Does a full vision restoration happen after treatment from being blind from birth?

A partial restoration of sight is possible in individuals blind from birth, thanks to the most recent advances in research. However, a group of researchers of the Mind/Brain Center of the University of Trento and of the University of Montréal in Canada have discovered that the functional reorganization of the brain happens in individuals who, for a long period, experienced a long sense deprivation, which could potentially impede complete sight restoration.

Implanted neurons fuse with pre-existing brain wiring in the lab

Among the many hurdles to be cleared before human embryonic stem cells can achieve their therapeutic potential is determining whether or not transplanted cells can functionally integrate into target organs or tissues.

Writing in the Proceedings of the National Academy of Sciences (PNAS) , a team of Wisconsin scientists reports, in a study funded by the US National Institutes of Health, that neurons, forged in the lab from blank slate human embryonic stem cells and implanted into the brains of mice, can successfully fuse with the brain's wiring, and both send and receive signals.

Neurons are specialized, impulse conducting cells that are the most elementary functional unit of the central nervous system. The 100 billion or so neurons in the human brain are constantly sending and receiving the signals that govern everything from walking and talking to thinking. The work represents a crucial step toward deploying customized cells to repair damaged or diseased brains, the most complex human organ.

"The big question was can these cells integrate in a functional way," says Jason P. Weick, the lead author of the new study and a staff scientist at the University of Wisconsin-Madison's Waisman Center. "We show for the first time that these transplanted cells can both listen and talk to surrounding neurons of the adult brain."

The Wisconsin team tested the ability of their lab grown neurons to integrate into the brain's circuitry by transplanting the cells into the adult mouse hippocampus, a well-studied region of the brain that plays a key role in processing memory and spatial navigation. The capacity of the cells to integrate was observed in live tissue taken from the animals that received the cell transplants.

Weick and colleagues also reported that the human neurons adopted the rhythmic firing behavior of many brain cells talking to one another in unison. And, perhaps more importantly, that the human cells could modify the way the neural network behaved.

A critical tool that allowed the UW group to answer this question was a new technology known as optogenetics, where light, instead of electric current, is used to stimulate the activity of the neurons.

"Previously, we've been limited in how efficiently we could stimulate transplanted cells. Now we have a tool that allows us to specifically stimulate only the transplanted human cells, and lots of them at once in a non-invasive way," says Weick.

Weick explains that the capacity to modulate the implanted cells was a necessary step in determining the function of implanted cells because previous technologies were too imprecise and unreliable to accurately determine what transplanted neurons were doing.

Embryonic stem cells, and the closely related induced pluripotent stem cells can give rise to all of the 220 types of tissues in the human body, and have been directed in the lab to become many types of cells, including brain cells.

The appeal of human embryonic stem cells and induced pluripotent cells is the potential to manufacture limitless supplies of healthy, specialized cells to replace diseased or damaged cells. Brain disorders such as Parkinson's disease and amyotrophic lateral sclerosis, more widely known as Lou Gehrig's disease, are conditions that scientists think may be alleviated by using healthy lab grown cells to replace faulty ones. Multiple studies over the past decade have shown that both embryonic stem cells and induced cells can alleviate deficits of these disorders in animal models.

The new study opens the door to the potential for clinicians to deploy light-based stimulation technology to manipulate transplanted tissue and cells. "The marriage between stem cells and optogenetics has the potential to assist in the treatment of a number of debilitating neurodegenerative disorders," notes Su-Chun Zhang, a UW-Madison professor of neuroscience and an author of the new PNAS report. "You can imagine that if the transplanted cells don't behave as they should, you could use this system to modulate them using light."

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Editorial note: Outcome from this research will have a major role to play in retinal diseases, since retina is considered to be a part of the brain, and most stem cell treatments have not been successful due to issues with connectivity of the newly formed retinal cells derived from stem cells, with the functional ones that preexist in the retina. 

Diabetes can lead to memory loss, depression and other cognitive impairment in older adults

Many complications of diabetes, including kidney disease, foot problems and vision problems are generally well recognized. But the disease's impact on the brain is often overlooked.

For the past five years, a team led by Beth Israel Deaconess Medical Center (BIDMC) neurophysiologist Vera Novak, MD, PhD, has been studying the effects of diabetes on cognitive health in older individuals and has determined that memory loss, depression and other types of cognitive impairment are a serious consequence of this widespread disease.

Now, Novak's team has identified a key mechanism behind this course of events. In a study published in the November 2011 issue of the journal Diabetes Care, they report that in older patients with diabetes, two adhesion molecules – sVCAM and sICAM – cause inflammation in the brain, triggering a series of events that affect blood vessels and, eventually, cause brain tissue to atrophy. Importantly, they found that the gray matter in the brain's frontal and temporal regions -- responsible for such critical functions as decision-making, language, verbal memory and complex tasks – is the area most affected by these events.

"In our previous work, we had found that patients with diabetes had significantly more brain atrophy than did a control group," explains Novak, Director of the Syncope and Falls in the Elderly (SAFE) Program in the Division of Gerontology at BIDMC and Associate Professor of Medicine at Harvard Medical School. "In fact, at the age of 65, the average person's brain shrinks about one percent a year, but in a diabetic patient, brain volume can be lowered by as much as 15 percent."

Diabetes develops when glucose builds up in the blood instead of entering the body's cells to be used as energy. Known as hyperglycemia, this condition often goes hand-in-hand with inflammation. Novak wanted to determine if chronic inflammation of the blood vessels was causing altered blood flow to the brain in patients with diabetes.

To test this hypothesis, Novak's team recruited 147 study subjects, averaging 65 years of age. Seventy one of the subjects had type 2 diabetes and had been taking medication to manage their conditions for at least five years. The other 76 were age and sex-matched non-diabetic controls.

