The asymmetric summation of kinetically distinct glutamate inputs across the dendrites of retinal 'starburst' amacrine cells is one of the several mechanisms that have been proposed to underlie their direction-selective properties, but experimentally verifying input kinetics has been a challenge. Here, we used two-photon glutamate sensor (iGluSnFR) imaging to directly measure the input kinetics across individual starburst dendrites. We found that signals measured from proximal dendrites were relatively sustained compared to those measured from distal dendrites. These differences were observed across a range of stimulus sizes and appeared to be shaped mainly by excitatory rather than inhibitory network interactions. Temporal deconvolution analysis suggests that the steady-state vesicle release rate was ~ 3 times larger at proximal sites compared to distal sites. Using a connectomics-inspired computational model, we demonstrate that input kinetics play an important role in shaping direction selectivity at low stimulus velocities. Together, these results provide direct support for the 'space-time wiring' model for direction selectivity.

Introduction Cerebral Small Vessel Disease (CSVD), a progressive degenerative disorder of small caliber cerebral vessels, represents a major contributor to stroke and vascular dementia incidence worldwide. We sought to conduct a systematic review of the role of retinal biomarkers in diagnosis and characterization of CSVD. Methods We conducted a systematic review of MEDLINE, PubMed, Scopus, the Cochrane Library Database, and Web of Science. We identified studies of sporadic CSVD (including CSVD not otherwise specified, Cerebral Amyloid Angiopathy, and Hypertensive Arteriopathy) and the most common familial CSVD disorders (including CADASIL, Fabry disease, and MELAS). Included studies used one or more of the following tools: visual fields assessment, fundus photography, Optical Coherence Tomography and OCT Angiography, Fluorescein Angiography, Electroretinography, and Visual Evoked Potentials. Results We identified 48 studies of retinal biomarkers in CSVD, including 9147 cases and 12276 controls. Abnormalities in retinal vessel diameter (11 reports, n = 11391 participants), increased retinal vessel tortuosity (11 reports, n = 617 participants), decreased vessel fractal dimension (5 reports, n = 1597 participants) and decreased retinal nerve fiber layer thickness (5 reports, n = 4509 participants) were the biomarkers most frequently associated with CSVD. We identified no reports conducting longitudinal retinal evaluations of CSVD, or systematically evaluating diagnostic performance. Conclusion Multiple retinal biomarkers were associated with CSVD or its validated neuroimaging biomarkers. However, existing evidence is limited by several shortcomings, chiefly small sample size and unstandardized approaches to both biomarkers’ capture and CSVD characterization. Additional larger studies will be required to definitively determine whether retinal biomarkers could be successfully incorporated in future research efforts and clinical practice.

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