CASE records of the Massachusetts General Hospital. Case 46152.
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Bipolar cells in the vertebrate retina have been characterized as nonspiking interneurons. Using patch-clamp recordings from goldfish retinal slices, we find, however, that the morphologically well-defined Mb1 bipolar cell is capable of generating spikes. Surprisingly, in dark-adapted retina, spikes were reliably evoked by light flashes and had a long (1-2 s) refractory period. In light-adapted retina, most Mb1 cells did not spike. However, an L-type Ca2+ channel agonist could induce periodic spiking in these cells. Spikes were determined to be Ca2+ action potentials triggered at the axon terminal and were abolished by 2-amino-4-phosphonobutyric acid (APB), an agonist that mimics glutamate. Signaling via spikes in a specific class of bipolar cells may serve to accelerate and amplify small photo-receptor signals, thereby securing the synaptic transmission of dim and rapidly changing visual input.
The vestibulo-ocular reflex (VOR) and the apparent motion of a spot stimulus fixated during head movement (apparent concomitant motion, ACM) were measured before and after an adaptation period during which subjects attempted fixation of a stimulus which moved either in the same or opposite direction as head oscillations. Movements of the head were voluntary and paced by a metronome at either 0.5 or 2.0 Hz during the 4 min adaptation period. Pre- and post-adaptation measures of VOR and ACM were obtained for both frequencies of head oscillation. VOR and ACM were altered similarly by the period of exposure to correlated head and stimulus motion. Viewing a stimulus moving in the same direction as head motion resulted in decreased VOR gain and increased ACM in the opposite direction as head motion. Viewing a stimulus moving opposite head motion resulted in increased VOR gain and increased ACM in the same direction as head movement. Differences between pre- and post-measures tended to be maximal at the adaptation frequency, but transferred to a lesser degree to the other frequency. The results indicate that changes in motor and perceptual systems are related, and are consistent with the proposal that VOR gain is a determinant of ACM.
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Anatomical and electrophysiological studies have demonstrated up-down asymmetries in vertical ocular motor pathways. We investigated whether these asymmetries extend to the capacity for short-term adaptation of the vertical vestibulo-ocular reflex (VVOR) in humans. Specifically, we asked whether smooth pursuit signals are sufficient to asymmetrically adapt the VVOR. Healthy human subjects (N=8), positioned 90 degrees left-ear-down and fixating with their eyes upon a small laser dot (diameter: 0.1 degrees) projected on a sphere (distance: 1.4 m) were trained toward low VVOR gain for 30 min with symmetric and asymmetric visual VVOR cancellation paradigms, while being oscillated (0.2 Hz, +/-20 degrees) on a motorized turntable about the interaural earth-vertical axis. During asymmetric VVOR cancellation, the target was head-fixed in either the pitch-up or pitch-down half-cycles of oscillation (= trained direction) and space-fixed during the other half-cycles (= untrained direction). During symmetric VVOR cancellation, the target was head-fixed throughout the oscillations. Before and after adaptation, the pitch-up and pitch-down VOR gains were assessed during turntable oscillation in complete darkness. Before adaptation, average gains of pitch-up (0.75+/-0.15 SD) and pitch-down (0.79+/-0.19 SD) VOR were not significantly different (paired t test: P>0.05). On an average, relative gain reductions induced by selective pitch-up (pitch-up VOR: 32%; pitch-down VOR: 21%) and pitch-down (pitch-up VOR: 18%; pitch-down VOR: 30%) VOR cancellation were significantly (P<0.05) larger in the trained than in the untrained direction. Symmetric visual VVOR cancellation led to a significantly (P<0.01) larger relative gain reduction of the pitch-down (41%) than the pitch-up (33%) VOR. None of the paradigms led to significant changes of phase or offset. We conclude that, in human subjects, the smooth pursuit system is capable to asymmetrically decrease the gain of the VVOR equally well in both the upward and downward direction. The unexpected asymmetric decrease of the VVOR gain after symmetric visual cancellation may be related to the directional preferences of vertical gaze-velocity sensitive Purkinje cells in the flocculus for the downward direction.
