The mammalian visual system operates over an extended range of ambient light levels by switching between rod and cone photoreceptors. Rod-driven vision is sluggish, highly sensitive, and operates in dim or scotopic lights, whereas cone-driven vision is brisk, less sensitive, and operates in bright or photopic lights. At intermediate or mesopic lights, vision transitions seamlessly from rod-driven to cone-driven, despite the profound differences in rod and cone response dynamics. The neural mechanisms underlying such a smooth handoff are not understood. Using an operant behavior assay, electrophysiological recordings, and mathematical modeling we examined the neural underpinnings of the mesopic visual transition in mice of either sex. We found that rods, but not cones, drive visual sensitivity to temporal light variations over much of the mesopic range. Surprisingly, speeding up rod photoresponse recovery kinetics in transgenic mice improved visual sensitivity to slow temporal variations, in the range where perceptual sensitivity is governed by Weber's law of sensation. In contrast, physiological processes acting downstream from phototransduction limit sensitivity to high frequencies and temporal resolution. We traced the paradoxical control of visual temporal sensitivity to rod photoresponses themselves. A scenario emerges where perceptual sensitivity is limited by: (1) the kinetics of neural processes acting downstream from phototransduction in scotopic lights, (2) rod response kinetics in mesopic lights, and (3) cone response kinetics as light levels rise into the photopic range.

The mammalian visual system has a remarkable capacity to detect differences in contrast across time, which is known as temporal contrast sensitivity (TCS). Details of the underlying neural mechanisms are rapidly emerging as a result of a series of elegant electrophysiological studies performed largely with the mouse as an experimental model. However, rigorous psychophysical methods are necessary to pair the electrophysiology with temporal visual behavior in mouse. The optomotor response is frequently used as a proxy for retinal temporal processing in rodents. However, subcortical reflexive pathways drive the optomotor response rather than cortical decision-making areas. To address this problem, we have developed an operant behavior assay that measures TCS in behaving mice. Mice were trained to perform a forced-choice visual task and were tested daily on their ability to distinguish flickering from nonflickering overhead lights. Correct responses (Hit and Correct Rejections) were rewarded. Contrast, temporal frequency, and mean illumination of the flicker were the independent variables. We validated and applied the theory of signal detection to estimate the discriminability factor (d´), a measure of performance that is independent of response bias and motivation. The empirical contrast threshold was defined as the contrast necessary to elicit d´ = 1 and TCS as the inverse of the contrast threshold. With this approach, we established in the mouse a model of human vision that shares fundamental properties of human temporal psychophysics such as Weber adaptation in response to low temporal frequency flicker and illumination-dependent increases in critical flicker frequency as predicted by the Ferry–Porter law.

The detection of temporal variations in amplitude of light intensity, or temporal contrast sensitivity (TCS), depends on the kinetics of rod photoresponse recovery. Uncharacteristically fast rod recovery kinetics are facets of both human patients and transgenic animal models with a P23H rhodopsin mutation, a prevalent cause of retinitis pigmentosa (RP). Here, we show that mice with this mutation (Rho P23H/+ ) exhibit an age-dependent and illumination-dependent enhancement in TCS compared with controls. At retinal illumination levels producing ≥1000 R*/rod/s or more, postnatal day 30 (P30) Rho P23H/+ mice exhibit a 1.2-fold to 2-fold increase in retinal and optomotor TCS relative to controls in response to flicker frequencies of 3, 6, and 12 Hz despite significant photoreceptor degeneration and loss of flash electroretinogram (ERG) b-wave amplitude. Surprisingly, the TCS of Rho P23H/+ mice further increases as degeneration advances. Enhanced TCS is also observed in a second model (rhodopsin heterozygous mice, Rho +/− ) with fast rod recovery kinetics and no apparent retinal degeneration. In both mouse models, enhanced TCS is explained quantitatively by a comprehensive model that includes photoresponse recovery kinetics, density and collecting area of degenerating rods. Measurement of TCS may be a non-invasive early diagnostic tool indicative of rod dysfunction in some forms of retinal degenerative disease.

Temporal contrast detected by rod photoreceptors is channeled into multiple retinal rod pathways that ultimately connect to cone photoreceptor pathways via Cx36 gap junctions or via chemical synapses. However, we do not yet understand how the different rod pathways contribute to the perception of temporal contrast (changes in luminance with time) at mesopic light levels, where both rods and cones actively respond to light. Here, we use a forced-choice, operant behavior assay to investigate rod-driven, temporal contrast sensitivity (TCS) in mice of either sex. Transgenic mice with desensitized cones (GNAT2 cpfl3 line) were used to identify rod contributions to TCS in mesopic lights. We found that at low mesopic lights (400 photons/s/m 2 at the retina), control and GNAT2 cpfl3 mice had similar TCS. Surprisingly, at upper mesopic lights (8000 photons/s/m 2), GNAT2 cpfl3 mice exhibited a relative reduction in TCS to low (Ͻ12 Hz) while maintaining normal TCS to high (12-36 Hz) temporal frequencies. The rod-driven responses to high temporal frequencies developed gradually over time (Ͼ30 min). Furthermore, the TCS of GNAT2 cpfl3 and GNAT2 cpfl3 ::Cx36 Ϫ/Ϫ mice matched closely, indicating that transmission of high-frequency signals (1) does not require the rod-cone Cx36 gap junctions as has been proposed in the past; and (2) a Cx36-independent rod pathway(s) (e.g., direct rod to OFF cone bipolar cell synapses and/or glycinergic synapses from AII amacrine cells to OFF ganglion cells) is sufficient for fast, mesopic rod-driven vision. These findings extend our understanding of the link between visual circuits and perception in mouse.