Neuroscience

Amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is marked by a cascade of cellular and inflammatory events that weakens and kills vital motor neurons in the brain and spinal cord. The process is complex, involving cells that ordinarily protect the neurons from harm. Now, a new study by scientists in The Research Institute at Nationwide Children’s Hospital points to a potential culprit in this good-cell-gone-bad scenario, a key step toward the ultimate goal of developing a treatment.

Motor neurons, or nerve cells, in the brain and spinal cord control the function of muscles throughout the body. In amyotrophic lateral sclerosis (ALS), motor neurons die and muscles weaken. Patients gradually lose the ability to move and as the disease progresses, are unable to breathe on their own. Most people with ALS die from respiratory failure within 3 to 5 years from the onset of symptoms.

For the study, published recently online in Neuron, researchers examined a protein involved in transcriptional regulation, called nuclear factor-kappa B (NF-κB), known to play a role in the neuroinflammatory response common in ALS. NF-κB has also been linked to cancer and a number of other inflammatory and autoimmune diseases.

Using animal models, the researchers studied disease progression in mice in which NF-κB had been inhibited in two different cell types — astrocytes, the most abundant cell type in the human brain and supporters of neuronal function; and microglia, macrophages in the brain and spinal cord that act as the first and main form of defense against invading pathogens in the central nervous system. Inhibiting NF-κB in microglia in mice slowed disease progression by 47 percent, says Brian Kaspar, MD, a principal investigator in the Center for Gene Therapy at Nationwide Children’s and senior author of the new study.

“The field has identified different cell types in addition to motor neurons involved in this disease, so one of our approaches was to find out what weapons these cells might be using to kill motor neurons,” Dr. Kaspar says. “And our findings suggest that the microglia utilize an NF-κB-mediated inflammatory response as one of its weapons.”

Inhibiting the protein in astrocytes had no impact on disease progression, so the search for the weapons that cell type uses against motor neurons continues. These preliminary findings also don’t tell scientists how or why NF-κB turns the ordinarily protective microglia into neuron-killing molecules. But despite the mysteries that remain, the study moves scientists closer to finding a treatment for ALS.

The search for an ALS therapy has been focused in two directions: identifying the trigger that leads to disease onset and understanding the process that leads to disease progression. Changes in motor neurons are involved in disease onset, but disease progression seems to be dictated by changes to astrocytes, microglia and oligodendrocytes. Some cases of ALS are hereditary but the vast majority of patients have no family ties to the disease. The complexity of the disease and the lack of a clear familiar tie make screening before disease onset nearly impossible, highlighting the importance of slowing the disease, Dr. Kaspar says.

“Focusing on stopping the changes that occur in astrocytes and microglia has clinical relevance because most people don’t know they’re getting ALS, says Dr. Kaspar, who also is an associate professor of pediatrics and neurosciences at The Ohio State University College of Medicine. “We have identified a pathway in microglia that may be targeted to ultimately slow disease progression in ALS and are exploring potential therapeutic strategies and may have broader implications for diseases such as Alzheimer’s and Parkinson’s Disease amongst others.”

Long-term brain damage caused by stroke could be reduced by saving cells called pericytes that control blood flow in capillaries, suggest researchers from Oxford University, UCL and the University of Copenhagen.

Until now, many scientists believed that blood flow within the brain was solely controlled by changes in the diameter of arterioles, blood vessels that branch out from arteries into smaller capillaries.

In this new study, the UK and Danish researchers reveal that the brain’s blood supply is in fact chiefly controlled by the narrowing or widening of capillaries as pericytes tighten or loosen around them.

Their study, published this week in the journal Nature, shows not only that pericytes are the main regulator of blood flow to the brain, but also that they tighten and die around capillaries after stroke. This significantly impairs blood flow in the long term, causing lasting damage to brain cells.

The scientists showed that certain chemicals can halve pericyte death from simulated stroke in the lab, and they hope to develop these into drugs to treat stroke victims.

