Optogenetics combines optics and genetics to control neuronal activity with cell-type specificity and millisecond temporal precision. Its use in model organisms such as rodents, Drosophila, and Caenorhabditis elegans is now well-established. However, application of this technology in nonhuman primates (NHPs) has been slow to develop. One key challenge has been the delivery of viruses and light to the brain through the thick dura mater of NHPs, which can only be penetrated with large-diameter devices that damage the brain. The opacity of the NHP dura prevents visualization of the underlying cortex, limiting the spatial precision of virus injections, electrophysiological recordings, and photostimulation. Here, we describe a new optogenetics approach in which the native dura is replaced with an optically transparent artificial dura. This artificial dura can be penetrated with fine glass micropipettes, enabling precisely targeted injections of virus into brain tissue with minimal damage to cortex. The expression of optogenetic agents can be monitored visually over time. Most critically, this optical window permits targeted, noninvasive photostimulation and concomitant measurements of neuronal activity via intrinsic signal imaging and electrophysiological recordings. We present results from both anesthetized-paralyzed (optical imaging) and awake-behaving NHPs (electrophysiology). The improvements over current methods made possible by the artificial dura should enable the widespread use of optogenetic tools in NHP research, a key step toward the development of therapies for neuropsychiatric and neurological diseases in humans.
Vision in natural situations is different from the paradigms generally used to study vision in the laboratory. In natural vision, stimuli usually appear in a receptive field as the result of saccadic eye movements rather than suddenly flashing into view. The stimuli themselves are rich with meaningful and recognizable objects rather than simple abstract patterns. In this study we examined the sensitivity of neurons in macaque area V1 to saccades and to complex background contexts. Using a variety of visual conditions, we find that natural visual response patterns are unique. Compared with standard laboratory situations, in more natural vision V1 responses have longer latency, slower time course, delayed orientation selectivity, higher peak selectivity, and lower amplitude. Furthermore, the influences of saccades and background type (complex picture vs. uniform gray) interact to give a distinctive, and presumably more natural, response pattern. While in most of the experiments natural images were used as background, we find that similar synthetic unnatural background stimuli produce nearly identical responses (i.e., complexity matters more than "naturalness"). These findings have important implications for our understanding of vision in more natural situations. They suggest that with the saccades used to explore complex images, visual context ("surround effects") would have a far greater effect on perception than in standard experiments with stimuli flashed on a uniform background. Perceptual thresholds for contrast and orientation should also be significantly different in more natural situations.
It has been proposed that low-threshold Ca2+ (LT)-associated bursts in the lateral geniculate nucleus (LGN) of awake animals communicate significant or unexpected visual events to cortex. The present study investigated this hypothesis by examining the incidence of LT bursts in 146 cells recorded from the LGN of three macaque monkeys. Bursts were defined as clusters of two or more action potentials separated by not more than 4 ms and preceded by a > or = 100-ms quiescent interval. The incidence of bursts was examined in several intensive-training Go-NoGo and target selection tasks as well as in training-free tasks where natural scenes with both familiar and novel contents were shown. Our chief findings were as follows. 1) Bursts occur in the majority of cells under every condition tested, 2) burst incidence is very low (<1 burst every 10 s), 3) bursts occur in association with a receptive field stimulus on average only once every 23 times in 65% of cells tested, 4) cells responding with bursts to the stimulus also tended to exhibit higher levels of spontaneous bursting, 5) the presence of bursts did not depend on the novelty of the stimulus or its behavioral relevance. When the monkeys explored static natural scenes, 6) bursts were not correlated with short-term changes in the image sampled by the cell's receptive field during saccades. Burst incidence 7) did not increase when images were novel or when they evoked an emotional reaction, and 8) bursts did not decrease when images were familiar. 9) Bursts were not correlated with saccades in the dark, but 10) more spikes participated in bursts in the dark. Although these results confirm the occurrence of LT bursts in LGN cells of awake monkeys, they do not support the hypothesis that these bursts are a privileged means of transferring sensory information, that they signal unexpected or significant visual events, or that they are involved uniquely in the coding of natural scenes.
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