Adaptation of retinal ganglion cell function during flickering light in the mouse

Abstract

Rapid dilation of retinal vessels in response to flickering light (functional hyperemia) is a well-known autoregulatory response driven by increased neural activity in the inner retina. Little is known about flicker-induced changes of activity of retinal neurons themselves. We non-invasively investigated flicker-induced changes of retinal ganglion cell (RGC) function in common inbred mouse strains using the pattern electroretinogram (PERG), a sensitive measure of RGC function. Flicker was superimposed on the pattern stimulus at frequencies that did not generate measurable flicker-ERG and alter the PERG response. Transition from flicker at 101 Hz (control) to flicker at 11 Hz (test) at constant mean luminance induced a slow reduction of PERG amplitude to a minimum (39% loss in C57BL/6J mice and 52% loss in DBA/2J mice) 4–5 minutes after 11 Hz flicker onset, followed by a slow recovery to baseline over 20 minutes. Results demonstrate that the magnitude and temporal dynamics of RGC response induced by flicker at 11 Hz can be non-invasively assessed with PERG in the mouse. This allows investigating the functional phenotype of different mouse strains as well as pathological changes in glaucoma and optic nerve disease. The non-contact flicker-PERG method opens the possibility of combined assessment of neural and vascular response dynamics.

Nicotinamide-Rich Diet in DBA/2J Mice Preserves Retinal Ganglion Cell Metabolic Function as Assessed by PERG Adaptation to Flicker

“…A number of studies have investigated in different mammals the magnitude and temporal dynamics of flicker-induced changes of retinal arterial diameter and blood flow [ 16 , 23 ], which is caused by increased metabolic demand of inner retinal neurons. We developed a tool to assess flicker-induced adaptation of RGC function as measured by PERG with superimposed flicker (F-PERG) [ 18 ]. The F-PERG has been used in this study to test whether RGCs’ ability to adapt their function upon flicker challenge is reduced in the D2 mouse model of glaucoma, and whether it is preserved in D2 mice fed with nicotinamide-rich diet that supports mitochondrial function.…”

“…The PERG technique for simultaneous recording from both eyes has been previously described in detail [ 9 , 21 ]. In the present study, we used a commercially available instrument for PERG recording (Jorvec Corp., Miami, FL, USA) modified to superimpose a flickering field to the patterned stimulus [ 18 ]. In brief, anesthetized mice were gently restrained in a holder allowing unobstructed vision and kept at a constant body temperature of 37.0 °C using feedback-controlled heating pad controlled by a rectal probe.…”

“…As RGCs are extremely high-maintenance neurons under normal conditions [ 14 , 15 ], it is conceivable that the addition of flickering light to the visual stimulus—known to increase metabolic demand and cause rapid vasodilation [ 16 , 17 ]—will increase the likelihood of an energetic crisis in D2 mice prone to glaucoma. We recently developed a non-invasive tool for testing neurovascular autoregulatory dynamics under metabolic challenge in the mouse eye in vivo [ 18 ]. The tool consists of superimposing a flickering light at 11 Hz to the pattern stimulus for PERG recording, resulting in a flicker PERG (F-PERG) response.…”

OTX2 Non-Cell Autonomous Activity Regulates Inner Retinal Function

“…Thus, the altered flicker responses that we observe represent a change in cone pathway activity at the level of the inner retina. Retinal ganglion cell dysfunction and degeneration in a model of glaucoma greatly alter the flicker response (Grozdanic et al, 2003), and the flicker ERG has been used to assess RGC function and hemodynamic changes in the mouse retina (Chou et al, 2019). The flicker response in macaques has been shown to be largely driven by spiking inner retinal neurons since it is increased at some frequencies by TTX and NMDA (Viswanathan et al, 2002).…”

OTX2 non-cell autonomous activity regulates inner retinal function

“…Thus, the altered flicker responses that we observe represents a change in cone pathway activity at the level of the inner retina. Retinal Ganglion Cell dysfunction and degeneration in a model of glaucoma greatly alters the flicker response (Grozdanic et al, 2003) and the flicker ERG has been used to assess RGC function and hemodynamic changes in the mouse retina (Chou et al, 2019). The flicker response in macaques has been shown to be largely driven by spiking inner retinal neurons since it is increased at some frequencies by TTX and NMDA (Viswanathan et al, 2002).…”