'This discovery offers radically new treatment approaches for stroke,' says study co-author Professor Alastair Buchan, Dean of Medicine and Head of the Medical Sciences Division at Oxford University. 'Importantly, we should now be able to identify drugs that target these cells. If we are able to prevent pericytes from dying, it should help restore blood flow in the brain to normal and prevent the ongoing slow damage we see after a stroke which causes so much neurological disability in our patients.'

Professor David Attwell of UCL, who led the study, explains: ‘At present, clinicians can remove clots blocking blood flow to the brain if stroke patients reach hospital early enough. However, the capillary constriction produced by pericytes may, by restricting the blood supply for a long time, cause further damage to nerve cells even after the clot is removed. Our latest research suggests that devising drugs to prevent capillary constriction may offer new therapies for reducing the disability caused by stroke.’

The new research also gives insight into the mechanisms underlying the use of functional magnetic resonance imaging to detect blood flow changes in the brain.

'Functional imaging allows us to see the activity of nerve cells within the human brain but until now we didn't quite know what we were looking at,' says Professor Martin Lauritzen of the University of Copenhagen. 'We have shown that pericytes initiate the increase in blood flow seen when nerve cells become active. So we now know that functional imaging signals are caused by a pericyte-mediated increase of capillary diameter. Knowing exactly what functional imaging shows will help us to better understand and interpret what we see.'

Working with genetically engineered mice, Johns Hopkins neuroscientists report they have identified what they believe is the cause of the vast disintegration of a part of the brain called the corpus striatum in rodents and people with Huntington’s disease: loss of the ability to make the amino acid cysteine. They also found that disease progression slowed in mice that were fed a diet rich in cysteine, which is found in foods such as wheat germ and whey protein.

Their results suggest further investigation into cysteine supplementation as a candidate therapeutic in people with the disease.

Up to 90 percent of the human corpus striatum, a brain structure that moderates mood, movement and cognition, degenerates in people with Huntington’s disease, a condition marked by widespread motor and intellectual disability. And while the genetic mutation underlying Huntington’s disease has long been known, the precise cause of that degeneration has remained a mystery.

In a report on their discovery in the advanced online publication of Nature on March 26, the Johns Hopkins researchers, led by Solomon Snyder, M.D., tracked the degenerative process to the absence of an enzyme, cystathionine gamma lyase, or CSE.

"Usually it’s very hard, if not impossible, to develop straightforward mechanisms that explain what’s going on in a disease. What’s even harder is even if you can find a mechanism that causes a tissue to rot, usually there’s nothing you can do about it,” says Snyder, a professor of neuroscience at the Johns Hopkins University School of Medicine. “In this case, there is."

Huntington’s disease, an inherited disorder, does its damage because of abnormal DNA coding for the amino acid glutamine. Healthy individuals have some 15 to 20 DNA “repeats” in that part of their genetic code, while Huntington’s disease gene carriers have more than 36 — and often upward of 100. Children born to a parent carrier have a 50/50 chance of inheriting the disorder, and the greater the number of repeats, the earlier the age of onset of the incurable disorder.

Bindu Diana Paul, Ph.D., a molecular neuroscientist and faculty instructor in Snyder’s laboratory, was studying mice lacking CSE, which helps make the amino acid cysteine and hydrogen sulfide that moderate blood pressure and heart function. Paul, who had previous research experience with Huntington’s disease, says she was startled to observe that her mutant mice also behaved a lot like those with the disease.

When a normal mouse is dangled upside down from its tail, it will twist and turn and try to bite the offending hand, she explains. But her CSE-knockout mice stayed relatively still and clasped their paws together — the same behavior she’d observed in mice with the rodent equivalent of Huntington’s disease. “It looked like there was a neurological deficit,” Paul says. “But nobody had looked at CSE in the brain.”