Among the subtypes of the Ca2+-dependent protein kinase C (PKC), which play a crucial role in long-term depression (LTD), both alpha and gamma are expressed in the cerebellar floccular Purkinje cells. To reveal the functional differences of PKC subtypes, we examined the adaptability of ocular reflexes of PKCgamma mutant mice, which show mild ataxia and normal LTD. In mutant mice, gains of the horizontal optokinetic eye response (HOKR) were reduced. Adaptation of the HOKR was not affected but its retinal slip dependency was altered in mutant mice. Sustained 1-h sinusoidal screen oscillation, which induced a relatively large amount of retinal slips in both mutant and wild-type mice, increased the HOKR gain in wild-type mice but not in mutant mice. In contrast, exposure to 1 h of sustained slower screen oscillations, which induced relatively small retinal slips in mutant and wild-type mice, increased the HOKR gain in both mutant and wild-type mice. Adaptation of the HOKR of the mutant mice to slow screen oscillation and those of wild-type mice to fast and slow screen oscillations were all abolished by local applications of a PKC inhibitor (chelerythrine) within the flocculi. Electrophysiological and anatomical studies showed no appreciable changes in the sources and magnitudes of climbing fibre inputs, which mediate retinal slip signals to the flocculus in the mutant mice. These results suggest that PKCgamma has a modulatory role in determining retinal slip dependency, and other PKC subtypes, e.g. PKCalpha, may play a crucial role in the adaptation of the HOKR.
The localization and regulation of chicken cryptochrome 1 (cCry1) mRNA expression in retina was investigated by laser capture microdissection and quantitative real-time RT-PCR. Laser capture microdissection (LCM) of retinal cell layers showed the highest level of cCry1 expression in the ganglion cell and photoreceptor layers. In both layers, expression was high during the daytime and low at night in subjects exposed to a 12:12 h light:dark cycle. Robust circadian oscillations of cCry1 mRNA levels were observed in constant (24 h day) light, but not in constant darkness, with the highest expression during daytime at zeitgeber time (ZT) 8. Unlike cCry1, circadian rhythms of the melatonin-synthesizing enzyme, arylalkylamine N-acetyltransferase, persisted in constant darkness, suggesting that rhythmic cCry1 expression is not essential for circadian clock function or output. On the second day of constant darkness, when cCry1 expression is arrhythmic, light exposure for 2 h significantly increased retinal cCry1 mRNA levels at ZT 4 and 8, times that cCry1 expression is induced in LD and LL. Similar light exposure ending at ZT 20 had no significant effect. Thus, expression of cCry1 mRNA is regulated dually by light and circadian clocks.
Acetylcholine acts as a neurotransmitter in the retina. Although previous physiological studies have indicated that some retinal ganglion cells may be cholinergic, several immunohistochemical studies using antibodies to choline acetyltransferase (ChAT) have stained only amacrine cells but not ganglion cells. Recently, we identified a splice variant of ChAT mRNA, lacking exons 6-9, in rat peripheral nervous system. The encoded protein was designated as ChAT of a peripheral type (pChAT), against which an antiserum was raised. In the present study, we examined expression of pChAT in rat retina, both at the protein level by immunohistochemistry using the antiserum and at the mRNA level by RT-PCR. Immunohistochemistry revealed that although no positive neurons were found in untreated intact retinas, many neurons became immunoreactive for pChAT after intravitreal injection of colchicine. Damage of the optic nerve was also effective in disclosing positive cells. Such positive neurons were shown to be ganglion cells by double labeling with a retrograde tracer that had been injected into the contralateral superior colliculus. Western blot analysis and RT-PCR revealed a corresponding band to the pChAT protein and to the amplified pChAT gene fragment, respectively, in retinal samples. In addition, ChAT activity was definitely detected in retinofugal fibers of the optic nerve. These results indicate the presence of cholinergic ganglion cells in rat retina.
