A. Cyrus Arman

Individual Differences among Grapheme-Color Synesthetes: Brain-Behavior Correlations

Grapheme-color synesthetes experience specific colors associated with specific number or letter characters. To determine the neural locus of this condition, we compared behavioral and fMRI responses in six grapheme-color synesthetes to control subjects. In our behavioral experiments, we found that a subjects synesthetic experience can aid in texture segregation (experiment 1) and reduce the effects of crowding (experiment 2). For synesthetes, graphemes produced larger fMRI responses in color-selective area human V4 than for control subjects (experiment 3). Importantly, we found a correlation within subjects between the behavioral and fMRI results; subjects with better performance on the behavioral experiments showed larger fMRI responses in early retinotopic visual areas (V1, V2, V3, and hV4). These results suggest that grapheme-color synesthesia is the result of cross-activation between grapheme-selective and color-selective brain areas. The correlation between the behavioral and fMRI results suggests that grapheme-color synesthetes may constitute a heterogeneous group.

Virally delivered Channelrhodopsin-2 Safely and Effectively Restores Visual Function in Multiple Mouse Models of Blindness

Previous work established retinal expression of channelrhodopsin-2 (ChR2), an algal cation channel gated by light, restored physiological and behavioral visual responses in otherwise blind rd1 mice. However, a viable ChR2-based human therapy must meet several key criteria: (i) ChR2 expression must be targeted, robust, and long-term, (ii) ChR2 must provide long-term and continuous therapeutic efficacy, and (iii) both viral vector delivery and ChR2 expression must be safe. Here, we demonstrate the development of a clinically relevant therapy for late stage retinal degeneration using ChR2. We achieved specific and stable expression of ChR2 in ON bipolar cells using a recombinant adeno-associated viral vector (rAAV) packaged in a tyrosine-mutated capsid. Targeted expression led to ChR2-driven electrophysiological ON responses in postsynaptic retinal ganglion cells and significant improvement in visually guided behavior for multiple models of blindness up to 10 months postinjection. Light levels to elicit visually guided behavioral responses were within the physiological range of cone photoreceptors. Finally, chronic ChR2 expression was nontoxic, with transgene biodistribution limited to the eye. No measurable immune or inflammatory response was observed following intraocular vector administration. Together, these data indicate that virally delivered ChR2 can provide a viable and efficacious clinical therapy for photoreceptor disease-related blindness.

Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities.

In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. Using mice that lack functional rods or in which rods are the only functional photoreceptors, we found that rods were solely responsible for photoentrainment at scotopic light intensities. Rods were also capable of driving circadian photoentrainment at photopic intensities at which they were incapable of supporting a visually guided behavior. Using mice in which cone photoreceptors were ablated, we found that rods signal through cones at high light intensities, but not at low light intensities. Thus, rods use two distinct retinal circuits to drive ipRGC function to support circadian photoentrainment across a wide range of light intensities.

Effects of feature-based attention on the motion aftereffect at remote locations.

Previous studies have shown that attention to a particular stimulus feature, such as direction of motion or color, enhances neuronal responses to unattended stimuli sharing that feature. We studied this effect psychophysically by measuring the strength of the motion aftereffect (MAE) induced by an unattended stimulus when attention was directed to one of two overlapping fields of moving dots in a different spatial location. When attention was directed to the same direction of motion as the unattended stimulus, the unattended stimulus induced a stronger MAE than when attention was directed to the opposite direction. Also, when the unattended location contained either uncorrelated motion or had no stimulus at all an MAE was induced in the opposite direction to the attended direction of motion. The strength of the MAE was similar regardless of whether subjects attended to the speed or luminance of the attended dots. These results provide further support for a global feature-based mechanism of attention, and show that the effect spreads across all features of an attended object, and to all locations of visual space.

Dark-adapted response threshold of OFF ganglion cells is not set by OFF bipolar cells in the mouse retina