Paul and Snyder began monitoring CSE in mouse and human brain tissues and found considerably less CSE in all diseased tissues. All people carry some normal huntingtin protein made by the Huntington’s disease gene, although the protein’s function remains elusive. But people with Huntington’s disease also carry mutant huntingtin proteins. Snyder and his team saw that the mutant proteins were attaching themselves to a crucial protein responsible for turning the CSE gene on or off, which ultimately led the diseased rodent and human brain tissues to be deprived of cysteine.

To see if loss of cysteine was directly responsible for the symptoms associated with Huntington’s disease, the Johns Hopkins team turned to readily available sources of the substance in everyday foods and fed mice a cysteine-rich diet.

The results, Paul says, were striking. When those mice were dangled from their tails, they resumed struggling, although with a bit less vigor than their healthy peers. They were able to grip an object with greater strength, and they took longer to fall off a balancing apparatus than CSE-knockout mice. Their life expectancies increased one to two weeks.

Snyder and Paul say they are cautiously optimistic about the results, noting that although they suggest a possible treatment for Huntington’s disease, it’s clear that a high cysteine diet merely slows rather than halts the progression of the disease. Moreover, the results in live mice may not occur in humans.

The problems people with autism have with memory formation, higher-level thinking and social interactions may be partially attributable to the activity of receptors inside brain cells, researchers at Washington University School of Medicine in St. Louis have learned.

(Image caption: Learning, social interactions and higher-level thinking in people with autism may be adversely affected by receptors inside brain cells, scientists at Washington University School of Medicine have learned. The type of receptor they studied glows green on the surface of this cell. Inside the cell, the receptor covers a membrane stained red. Credit: Yuh-Jiin I. Jong)

Scientists were already aware that the type of receptor in question was a potential contributor to these problems – when located on the surfaces of brain cells. Until now, though, the role of the same type of receptor located inside the cell had gone unrecognized. Such receptors inside cells significantly outnumber the same type of receptors on the surface of cells.

The receptor under study, known as the mGlu5 receptor, becomes activated when it binds to the neurotransmitter glutamate, which is associated with learning and memory. This leads to chain reactions that convert the glutamate’s signal into messages traveling inside the cell.

In the new study, scientists working with cells in a dish linked mGlu5 receptors inside cells to processes that turn down the volume at which brain cells talk to each other. These volume changes, essential for learning and memory, may become exaggerated in people with autism.

Pharmaceutical companies have developed therapeutic compounds to decrease signaling associated with the mGlu5 receptor, moderating its effects on brain cells’ volume knobs. But the compounds were designed to target mGlu5 surface receptors. In light of the new findings, the scientists question if those drugs will reach the receptors inside cells.

“Our results suggest that to have the greatest therapeutic benefit, we may need to make sure we’re blocking all of this type of receptor, both inside and on the surface of the cell,” said senior investigator Karen O’Malley, PhD, professor of neurobiology.

The findings, published March 25 in The Journal of Neuroscience, also add a significant new dimension to basic brain cell function. Scientists have long assumed that brain cell receptors are only active on the surface of cells. The new study shows that receptors can be active inside cells, and their effects can be considerably different from the same receptors located on the cell surface.

“The traditional wisdom was that receptors inside the cell were either waiting to go to work on the surface or had just finished working there,” said O’Malley. “But when we compared how much of the mGlu5 receptor was on the surface of cells to how much was inside it, we were seeing so much more receptor inside the cell – at least 50 percent, and in some cases as much as 90 percent – that we wondered if the interior receptors had separate functions.”

In earlier studies, O’Malley and her collaborators showed that mGlu5 receptors on the cell surface sent completely different messages than the same receptors inside the cell.

The scientists knew that most autism studies were conducted with compounds that blocked mGlu5 receptors but could not get into the cell. To determine whether blocking inside receptors would have different effects, O’Malley collaborated with Yukitoshi Izumi, MD, PhD, research professor of psychiatry, and Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry, who study cell-based models of learning and memory.

