Form deprivation (FD) was induced in 61 guinea pigs with a diffuser worn on one eye. The form-deprived eye elongated and developed myopia within 6 days in animals raised under a 12:12 h light/dark cycle, but not when reared in darkness. After 11 days of FD, the average eye was -6.6 D more myopic and 146 microm longer than its fellow eye. Initially the myopia was mostly from vitreous chamber elongation, but with longer periods of FD, corneal power increases predominated. These effects were confirmed in schematic eyes. After a delay, FD also elongated the vitreous chamber of the non-deprived eye. The myopia rapidly abated once the diffusers were removed (65% within 24 h) due to inhibition of elongation and choroidal thickening. The guinea pig provides a fast mammalian model of FD myopia and corneal curvature regulation.

When a young growing eye wears a negative or positive spectacle lens, the eye compensates for the imposed defocus by accelerating or slowing its elongation rate so that the eye becomes emmetropic with the lens in place. Such spectacle lens compensation has been shown in chicks, tree-shrews, marmosets and rhesus monkeys. We have developed a model of emmetropisation using the guinea pig in order to establish a rapid and easy mammalian model. Guinea pigs were raised with a +4D, +2D, 0D (plano), -2D or -4D lens worn in front of one eye for 10 days or a +4D on one eye and a 0D on the fellow eye for 5 days or no lens on either eye (littermate controls). Refractive error and ocular distances were measured at the end of these periods. The difference in refractive error between the eyes was linearly related to the lens-power worn. A significant compensatory response to a +4D lens occurred after only 5 days and near full compensation occurred after 10 days when the effective imposed refractive error was between 0D and 8D of hyperopia. Eyes wearing plano lenses were slightly more myopic than their fellow eyes (-1.7D) but showed no difference in ocular length. Relative to the plano group, plus and minus lenses induced relative hyperopic or myopic differences between the two eyes, inhibited or accelerated their ocular growth, and expanded or decreased the relative thickness of the choroid, respectively. In individual animals, the difference between the eyes in vitreous chamber depth and choroid thickness reached +/-100 and +/-40microm, respectively, and was significantly correlated with the induced refractive differences. Although eyes responded differentially to plus and minus lenses, the plus lenses generally corrected the hyperopia present in these young animals. The effective refractive error induced by the lenses ranged between -2D of myopic defocus to +10D of hyperopic defocus with the lens in place, and compensation was highly linear between 0D and 8D of effective hyperopic defocus, beyond which the compensation was reduced. We conclude that in the guinea pig, ocular growth and refractive error are visually regulated in a bidirectional manner to plus and minus lenses, but that the eye responds in a graded manner to imposed effective hyperopic defocus.

A growing eye becomes myopic after form deprivation (FD) or compensates for the power and sign of imposed spectacle lenses. A possible mediator of the underlying growth changes is all-trans retinoic acid (RA). Eye elongation and refractive error (RE) was manipulated by raising guinea pigs with FD, or a spectacle lens worn on one eye. We found retinal-RA increased in myopic eyes with accelerated elongation and was lower in eyes with inhibited elongation. RA levels in the choroid/sclera combined mirrored these directional changes. Feeding RA (25 mg/kg) repeatedly to guinea pigs, also resulted in rapid eye elongation (up to 5 times normal), and yet the RE was not effected. In conclusion, RA may act as a signal for the direction of ocular growth.