The nervous system frequently integrates parallel streams of information to encode a broad range of stimulus strengths. In mammalian retina it is generally believed that signals generated by rod and cone photoreceptors converge onto cone bipolar cells prior to reaching the retinal output, the ganglion cells. Near absolute visual threshold a specialized mammalian retinal circuit, the rod bipolar pathway, pools signals from many rods and converges on depolarizing (AII) amacrine cells. However, whether subsequent signal flow to OFF ganglion cells requires OFF cone bipolar cells near visual threshold remains unclear. Glycinergic synapses between AII amacrine cells and OFF cone bipolar cells are believed to relay subsequently rod-driven signals to OFF ganglion cells. However, AII amacrine cells also make glycinergic synapses directly with OFF ganglion cells. To determine the route for signal flow near visual threshold, we measured the effect of the glycine receptor antagonist strychnine on response threshold in fully dark-adapted retinal cells. As shown previously, we found that response threshold for OFF ganglion cells was elevated by strychnine. Surprisingly, strychnine did not elevate response threshold in any subclass of OFF cone bipolar cell. Instead, in every OFF cone bipolar subclass strychnine suppressed tonic glycinergic inhibition without altering response threshold. Consistent with this lack of influence of strychnine, we found that the dominant input to OFF cone bipolar cells in darkness was excitatory and the response threshold of the excitatory input varied by subclass. Thus, in the dark-adapted mouse retina, the high absolute sensitivity of OFF ganglion cells cannot be explained by signal transmission through OFF cone bipolar cells.

Optimal processing of photoreceptor signals is required to maximize behavioural sensitivity

The sensitivity of receptor cells places a fundamental limit upon the sensitivity of sensory systems. For example, the signal‐to‐noise ratio of sensory receptors has been suggested to limit absolute thresholds in the visual and auditory systems. However, the necessity of optimally processing sensory receptor signals for behaviour to approach this limit has received less attention. We investigated the behavioural consequences of increasing the signal‐to‐noise ratio of the rod photoreceptor single‐photon response in a transgenic mouse, the GCAPs−/− knockout. The loss of fast Ca2+ feedback to cGMP synthesis in phototransduction for GCAPs−/− mice increases the magnitude of the rod single‐photon response and dark noise, with the increase in size of the single‐photon response outweighing the increase in noise. Surprisingly, despite the increased rod signal‐to‐noise ratio, behavioural performance for GCAPs−/− mice was diminished near absolute visual threshold. We demonstrate in electrophysiological recordings that the diminished performance compared to wild‐type mice is explained by poorly tuned postsynaptic processing of the rod single‐photon response at the rod bipolar cell. In particular, the level of postsynaptic saturation in GCAPs−/− rod bipolar cells is not sufficient to eliminate rod noise, and degrades the single‐photon response signal‐to‐noise ratio. Thus, it is critical for retinal processing to be optimally tuned near absolute threshold; otherwise the visual system fails to utilize fully the signals present in the rods.

Perceptual deterioration is reflected in the neural response: fMRI study of nappers and non-nappers

Repeated training on a perceptual task can result in performance deterioration. In the case of vision, this practice-dependent decrease, or perceptual deterioration is restored by changing the target orientation, spatial location, or by taking a daytime nap. Behavioral studies suggest the locus of these performance changes to be primary visual cortex. We used fMRI to directly probe whether perceptual deterioration and nap-dependent maintenance of performance can be detected at the level of primary visual cortex. We also asked whether these changes are due to a bottom–up, stimulus-driven response or a top–down plasticity of attentional mechanisms. Subjects were scanned while performing a texture-discrimination task. Half the subjects took a nap between sessions. We measured the relationship between changes in performance and changes in BOLD signal modulation between the two groups. Non-nappers showed performance deterioration that was significantly correlated with decreased BOLD signal modulation, exclusively in area V1 and limited to the bottom–up condition. In contrast, no change was detected in performance and BOLD response in the two conditions for nappers. These results indicate that napping prevented performance deterioration, which was reflected in the fMRI response of neurons in V1. Without a nap, perceptual deterioration was related to decreases in the stimulus-driven, bottom–up representation, rather than decreases in attentional modulation to the stimulus.

Patch Clamp Recordings from Mouse Retinal Neurons in a Dark-adapted Slice Preparation

Our visual experience is initiated when the visual pigment in our retinal photoreceptors absorbs photons of light energy and initiates a cascade of intracellular events that lead to closure of cyclic-nucleotide-gated channels in the cell membrane. The resulting change in membrane potential leads in turn to reductions in the amount of neurotransmitter release from both rod and cone synaptic terminals. To measure how the light-evoked change in photoreceptor membrane potential leads to downstream activity in the retina, scientists have made electrophysiological recordings from retinal slice preparations for decades. In the past these slices have been cut manually with a razor blade on retinal tissue that is attached to filter paper; in recent years another method of slicing has been developed whereby retinal tissue is embedded in low gelling temperature agar and sliced in cool solution with a vibrating microtome. This preparation produces retinal slices with less surface damage and very robust light-evoked responses. Here we document how this procedure can be done under infrared light to avoid bleaching the visual pigment.