Increased Light May Moderate Fearful Reactions

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Posted on 12th August 2011 by Pacific ClearVision Institute in Retina

Biologists and psychologists know that light affects mood, but a new University of Virginia study indicates that light may also play a role in modulating fear and anxiety.

Psychologist Brian Wiltgen and biologists Ignacio Provencio and Daniel Warthen of U.Va.’s College of Arts & Sciences worked together to combine studies of fear with research on how light affects physiology and behavior.

Using mice as models, they learned that intense light enhances fear or anxiety in mice, which are nocturnal, in much the same way that darkness can intensify fear or anxiety in diurnal humans.

The finding is published in the Aug. 1 issue of the journal Proceedings of the National Academy of Sciences.

“We looked at the effect of light on learned fear, because light is a pervasive feature of the environment that has profound effects on behavior and physiology,” said Wiltgen, an assistant professor of psychology and an expert on learning. “Light plays an important role in modulating heart rate, circadian rhythms, sleep/wake cycles, digestion, hormones, mood and other processes of the body. In our study we wanted to see how it affects learned fear.”

Fear is a natural mechanism for survival. Some fears — such as of loud noise, sudden movements and heights — appear to be innate. Humans and other mammals also learn from their experiences, which include dangerous or bad situations. This “learned fear” can protect us from dangers.

That fear also can become abnormally enhanced in some cases, sometimes leading to debilitating phobias. About 40 million people in the United States suffer from dysregulated fear and heightened states of anxiety.

“Studies show that light influences learning, memory and anxiety,” Wiltgen said. “We have now shown that light also can modulate conditioned fear responses.”

“In this work we describe the modulation of learned fear by ambient light,” said Provencio, an expert on light and photoreception. “The dysregulation of fear is an important component of many disorders, including generalized anxiety disorder, panic disorder, specific phobias and post-traumatic stress disorder. Understanding how light regulates learned fear may inform therapies aimed at treating some of these fear-based disorders.”

The researchers used a common method for studying learned fear. They cued their mice with a minute-long tone that was followed two seconds later by a quick, mild electrical shock. The mice learned to associate the tone with the shock and quickly became conditioned to duck down and remain motionless when they heard the tone, in the same way they would if a predator appeared.

The researchers discovered that by intensifying the ambient light, the mice showed a greater fear reaction to the tone than when the light was dimmer. This makes sense Wiltgen said, because mice naturally avoid detection by predators by hunkering down motionless as a defense mechanism. In a natural habitat they likewise would become particularly anxious in the presence of a predator in bright light where they would be more easily detected.

“We showed that light itself does not necessarily enhance fear, but more light enhances learned fear,” Wiltgen said. “It may be similar to a person learning to be more fearful in the dark.”

The researchers wanted to understand what visual pathways to the brain in mammals may be responsible for this behavior in the presence of more light. The eye has two pathways that begin in the retina and end in the brain: one is image-forming and made up of rods and cones; the other is the non-image-forming retinal ganglion cells where melanopsin, a circadian rhythm-regulating photo-pigment, is located.

Using two types of mutant mice, ones without rods and cones but with the melanopsin retinal ganglion cells, the others without functioning melanopsin ganglion cells but with rods and cones, the researchers were able to determine that the visual pathway affecting light behavior was in the rods and cones — the image-forming pathway.

“Both pathways have connections to the emotional circuitry of the brain,” Wiltgen said. “The two types of mice are a nice tool for figuring out which pathway controls the light effect.”

By indexing the two types of fear reactions in the presence of increased light, the researchers learned that the image-forming pathway of the rods and cones had the modulating effect on fear.

“The implications of this in humans is this: that being diurnal, the absence of light can be a source of fear,” Wiltgen said. “But increased light can be used to reduce fear and anxiety and to treat depression. If we can come to understand the cellular mechanisms that affect this, then eventually abnormal anxiety and fear might be treated with improved pharmaceuticals to mimic or augment light therapy.”

Researchers Develop Risk Assessment Model for Advanced Age-Related Macular Degeneration

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Posted on 12th August 2011 by Pacific ClearVision Institute in Retina

A new risk assessment model may help predict development of advanced age-related macular degeneration, according to a report published Online First by Archives of Ophthalmology, one of the JAMA/Archives journals.

Age-related macular degeneration (AMD) is a leading cause of blindness in the United States and the Western world, according to background information in the article. “As progress in designing better preventive measures and earlier treatment options accelerates and new gene associations are identified that add to currently known risk factors, the desirability of having a reliable risk assessment model has become of considerable interest and potential value,” write the authors. The model, they explain, should identify individuals with early AMD who are at greatest risk to progress to advanced AMD and should be able to predict when that progression might occur.

