Improvement of Eye Alignment in Adult Strabismic Monkeys by Sustained IGF-1 Treatment

Purpose: The goal of this study was to determine if continuous application of insulin-like growth factor-1 (IGF-1) could improve eye alignment of adult strabismic nonhuman primates and to assess possible mechanisms of effect. Methods: A continuous release pellet of IGF-1 was placed on one medial rectus muscle in two adult nonhuman primates (M1, M2) rendered exotropic by the alternating monocular occlusion method during the first months of life. Eye alignment and eye movements were recorded for 3 months, after which M1 was euthanized, and the lateral and medial rectus muscles were removed for morphometric analysis of fiber size, nerve, and neuromuscular density. Results: Monkey 1 showed a 40% reduction in strabismus angle, a reduction of exotropia of approximately 11° to 14° after 3 months. Monkey 2 showed a 15% improvement, with a reduction of its exotropia by approximately 3°. The treated medial rectus muscle of M1 showed increased mean myofiber cross-sectional areas. Increases in myofiber size also were seen in the contralateral medial rectus and lateral rectus muscles. Similarly, nerve density increased in the contralateral medial rectus and yoked lateral rectus. Conclusions: This study demonstrates that in adult nonhuman primates with a sensory-induced exotropia in infancy, continuous IGF-1 treatment improves eye alignment, resulting in muscle fiber enlargement and altered innervational density that includes the untreated muscles. This supports the view that there is sufficient plasticity in the adult ocular motor system to allow continuous IGF-1 treatment over months to produce improvement in eye alignment in early-onset strabismus

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Attentional Modulation of Visual Responses by Flexible Input Gain

Although it is clear that sensory responses in the cortex can be strongly modulated by stimuli outside of classical receptive fields as well as by extraretinal signals such as attention and anticipation, the exact rules governing the neuronal integration of sensory and behavioral signals remain unclear. For example, most experiments studying sensory interactions have not explored attention, while most studies of attention have relied on the responses to relatively limited sets of stimuli. However, a recent study of V4 responses, in which location, orientation, and spatial attention were systematically varied, suggests that attention can both facilitate and suppress specific sensory inputs to a neuron according to behavioral relevance. To explore the implications of such input gain, we modeled the effects of a center-surround organization of attentional modulation using existing receptive field models of sensory integration. The model is consistent with behavioral measurements of a suppressive effect that surrounds the facilitatory locus of spatial attention. When this center-surround modulation is incorporated into realistic models of sensory integration, it is able to explain seemingly disparate observations of attentional effects in the neurophysiological literature, including spatial shifts in receptive field position and the preferential modulation of low contrast stimuli. The model is also consistent with recent formulations of attention to features in which gain is variably applied among cells with different receptive field properties. Consistent with functional imaging results, the model predicts that spatial attention effects will vary between different visual areas and suggests that attention may act through a common mechanism of selective and flexible gain throughout the visual system

Temporal Precision of Neuronal Information in a Rapid Perceptual Judgment

In many situations, such as pedestrians crossing a busy street or prey evading predators, rapid decisions based on limited perceptual information are critical for survival. The brevity of these perceptual judgments constrains how neuronal signals are integrated or pooled over time because the underlying sequence of processes, from sensation to perceptual evaluation to motor planning and execution, all occur within several hundred milliseconds. Because most previous physiological studies of these processes have relied on tasks requiring considerably longer temporal integration, the neuronal basis of such rapid decisions remains largely unexplored. In this study, we examine the temporal precision of neuronal activity associated with a rapid perceptual judgment. We find that the activity of individual neurons over tens of milliseconds can reliably convey information about sensory events and was well correlated with the animals' judgments. There was a strong correlation between sensory reliability and the correlation with behavioral choice, suggesting that rapid decisions were preferentially based on the most reliable sensory signals. We also find that a simple model in which the responses of a small number of individual neurons (<5) are summed can completely explain behavioral performance. These results suggest that neuronal circuits are sufficiently precise to allow for cognitive decisions to be based on small numbers of action potentials from highly reliable neurons

Temporal Production Signals in Parietal Cortex

<div><p>We often perform movements and actions on the basis of internal motivations and without any explicit instructions or cues. One common example of such behaviors is our ability to initiate movements solely on the basis of an internally generated sense of the passage of time. In order to isolate the neuronal signals responsible for such timed behaviors, we devised a task that requires nonhuman primates to move their eyes consistently at regular time intervals in the absence of any external stimulus events and without an immediate expectation of reward. Despite the lack of sensory information, we found that animals were remarkably precise and consistent in timed behaviors, with standard deviations on the order of 100 ms. To examine the potential neural basis of this precision, we recorded from single neurons in the lateral intraparietal area (LIP), which has been implicated in the planning and execution of eye movements. In contrast to previous studies that observed a build-up of activity associated with the passage of time, we found that LIP activity decreased at a constant rate between timed movements. Moreover, the magnitude of activity was predictive of the timing of the impending movement. Interestingly, this relationship depended on eye movement direction: activity was negatively correlated with timing when the upcoming saccade was toward the neuron's response field and positively correlated when the upcoming saccade was directed away from the response field. This suggests that LIP activity encodes timed movements in a push-pull manner by signaling for both saccade initiation towards one target and prolonged fixation for the other target. Thus timed movements in this task appear to reflect the competition between local populations of task relevant neurons rather than a global timing signal.</p> </div

Intersaccade durations by direction (A) and sequence number (B) for both animals.

<p>(A) Average intersaccade durations (dots) by direction of movement with standard deviations (bars). Intersaccadic intervals were calculated prior to the upcoming saccade indicated on the <i>x</i>-axis. (B) Same as in (A) showing intersaccade durations by sequence number for the first five saccadic intervals that displayed static targets. Intersaccadic intervals were tightly distributed around the trained interval of 1,000 ms with standard deviations less than the allowable error (±200 ms, dashed lines in A and B). Interval durations are similar between directions and intervals within each animal and between animals. Gray color indicates animal 1. Black color indicates animal 2.</p

Neural responses during self-timed, mapping, and memory saccade tasks.

<p>(A) Average neuronal response of an example cell (<i>N</i> = 1 cell). (B) Average combined population activity during the self-timed task (<i>N</i> = 100 cells). Zero time point (vertical dashed line) indicates time of saccade onset. Red lines indicate response periods during peripheral target fixation, while blue lines indicate response periods during central target fixation. All traces in (A and B) are aligned to saccade onset. Activity decreases at a constant rate prior to both directions of saccades. (C) Average self-timed (<i>N</i> = 100) and mapping responses for the subset of our data with complete mapping runs (<i>N</i> = 39). Black line indicates response obtained during the mapping task (aligned to peripheral target onset on left and peripheral saccade onset on right), as in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001413#pbio-1001413-g003" target="_blank">Figure 3C</a>. The blue line indicates periods of central fixation (blue shading) aligned following central saccade onset (left, C) and prior to peripheral saccade onset (right, C). (D) Same as in (C) except the comparison is between self-timed (blue) and memory trials (black, <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001413#pbio-1001413-g003" target="_blank">Figure 3D</a>) (<i>N</i> = 100). Shading along the <i>x</i>-axis in (C and D) represents the presence of a target stimulus within the RF. Activity during intersaccadic intervals of the self-timed task is different from what is observed from the same cells during mapping and memory-guided saccade tasks in which only a single saccade is required, the reward can be anticipated, and the saccade is cued with a stimulus event (C and D). Shading of firing activity represents standard deviation of the mean.</p