This paper compares observed changes of ocular transmittance at short and long wavelengths in diabetic patients with values predicted by a model based on the Rayleigh light scattering properties of albumin. Selective chromatic adaptation was used to obtain critical flicker fusion (CFF) frequency thresholds from 21 subjects and 18 patients with insulin-dependent diabetes. The Ferry-Porter characteristic of each color-sensitive mechanism of each patient was compared to age-specific control values. For those eyes without an indication of neural injury, changes in optical density associated with the red- and blue-sensitive mechanisms were calculated and adjusted to reflect accelerated yellowing of the lens produced by increased duration of diabetes. The range of concentration of glycosylated albumin required to fit the model to the adjusted short-wavelength changes in optical density was determined and used to calculate the theoretical long-wavelength changes in optical density. The experimentally derived long-wavelength changes in optical density fell within the 95% confidence level of the values described by the model. These results support the premise that the apparent decrease in optical transmittance observed in patients with diabetes mellitus is caused by light scattering produced by dilute increase of plasma proteins within the retina.
Three recent discoveries have substantially improved our knowledge of cerebellar function. First, the forelimb regions of the interpositus nuclei specialize in control of one particular limb movement, reach to grasp. Second, a new model indicates that vestibulo-ocular reflex adaptation requires neural changes in both the cerebellum and the brainstem. Finally, the caudal fastigial nucleus uses both short- and long-term influences to maintain saccade accuracy.
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We present a case of decompensated nerve IV palsy with vertical diplopia afer bilateral laser in situ keratomileusis. As the patient was given monovision, we believe diplopia occurred with a decrease in vision in 1 eye and interruption of fusion. Although corrective spectacles to restore equal vision at distance were prescribes, the patient needed a prism to eliminate her double vision. We suggest a careful cover/uncover test and versions assessment in all candidates for refractive surgery who want monovision correction and a full ocular motility evaluation if there is any doubt about binocular issues.
The gain of the vestibulo-ocular reflex (VOR) normally depends on the distance between the subject and the visual target, but it remains uncertain whether vergence angle can be linked to changes in VOR gain through a process of context-dependent adaptation. In this study, we examined this question with an adaptation paradigm that modified the normal relationship between vergence angle and retinal image motion. Subjects were rotated sinusoidally while they viewed an optokinetic (OKN) stimulus through either diverging or converging prisms. In three subjects the diverging prisms were worn while the OKN stimulus moved out of phase with the head, and the converging prisms were worn when the OKN stimulus moved in-phase with the head. The relationship between the vergence angle and OKN stimulus was reversed in the fourth subject. After 2 h of training, the VOR gain at the two vergence angles changed significantly in all of the subjects, evidenced by the two different VOR gains that could be immediately accessed by switching between the diverged and converged conditions. The results demonstrate that subjects can learn to use vergence angle as the contextual cue that retrieves adaptive changes in the angular VOR.
Arrestins participate in the termination of phototransduction in both vertebrates and invertebrates. However, the visual arrestins of invertebrates and vertebrates differ significantly from one another in that the invertebrate visual arrestins become phosphorylated rapidly in response to light while those in the photoreceptors of vertebrates do not. In an effort to understand the functional relevance of arrestin phosphorylation, we examined this process in the photoreceptors of the horseshoe crab Limulus polyphemus. We report that Limulus visual arrestin can be phosphorylated at three sites near its C-terminus and show that arrestin molecules phosphorylated on one, two, and three sites are normally present in both light- and dark-adapted photoreceptors. Light adaptation increases the amount of arrestin phosphorylated at three sites.
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In the vertebrate eye, the retinal pigment epithelium (RPE) and the neural retina arise from a single layer of neuroectoderm. Factors influencing the differentiation of retinal neurons have been identified; however, little is known about molecules directing the differentiation of the RPE. Here we have found that the neurotrophin brain-derived neurotrophic factor (BDNF) plays an autocrine role in the differentiation and survival of Xenopus laevis RPE. Fluorescent in situ hybridization studies showed a precise co-expression of BDNF and its receptor trkB in the retinal neuroepithelium and actively differentiating RPE; in vitro studies demonstrated survival- and differentiation-promoting effects in serum-free explants and dissociated cultures. When a dominant negative mutant of the trkB receptor was expressed in developing embryos, severe arrest of RPE differentiation was seen with persistence of nestin- and Notch-positive neuroblasts.