Michael L. Klein, M.D., from the Casey Eye Institute, Oregon Health & Science University, Portland, and colleagues sought to design a risk assessment model for development of advanced AMD that included phenotypic (related to observable physical characteristics), demographic, environmental and genetic risk factors. They used longitudinal data from the Age-Related Eye Disease Study, including participants’ DNA samples, ocular and medical histories and examinations. The researchers identified two endpoints: development of advanced AMD in either eye by participants who did not have this condition at baseline, and advanced AMD in a second eye by participants who, at baseline, had it in one eye. Patients were followed for an average of 9.3 years.

The variables included in the final model included simple scale score (a sum of clinical risk factors in both eyes), two genotypes, very large drusen (deposits on the retina associated with AMD), smoking, family history, advanced AMD in one eye and age. The complete model appeared to perform well and to discriminate an individual’s risk of advanced AMD. Of the 2,602 participants in the final model who, at baseline, had no advanced AMD, 24 percent (n = 635) developed advanced AMD during follow-up. Of those with advanced AMD at baseline, 82 percent who had the geographic atrophy (gradual deterioration of retinal cells, called “dry AMD”) type and 56 percent who had the neovascular type (new blood vessel formation and leakage, called “wet AMD”) developed advanced AMD in the other eye.

The results “can be of potential value in clinical practice by helping determine the frequency of follow-up examinations, the use of home monitoring of central vision, and the advisability of initiating preventive measures including beneficial lifestyle changes such as dietary alterations and nutritional supplement use,” the authors note. “The short-term end points (e.g., 2 years) may be helpful in planning clinical trials.” They add that the model performed well on measures of discrimination, calibration and overall performance. “We believe our current model is of substantial value in assessing AMD risk, and we expect that future advances will further improve its accuracy,” they write.

How a Particular Gene Makes Night Vision Possible

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Posted on 12th August 2011 by Pacific ClearVision Institute in Retina

A scientist from the Florida campus of The Scripps Research Institute has determined how a particular gene makes night vision possible. The study, which was published in the August 10, 2011 edition of The Journal of Neuroscience, focuses on a gene called nyctalopin. Mutations in the gene result in inherited “night blindness,” a loss of vision in low-light environments.

“Until now, our understanding of the role of this gene in the visual signaling pathway has been very limited,” said Kirill Martemyanov, an associate professor on the Florida campus of The Scripps Research Institute. “This is the first time we have uncovered a functional role for it — and we linked that function to a much larger molecular complex that’s needed for low-light vision.”

Quick as a Flash:

Our vision begins when photons hit light-sensitive photoreceptor cells in the retina. When excited by light, photoreceptors generate a response that needs to be rapidly transmitted to the downstream neurons (nerve cells) for the signal to be processed and sent to the brain, which then interprets the visual picture. The hand off of the information occurs at the specialized contact points called synapses.

“The proper function of a particular type of synapse between rod photoreceptors and bipolar cells is absolutely critical for the transduction of the visual signal,” Martemyanov explained. “Even if rods generate response to light but are unable to properly transmit the signal, this results in an inability to see in the dark. Without this signaling, we’d have a tough time surviving in the world where it is dark half of the time.”

In addition, the transmission across the synapse must occur rapidly. “The quickness of our signaling response to light creates a clear temporal resolution of what we see,” he said. “For example, when you turn your head suddenly, you see different objects clearly, not just a blur. We couldn’t drive a car without it.”

In the new research, the scientists searched for proteins associated with nyctalopin in the mouse retina. Scientists had known for a decade that the gene encoding nyctalopin is one of the most frequent culprits of night blindness, but its function had remained a mystery. The results showed that the protein expressed by the gene serves as a kind of molecular glue that holds together key elements of the signal transduction machinery at the synapse, allowing for the rapid and intact transmission of these sensory signals.

In molecular terms, the study strongly suggests that nyctalopin coordinates the assembly and precise delivery to the synapse of the macromolecular complex consisting of mGluR6, a neurotransmitter receptor protein, which directly communicates with rod photoreceptors and TRPM1, a protein channel that generates the response, making vision possible.