Study subjects underwent a series of cognitive tests, balance tests and standard blood-pressure and blood-glucose tests. Serum samples were also collected to measure adhesion molecules and several other markers of systemic inflammation. To determine perfusion (blood flow) measures in the brain, patients also underwent functional MRI testing, in which a specialized imaging technique known as arterial spin labeling (developed by BIDMC MR physicist David Alsop, PhD) was used in conjunction with a standard MRI to measure vascular reactivity in several brain regions and to show changes in blood flow.

As predicted, the scans showed that the diabetic patients not only had greater blood vessel constriction than the control subjects, but they also had more atrophied brain tissue, particularly gray matter. The results also showed that, in the patients with diabetes, the frontal, temporal and parietal regions of the brain were most affected. Similarly, the team's measurements of serum markers confirmed that high glucose levels were strongly correlated with higher levels of inflammatory cytokines.

"It appears that chronic hyperglycemia and insulin resistance – the hallmarks of diabetes – trigger the release of adhesion molecules [sVCAM and sICAM] and set off a cascade of events leading to the development of chronic inflammation," says Novak. "Once chronic inflammation sets in, blood vessels constrict, blood flow is reduced, and brain tissue is damaged. "

This discovery now provides two biomarkers of altered vascular reactivity in the brain. "If these markers can be identified before the brain is damaged, we can take steps to try and intervene," says Novak, explaining that some data indicates that medications may improve vascoreactivity.

But more important, she says, the new findings provide still more reason for doctors and patients to focus greater attention on the management – and prevention – of diabetes.

"Cognitive decline affects a person's ability to successfully complete even the simplest of everyday tasks, such as walking, talking or writing," says Novak. "There are currently 25.8 million cases of type 2 diabetes in the United States alone, which is more than eight percent of our total population. The effects of diabetes on the brain have been grossly neglected, and, as our findings confirm, are issues that need to be addressed."

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Is pupillary light reflex really controlled by the brain?

You’ve seen it on television: A doctor shines a bright light into an unconscious patient’s eye to check for brain death. If the pupil constricts, the brain is OK, because in mammals, the brain controls the pupil. Or does it? Now, researchers at Johns Hopkins have discovered that in most mammals, in fact in most vertebrates, the pupil can constrict without any input from the brain. Their work, which also describes for the first time the molecular mechanism underlying this process, appears in the Nov. 3 issue of Nature.

“It was established more than 40 years ago that animals like amphibians and fish have photosensitive irises and don’t necessarily require the brain for the pupillary light reflex, whereas it was thought that mammals generally required brain circuitry,” says King-Wai Yau, Ph.D., professor of neuroscience and ophthalmology at the Johns Hopkins University School of Medicine and member of the Institute for Basic Biomedical Sciences Center for Sensory Biology. “But in neither case did anyone know what the molecular switch was, and now we have found that it’s the pigment melanopsin.”

The research team examined isolated irises from a wide range of mammals by attaching a tiny meter that measures the force of the sphincter muscle that constricts the pupil. They then shined a bright light onto this muscle and measured any contraction. Irises from nocturnal animals including mouse, rat, hamster, dog, cat, rabbit and the Nile grass rat all showed responses to light. Irises from diurnal animals including guinea pig, ground squirrel and pig did not, nor did those from rhesus monkey, marmoset, owl monkey and bush baby, even though the owl monkey and bush baby are nocturnal.

“Most non-primate mammals are considered nocturnal or crepuscular — active at dawn and dusk — including those, like dogs, that have been domesticated and have picked up human circadian rhythms,” says Yau. “We don’t really know why primates, including us, as well as other daytime functioning animals don’t have this ability.” According to Yau, the eyes of nocturnal animals, because they function in the dark, contain more cells that are sensitive to low light and exposure to bright light could cause eye damage. Perhaps, he suggests, the built-in pupil reflex is a good way to protect the eye.

“So we wanted to know what pigment molecules are involved in triggering pupil constriction,” says Yau. Having previously genetically engineered mice to lack melanopsin, the team first tested the pupillary light reflex on irises from these mice. “That was a really exciting result—they didn’t respond to the light,” says Tian Xue, a research associate with Yau. They also tested mice engineered to lack other light-capturing pigments, but all of them responded normally, suggesting that only melanopsin is required for the local pupil reflex. Using mouse genetics, the team then continued to try to identify other proteins that work with melanopsin to cause the pupil to contract in response to light.

Because melanopsin is closely related to the pigment responsible for capturing light in fly eyes, and that molecular pathway has been well studied, Yau’s team hypothesized that the mammalian counterparts to these fly molecules might be what works with melanopsin. So they tested mice engineered to lack some of these molecules. They found that irises from mice lacking the PLC enzyme were unresponsive to light, showing that PLC also is involved in this reflex.

There still are a lot of things we don’t know that we would like to study,” says Yau. “Now that we know what captures the light and starts the local reflex, we would like to know what proteins in the muscle trigger the actual contraction.”

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Nature's Editorial Summary: "Mammalian pupil sees the light"

Contraction of the mammalian iris in response to light has been thought to require neuronal circuitry connecting the retina to the brain. Now King Yau and colleagues report the surprising observation that in a wide variety of mammals, the eye's pupil is intrinsically photosensitive. Iris muscles isolated from nocturnal mammals such as mice — but not from primates — contract when exposed to light through the action of a melanopsin-based signalling pathway that partially overlaps with its retinal counterpart. Previously, the intrinsic pupillary reflex was thought to be an exclusive property of lower vertebrates such as fish, amphibians and birds. For those who want to read the article in detail, please click here.