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Optogenetic Stimulation of Cholinergic Amacrine Cells Improves Capillary Blood Flow in Diabetic Retinopathy.

ABSTRACT: Purpose:Disruption in blood supply to active retinal circuits is the earliest hallmark of diabetic retinopathy (DR) and has been primarily attributed to vascular deficiency. However, accumulating evidence supports an early role for a disrupted neuronal function in blood flow impairment. Here, we tested the hypothesis that selectively stimulating cholinergic neurons could restore neurovascular signaling to preserve the capillary circulation in DR. Methods:We used wild type (wt) and choline acetyltransferase promoter (ChAT)-channelrhodopsin-2 (ChR2) mice expressing ChR2 exclusively in cholinergic cells. Mice were made diabetic by streptozotocin (STZ) injections. Two to 3 months after the last STZ injection, the rate of capillary blood flow was measured in vivo within each retinal vascular layer using high speed two-photon imaging. Measurements were done at baseline and following ChR2-driven activation of retinal cholinergic interneurons, the sole source of the vasodilating neurotransmitter acetylcholine. After recordings, retinas were collected and assessed for physiological and structural features. Results:In retinal explants from ChAT-ChR2 mice, we found that channelrhodopsin2 was selectively expressed in all cholinergic amacrine cells. Its direct activation by blue light led to dilation of adjacent retinal capillaries. In living diabetic ChAT-ChR2 animals, basal capillary blood flow was significantly higher than in diabetic mice without channelrhodopsin. However, optogenetic stimulation with blue light did not result in flickering light-induced functional hyperemia, suggesting a necessity for a concerted neurovascular interaction. Conclusions:These findings provide direct support to the utility and efficacy of an optogenetic approach for targeting selective retinal circuits to treat DR and its complications.

SUBMITTER: Ivanova E

PROVIDER: S-EPMC7452855 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Optogenetic Stimulation of Cholinergic Amacrine Cells Improves Capillary Blood Flow in Diabetic Retinopathy.

Ivanova Elena E Bianchimano Paola P Corona Carlo C Eleftheriou Cyril G CG Sagdullaev Botir T BT

Investigative ophthalmology & visual science 20200801 10

<h4>Purpose</h4>Disruption in blood supply to active retinal circuits is the earliest hallmark of diabetic retinopathy (DR) and has been primarily attributed to vascular deficiency. However, accumulating evidence supports an early role for a disrupted neuronal function in blood flow impairment. Here, we tested the hypothesis that selectively stimulating cholinergic neurons could restore neurovascular signaling to preserve the capillary circulation in DR.<h4>Methods</h4>We used wild type (wt) and ...[more]

PMID: 32841313

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Project description:To establish adaptive optics scanning laser ophthalmoscopy as a method to detect and characterize microscopic signs of diabetic retinopathy in capillaries and cone photoreceptors in the parafovea.Recently, adaptive optics scanning laser ophthalmoscope (AOSLO) has enabled noninvasive assessment of photoreceptors, capillaries, and leukocytes in the retinas of live human subjects. Repeated application of AOSLO imaging along with comparison to fluorescein angiography was used to track individual capillaries near the foveal avascular zone (FAZ) from one eye affected with severe non-proliferative diabetic retinopathy. Fluorescein angiography was used to identify clinical signs of diabetic retinopathy, such as microaneurysms and intraretinal microvascular abnormalities, and corresponding regions were imaged and assessed using the AOSLO. In addition, the structural integrity of photoreceptors and the spatial distribution of leukocytes around the parafoveal capillary network were quantitatively assessed.Capillaries and cone photoreceptors were visualized using the AOSLO without the use of injected contrast agents. Although the majority of capillaries were stable over a period of 16 months, one capillary at the edge of the FAZ dropped out, leading to a small but significant increase in FAZ size. Longitudinal assessment of the capillaries also showed microaneurysm formation and disappearance as well as the formation of tiny capillary bends similar in appearance to intraretinal microvascular abnormalities. The leukocytes in the capillary network were found to preferentially travel through the same routes in all four visits, suggesting that these channels are robust against small changes to the surrounding capillaries. In this eye, cone photoreceptor spacing was increased in the fovea when compared with normal data but stable across all visits.AOSLO imaging can be used to longitudinally track capillaries, leukocytes, and photoreceptors in diabetic retinopathy. Capillary changes that can be detected include dropout of individual capillaries as well as formation and disappearance of microaneurysms.

Dataset Information

Optogenetic Stimulation of Cholinergic Amacrine Cells Improves Capillary Blood Flow in Diabetic Retinopathy.

Publications

Optogenetic Stimulation of Cholinergic Amacrine Cells Improves Capillary Blood Flow in Diabetic Retinopathy.

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