A model of the axial change in ocular parameters of the guinea pig eye from 2 to 825 days of age was developed and a corresponding paraxial schematic eye model applicable from 2 to 100 days of age was constructed. Axial distances increased logarithmically over time except for the lens in which growth was more complex. Over the first 30 days, ocular elongation was approximately linear: ocular length increased by 37 microm/day, the majority due lens expansion. The choroid and sclera thickened with age, while the retina thinned in proportion to the increased ocular size, and the model suggests that there is no small eye artefact for white light retinoscopy. Refractive error just after birth was +4.8D but halved within the first week. Emmetropization occurred within the first month of life similar to that in other species when aligned at the point of sexual maturity and scaled by the time taken to reach adulthood. The power of the eye was 227D at 2 days of age and reduced by 19.7D by 100 days due to a 22% decrease in the power of the cornea. The posterior nodal distance (PND) was 4.7 mm at 30 days of age, with a maximum rate of change of 13 microm/day during the first week. The ratio of PND to axial length declined until at least 100 days of age, well after emmetropia was reached. This suggests that the maintenance of emmetropia is not sustained through proportional axial growth, but involves some active mechanism beyond simple scaling. The model predicts that 1D of myopia requires an elongation of between 23 and 32 microm, depending upon age, suggesting that a resolution of at least 50 microm is required in methods used to determine the significance of ocular length changes in guinea pig models of refractive development. Retinal magnification averaged 80 microm/degree, and the maximum potential brightness of the retinal image was high, which together with a ratio of lens power to corneal power of 1.7-2.0 suggests that the guinea pig eye is adapted for nocturnal conditions.

A slow mechanism of retinal synaptic inhibition involves hydrolysis of ATP released from pannexin 1 channels (from the tips of horizontal cell dendrites); the resulting protons and phosphates acidify the synaptic cleft, which inhibits neurotransmitter release.

An animal’s ability to survive depends on its sensory systems being able to adapt to a wide range of environmental conditions, by maximizing the information extracted and reducing the noise transmitted. The visual system does this by adapting to luminance and contrast. While luminance adaptation can begin at the retinal photoreceptors, contrast adaptation has been shown to start at later stages in the retina. Photoreceptors adapt to changes in luminance over multiple time scales ranging from tens of milliseconds to minutes, with the adaptive changes arising from processes within the phototransduction cascade. Here we show a new form of adaptation in cones that is independent of the phototransduction process. Rather, it is mediated by voltage-gated ion channels in the cone membrane and acts by changing the frequency response of cones such that their responses speed up as the membrane potential modulation depth increases and slow down as the membrane potential modulation depth decreases. This mechanism is effectively activated by high-contrast stimuli dominated by low frequencies such as natural stimuli. However, the more generally used Gaussian white noise stimuli were not effective since they did not modulate the cone membrane potential to the same extent. This new adaptive process had a time constant of less than a second. A critical component of the underlying mechanism is the hyperpolarization-activated current, Ih, as pharmacologically blocking it prevented the long- and mid- wavelength sensitive cone photoreceptors (L- and M-cones) from adapting. Consistent with this, short- wavelength sensitive cone photoreceptors (S-cones) did not show the adaptive response, and we found they also lacked a prominent Ih. The adaptive filtering mechanism identified here improves the information flow by removing higher-frequency noise during lower signal-to-noise ratio conditions, as occurs when contrast levels are low. Although this new adaptive mechanism can be driven by contrast, it is not a contrast adaptation mechanism in its strictest sense, as will be argued in the Discussion.

Congenital nystagmus, involuntary oscillating small eye movements, is commonly thought to originate from aberrant interactions between brainstem nuclei and foveal cortical pathways. Here, we investigated whether nystagmus associated with congenital stationary night blindness (CSNB) results from primary deficits in the retina. We found that CSNB patients as well as an animal model (nob mice), both of which lacked functional nyctalopin protein (NYX, nyx) in ON bipolar cells (BCs) at their synapse with photoreceptors, showed oscillating eye movements at a frequency of 4–7 Hz. nob ON direction-selective ganglion cells (DSGCs), which detect global motion and project to the accessory optic system (AOS), oscillated with the same frequency as their eyes. In the dark, individual ganglion cells (GCs) oscillated asynchronously, but their oscillations became synchronized by light stimulation. Likewise, both patient and nob mice oscillating eye movements were only present in the light when contrast was present. Retinal pharmacological and genetic manipulations that blocked nob GC oscillations also eliminated their oscillating eye movements, and retinal pharmacological manipulations that reduced the oscillation frequency of nob GCs also reduced the oscillation frequency of their eye movements. We conclude that, in nob mice, synchronized oscillations of retinal GCs, most likely the ON-DCGCs, cause nystagmus with properties similar to those associated with CSNB in humans. These results show that the nob mouse is the first animal model for a form of congenital nystagmus, paving the way for development of therapeutic strategies.

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