Running, Combined with Visual Experience, Restores Brain Function

In a new study by UC San Francisco scientists, running, when accompanied by visual stimuli, restored brain function to normal levels in mice that had been deprived of visual experience in early life.

In addition to suggesting a novel therapeutic strategy for humans with blindness in one eye caused by a congenital cataract, droopy eyelid, or misaligned eye, the new research—the latest in a series of UCSF studies exploring effects of locomotion on brain function—suggests that the adult brain may be far more capable of rewiring and repairing itself than previously thought.

In 2010, Michael P. Stryker, PhD, the W.F. Ganong Professor of Physiology, and postdoctoral fellow Cris Niell, PhD, now at the University of Oregon, made the surprising discovery that neurons in the visual area of the mouse brain fired much more robustly whenever the mice walked or ran.

Earlier this year, postdoctoral fellow Yu Fu, PhD, Stryker and a number of colleagues built on these findings, identifying and describing the neural circuit responsible for this locomotion-induced “high-gain state” in the visual cortex of the mouse brain.

Neither of these studies made clear, however, whether this circuit might have broader functional or clinical significance.

It has been known since the 1960s that visual areas of the brain do not develop normally if deprived of visual input during a “critical period” of brain development early in life. For example, in humans, if amblyopia (“lazy eye”) or other major eye problems are not surgically corrected in infancy, vision will never be normal in the affected eye—if such individuals lose sight in their “good” eye in later life, they are blind.

In the new research, published June 26, 2014 in the online journal eLife, Stryker and UCSF postdoctoral fellow Megumi Kaneko, MD, PhD, closed one eyelid of mouse pups at about 20 days after birth, and that eye was kept closed until the mice reached about five months of age.

As expected, the mice in which one eye had been closed during the critical developmental period showed sharply reduced neural activity in the part of the brain responsible for vision in that eye.

As in the previous UCSF experiments in this area, some mice were allowed to run freely on Styrofoam balls suspended on a cushion of air while recordings were made from their brains.

Little improvement was seen in the mice that had been deprived of visual input either when they were simply allowed to run or when they received visual training with the deprived eye not accompanied by walking or running.

But when the mice were exposed to the visual stimuli while they were running or walking, the results were dramatic: within a week the brain responses to those stimuli from the deprived eye were nearly identical to those from the normal eye, indicating that the circuits in the visual area of the brain representing the deprived eye had undergone a rapid reorganization, known in neuroscience as “plasticity.”

Interestingly, this recovery was stimulus-specific: if the brain activity of the mice was tested using a stimulus other than that they had seen while running, little or no recovery of function was apparent.

“We have no idea yet whether running puts the human cortex into a high-gain state that enhances plasticity, as it does the visual cortex of the mouse,” Stryker said, “but we are designing experiments to find out.”

Re-learning how to see: researchers find crucial on-off switch in visual development

A new discovery by a University of Maryland-led research team offers hope for treating “lazy eye” and other serious visual problems that are usually permanent unless they are corrected in early childhood.

Amblyopia afflicts about three percent of the population, and is a widespread cause of vision loss in children. It occurs when both eyes are structurally normal, but mismatched – either misaligned, or differently focused, or unequally receptive to visual stimuli because of an obstruction such as a cataract in one eye.

During the so-called “critical period” when a young child’s brain is adapting very quickly to new experiences, the brain builds a powerful neural network connecting the stronger eye to the visual cortex. But the weaker eye gets less stimulation and develops fewer synapses, or points of connection between neurons. Over time the brain learns to ignore the weaker eye. Mild forms of amblyopia such as “lazy eye” result in problems with depth perception. In the most severe form, deprivation amblyopia, a cataract blocks light and starves the eye of visual experiences, significantly altering synaptic development and seriously impairing vision.

Because brain plasticity declines rapidly with age, early diagnosis and treatment of amblyopia is vital, said neuroscientist Elizabeth M. Quinlan, an associate professor of biology at UMD. If the underlying cause of amblyopia is resolved early enough, the child’s vision can recover to normal levels. But if the treatment comes after the end of the critical period and the loss of synaptic plasticity, the brain cannot relearn to see with the weaker eye.

“If a child is born with a cataract and it is not removed very early in life, very little can be done to improve vision,” Quinlan said. “The severe amblyopia that results is the most difficult to treat. For that reason, science has the most to gain by a better understanding of the underlying mechanisms.”

Quinlan, who specializes in studying how communication through the brain’s circuits changes over the course of a lifetime, wanted to find out what process controls the timing of the critical period of synaptic plasticity. If researchers could find the neurological on-off switch for the critical period, she reasoned, clinicians could use the information to successfully treat older children and adults.

Researchers in Quinlan’s University of Maryland lab teamed up with the laboratory of Alfredo Kirkwood at Johns Hopkins University to address two questions: What are the age boundaries of the critical period for synaptic plasticity, when it comes to determining eye dominance? And what developmental processes are involved?

Experiments in rodents suggested the timing of the critical period is controlled by a specific class of inhibitory neurons, which come into play after a visual stimulus activates excitatory neurons that link the eye to the visual cortex. The inhibitory neurons act as signal controllers, affecting the interactions between excitatory neurons and synapses.