While the new findings are relevant to the processing of low-light vision, Martemyanov said, the role of nyctalopin might go far beyond the eye. Proteins similar to nyctalopin exist in the central nervous system, and it is possible that they coordinate synaptic signaling in a manner similar to the retina. Indeed, communication between neurons across synapses is fundamental to the nervous system function and disruption of this process is thought to be the main factor contributing to a range of the neuropsychiatric diseases.

The study was supported by the National Institutes of Health.

New Genetic Cause of Blinding Eye Disease

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Posted on 12th August 2011 by Pacific ClearVision Institute in Retina

Combining the expertise of several different labs, University of Iowa researchers have found a new genetic cause of the blinding eye disease retinitis pigmentosa (RP) and, in the process, discovered an entirely new version of the message that codes for the affected protein.

The study, which was published online Aug. 8 in the Proceedings of the National Academy of Sciences (PNAS) Early Edition, suggests that the mutation may be a significant cause of RP in people of Jewish descent. The findings also lay the groundwork for developing prevention and treatment for this form of RP using a combination of genetic testing, gene therapy and cell replacement approaches.

Using the latest DNA sequencing techniques to analyze the protein-coding regions of a single RP patient’s genome, the researchers found a mutation in a gene called MAK (male germ cell associated kinase). This gene had not previously been associated with eye disease in humans. However, examining tissue from donated eyes showed that MAK protein was located in the parts of the retina that are affected by the disease.

The researchers then generated induced pluripotent stem cells (iPSCs) from the patient’s own skin cells and coaxed these immature cells to develop into retinal tissue. Analyzing this tissue showed that the gene mutation caused the loss of the MAK protein in the retina.

“These new technologies have greatly enhanced our ability to find and validate disease-causing mutations, which is critical to our ability to progress to the next step of actually treating diseases like RP,” said Budd Tucker, Ph.D., UI assistant professor of ophthalmology and visual science and lead study author.

RP is an uncommon, inherited blinding eye disease that affects about 1 in 4,000 people in the United States. It is thought to be caused by mutations in more than 100 different genes, only half of which have been identified.

Having found the MAK mutation in one patient, UI researchers led by Edwin Stone, M.D., Ph.D., a Howard Hughes Medical Institute investigator and director of the UI Institute for Vision Research, screened the DNA of 1,798 patients with RP and identified 20 additional individuals with the same MAK mutation. This result suggests that the new MAK mutation accounts for about 1.2 percent of RP cases in the general population. Interestingly, all 21 of the RP patients with the MAK mutation were of Jewish descent, suggesting that the mutation may be a significant cause of RP in this population.

Work in the lab of Robert Mullins, Ph.D., UI associate professor of ophthalmology and visual sciences, showed that MAK protein was produced in the cells most affected by RP. These findings prompted Tucker and colleagues to make iPSCs from the original patient.

“Induced pluripotent stem cells allow us to generate affected tissue from patients with genetic disorders and analyze how specific genetic mutations cause disease,” Tucker said. “It’s particularly powerful when we are looking at inaccessible tissues such as the retina and brain which are not usually biopsied in living individuals.”

Although the MAK gene was previously thought to have 13 protein-coding segments known as exons, when the UI team cloned and sequenced the MAK gene, they discovered a new version of the gene found only in the retina, which has an extra protein-coding exon.

The team also found that the MAK mutation, which involves an insertion of a large piece of DNA into the MAK gene, disrupts the gene in such a way that retinal cells lose the ability to make the longer version of MAK protein.

“What we found was a new retina-specific exon; no other tissue that we tested had this version of the protein-coding transcript” Tucker said. “This is important because the gene mutation identified prevents the production of the retina-specific MAK protein.

“Evidence from the iPSC work validated the role of this genetic mutation in retinal disease. Showing that retinal cells generated from the affected patient could not make the mature retinal MAK protein provided strong evidence of the pathophysiologic mechanism of this mutation in RP,” Tucker explained.

Based on the new work, the UI team hopes to explore gene therapy and cell replacement strategies as potential therapies for this form of RP.

The study was funded in part by grants from the National Eye Institute, National Institutes of Health New Innovator Award program and the Foundation Fighting Blindness.

“We are excited to see the University of Iowa and its collaborators bringing together several different research modalities, including genetics and stem cells, to save vision,” said Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. “Their innovation and teamwork are greatly accelerating the development of treatments which our constituents are depending on.”

In addition to Tucker, Stone and Mullins, the research team included Todd Scheetz, Val Sheffield, Adam DeLuca, Jeremy Hoffman and Rebecca Johnston of the UI and Samuel Jacobson of the Scheie Eye Institute at the University of Pennsylvania.