Our results show that dysfunction of ON pathways leads to reductions in contrast sensitivity, spatial frequency threshold, and retinal dopamine turnover whereas partial loss of the OFF pathway has minimal effect. We conclude that ON pathways play a critical role in visual reflexes and retinal dopamine signaling, highlighting a potential association for future investigations.

Association of Age of Menopause and Glaucoma Diagnosis in Female Veterans.

Purpose: Age of menopause has been associated with the risk of developing glaucoma; however, it is unclear if the onset of menopause is directly associated with the development of glaucoma. Our objective was to determine if there is an association between the age at diagnosis of menopause and glaucoma. Methods: This retrospective, case-only analysis was performed using the Veterans Affairs (VA) Corporate Data Warehouse of female veterans from 2000 to 2019. Women with both menopause and glaucoma diagnoses were matched based on covariates. The two matched cohorts were early menopause-early comparative (EM-EC; n = 1075) and late menopause-late comparative (LM-LC; n = 1050) women. We used a Pearson correlation to examine the linear relationship between age at diagnosis of menopause and glaucoma. Afterward, we used a multivariate linear regression model with age at diagnosis of glaucoma serving as the outcome variable to account for the covariates. Results: We found that EM women developed glaucoma 6.0 years (interquartile range [IQR], 5.1-6.5) earlier than the EC group (P < 0.001), and LM women developed glaucoma an average of 5.2 years (IQR, 4.8-5.7) later than the LC group (P < 0.001). There was a modest linear relationship between the age of menopause and glaucoma diagnoses in the EM-EC (r = 0.40) and LM-LC (r = 0.46) cohorts. In our multivariate analysis, age at diagnosis of menopause was the largest factor related to age at diagnosis of glaucoma while accounting for our covariates. Our models predicted a 0.67-year delay in age at diagnosis of glaucoma with each additional premenopausal year. Conclusions: This case-only analysis elucidates a temporal association between menopause and glaucoma, highlighting the need to characterize the role of menopause in the onset of glaucoma for women.

Postmenopausal Hormone Therapy Was Associated With Later Age of Onset Among Glaucoma Cases.

Purpose: Hormonal therapy (HT) has been suggested to lower the risk of developing glaucoma. Our goal was to investigate the association between HT use and the onset of glaucoma diagnosis in postmenopausal women. Methods: This retrospective case-only study included female veterans with open-angle glaucoma from VA records between 2000 to 2019. Propensity score matching was used to match HT (n = 1926) users to untreated (n = 1026) women on multiple covariates (e.g., age of menopause, BMI, blood pressure, antihypertensive medications, and a co-morbidity index). A simple linear regression was used to evaluate the impact of HT duration on the age of glaucoma diagnosis, and multivariate linear regression analysis was used to determine which factors contributed to the age at diagnosis of glaucoma. Results: We found a linear relationship between the age at diagnosis of glaucoma and menopause in women with (r = 0.54) and without HT (r = 0.57) use. HT users tended to have a later diagnosis of glaucoma. Our multivariate analysis found that 0-2 years, 2-5 years, and >5 years of HT use were associated with a 2.20 [confidence interval (CI), 1.64, 2.76], 3.74 [CI, 3.02, 4.46], and 4.51 [CI, 3.84, 5.18] years later diagnosis of glaucoma. An interaction (-0.009 [-0.015, -0.003]) was observed between HT duration and age of menopause diagnosis, with the impact of HT decreasing for later menopause ages. Conclusions: Longer duration of HT use was associated with a later diagnosis of glaucoma in postmenopausal women in this case-only analysis. The impact of HT may be modulated by menopausal age, although further study is needed. The findings support a protective role of estrogen in glaucoma pathogenesis.

Genetic architecture distinguishes tinnitus from hearing loss.

Tinnitus is a heritable, highly prevalent auditory disorder treated by multiple medical specialties. Previous GWAS indicated high genetic correlations between tinnitus and hearing loss, with little indication of differentiating signals. We present a GWAS meta-analysis, triple previous sample sizes, and expand to non-European ancestries. GWAS in 596,905 Million Veteran Program subjects identified 39 tinnitus loci, and identified genes related to neuronal synapses and cochlear structural support. Applying state-of-the-art analytic tools, we confirm a large number of shared variants, but also a distinct genetic architecture of tinnitus, with higher polygenicity and large proportion of variants not shared with hearing difficulty. Tissue-expression analysis for tinnitus infers broad enrichment across most brain tissues, in contrast to hearing difficulty. Finally, tinnitus is not only correlated with hearing loss, but also with a spectrum of psychiatric disorders, providing potential new avenues for treatment. This study establishes tinnitus as a distinct disorder separate from hearing difficulties.

Voluntary exercise preserves visual function and reduces inflammatory response in an adult mouse model of autosomal dominant retinitis pigmentosa.

Whole-body physical exercise has been shown to promote retinal structure and function preservation in animal models of retinal degeneration. It is currently unknown how exercise modulates retinal inflammatory responses. In this study, we investigated cytokine alterations associated with retinal neuroprotection induced by voluntary running wheel exercise in a retinal degeneration mouse model of class B1 autosomal dominant retinitis pigmentosa, I307N Rho. I307N Rho mice undergo rod photoreceptor degeneration when exposed to bright light (induced). Our data show, active induced mice exhibited significant preservation of retinal and visual function compared to inactive induced mice after 4 weeks of exercise. Retinal cytokine expression revealed significant reductions of proinflammatory chemokines, keratinocyte-derived chemokine (KC) and interferon gamma inducible protein-10 (IP-10) expression in active groups compared to inactive groups. Through immunofluorescence, we found KC and IP-10 labeling localized to retinal vasculature marker, collagen IV. These data show that whole-body exercise lowers specific retinal cytokine expression associated with retinal vasculature. Future studies should determine whether suppression of inflammatory responses is requisite for exercise-induced retinal protection.