“The generally accepted view has been that as the inhibitory neurons develop, synaptic plasticity declines, which was thought to occur at about five weeks of age in rodents,” roughly equivalent to five years of age in humans, Quinlan said. But in earlier experiments, Quinlan and Kirkwood found no correlation between the development of these inhibitory neurons and the loss of plasticity. In fact, they found the visual circuitry in rodents was highly adaptable at ages beyond five weeks.

In their latest research the UMD-led team looked “one synapse upstream from these inhibitory neurons,” Quinlan said, studying the control of that synapse by a protein called NARP (Neuronal Activity-Regulated Pentraxin). Working with two sets of mice – one group genetically similar to wild mice and another that lacked the NARP gene - the researchers covered one eye in each animal to simulate conditions that produce amblyopia.

The mice that were genetically similar to wild mice developed amblyopia, with characteristic dominance of the normal eye over the deprived eye. But the mice that lacked NARP did not develop amblyopia, regardless of age or the length of time one eye was deprived of stimulation.

The study, published in the current issue of the peer-reviewed journal Neuron, demonstrated that only one specific class of synapses was affected by the absence of NARP. Without NARP, the mice simply had no critical period in which the brain circuitry was weakened in response to the impaired blocking vision in one eye, Quinlan said. Except for the lack of this plasticity, their vision was normal.

“It’s remarkable how specific the deficit is,” Quinlan said. Without the NARP protein, “these animals develop normal vision. Their brain circuitry just isn’t plastic. We can completely turn off the critical period for plasticity by knocking out this protein.”

Since there are indications that NARP levels vary with age, the discovery raises hope that a treatment targeting NARP levels in humans could allow correction of amblyopia late in life, without affecting other aspects of vision.

Vision restored with total darkness

Restoring vision might sometimes be as simple as turning out the lights. That’s according to a study reported on February 14 in Current Biology, a Cell Press publication, in which researchers examined kittens with a visual impairment known as amblyopia before and after they spent 10 days in complete darkness.

Researchers Kevin Duffy and Donald Mitchell of Dalhousie University in Canada believe that exposure to darkness causes some parts of the visual system to revert to an early stage in development, when there is greater flexibility.

"There may be ways to increase brain plasticity and recover from disorders such as amblyopia without drug intervention," Duffy says. "Immersion in total darkness seems to reset the visual brain to enable remarkable recovery."

Amblyopia affects about four percent of the general population and is thought to develop when the two eyes do not see equally well in early life, as the connections from the eyes to visual areas in the brain are still being refined. Left untreated, that imbalance of vision can lead to permanent vision loss.

In the new study, the researchers examined kittens with amblyopia induced by experimentally depriving them of visual input to one eye. After those animals were plunged into darkness, their vision made a profound and rapid recovery. Further examination suggested that the restoration of vision depends on the loss of neurofilaments that hold the visual system in place. With those stabilizing elements gone, the visual system becomes free to correct itself.

Darkness therapy holds promise for the treatment of children with amblyopia, the researchers say, but don’t try this at home. They think that the darkness must be absolute to work, with no stray light at any time. It is also important to address the original cause of the amblyopia first, and to ensure that a period of darkness will not harm an individual’s good eye.

The researchers are still working out just how much darkness is required, and for how long. Regardless, they say it is unlikely that a drug could ever adequately mimic the effects of darkness that they’ve seen.

"The advantage of a simple nonpharmacological sensory manipulation, such as a period of darkness, is that it may initiate changes in a constellation of molecules in a beneficial temporal order and in appropriate brain regions," they write.

Abnormal Involuntary Eye Movements in the “Lazy Eye” Disease Amblyopia Linked to Changes in Subcortical Regions of the Brain

The neural mechanism underlying amblyopia, also called “lazy eye” is still not completely clear. A new study now reports abnormal eye movements of the lazy eye, which suggests that disturbed functioning of eye movement coordination between both eyes and not primarily the dysfunction of the visual cortex may be a cause of amblyopia (Xue-feng Shi et al.).

Little is known about oculomotor function in amblyopia, or “lazy eye,” despite the special role of eye movements in vision. A group of scientists has discovered that abnormal visual processing and circuitry in the brain have an impact on fixational saccades (FSs), involuntary eye movements that occur during fixation and are important for the maintenance of vision. The results, which raise the question of whether the alterations in FS are the cause or the effect of amblyopia and have implications for amblyopia treatment, are available online in advance of publication in the November issue of Restorative Neurology and Neuroscience.

“Although FSs are of great functional significance in neural coding, visual perception, and visual task execution, their behavioral characteristics in visual and neurological disease have been rarely studied,” says lead investigator Xue-Feng F. Shi, MD, PhD, of the Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, College of Clinical Ophthalmology, Tianjin Medical University, and the Department of Pediatric Ophthalmology and Strabismus, Tianjin Eye Hospital, Tianjin, China. “We carried out quantitative and detailed analysis of fixational saccades in amblyopia for the first time.”