When the scientists examined these model systems using compounds that allowed them to activate only mGlu5 receptors within cells, they found that these receptors played a bigger role in turning down the volume of brain cell communications than did the cell surface receptors.

In the last few years, scientists have found that 20 or more types of brain cell receptors located on cell surfaces also are present at high levels inside cells, O’Malley noted.

“This should be a factor we consider when we design drugs to target brain cell receptors,” she said. “Do we want to reach cell surface receptors, receptors inside the cell or both?”

Following ischemic stroke, the integrity of the blood-brain barrier (BBB), which prevents harmful substances such as inflammatory molecules from entering the brain, can be impaired in cerebral areas distant from initial ischemic insult. This disruptive condition, known as diaschisis, can lead to chronic post-stroke deficits, University of South Florida researchers report.

(Image credit: Mosby’s Medical Dictionary, 8th edition. © 2009, Elsevier)

In experiments using laboratory rats modeling ischemic stroke, USF investigators studied the consequences of the compromised BBB at the chronic post-stroke stage. Their findings appear in a recent issue of the Journal of Comparative Neurology.

“Following ischemic stroke, the pathological changes in remote areas of the brain likely contribute to chronic deficits,” said neuroscientist and study lead author Svitlana Garbuzova-Davis, PhD, associate professor in the USF Health Department of Neurosurgery and Brain Repair. “These changes are often related to the loss of integrity of the BBB, a condition that should be considered in the development of strategies for treating stroke and its long-term effects.”

Edward Haller of the USF Department of Integrative Biology, the coauthor who performed electron microscopy and contributed to image analysis, emphasized that “major BBB damage was found in endothelial and pericyte cells, leading to capillary leakage in both brain hemispheres.” These findings were essential in demonstrating persistence of microvascular alterations in chronic ischemic stroke.

While acute stroke is life-threatening, the authors point out that survivors often suffer insufficient blood flow to many parts of the brain that can contribute to persistent damage and disability. Their previous investigation of subacute ischemic stroke showed far-reaching microvascular damage even in areas of the brain opposite from the initial stroke injury. While most studies of stroke and the BBB explore the acute phase of stroke and its effect on the blood-brain barrier, the present study revealed the longer-term effects in various parts of the brain.

The pathologic processes of stroke-induced vascular injury tend to occur in a “time-dependent manner,” and can be separated into acute (minutes to hours), subacute (hours to days), and chronic (days to months). BBB incompetence during post-stroke changes is well-documented, with some studies showing the BBB opening can last up to four to five days after stroke. This suggests that harmful substances entering the brain during this prolonged BBB leakage might increase post-ischemic brain injury.

In this study, the researchers used laboratory rats modeling ischemic stroke and observed injury not only in the primary area of the stroke, but also in remote areas, where persistent BBB damage could cause chronic loss of competence.

“Our results showed that the compromised BBB integrity detected in post-ischemic rat cerebral hemisphere capillaries — both ipsilateral and contralateral to initial stroke insult — might indicate chronic diaschisis,” Garbuzova-Davis said. “Widespread microvascular damage caused by endothelial cell impairment could aggravate neuronal deterioration. For this reason, chronic diaschisis poses as a therapeutic target for stroke.”

The primary focus for therapy development could be restoring endothelial and/or astrocytic integrity towards BBB repair, which may be “beneficial for many chronic stroke patients,” senior authors Cesar V. Borlongan and Paul R. Sanberg suggest. The researchers also recommend that cell therapy might be used to replace damaged endothelial cells.

“A combination of cell therapy and the inhibition of inflammatory factors crossing the blood-brain barrier may be a beneficial treatment for stroke,” Garbuzova-Davis said.

The same gene family that may have helped the human brain become larger and more complex than in any other animal also is linked to the severity of autism, according to new research from the University of Colorado Anschutz Medical Campus.

The gene family is made up of over 270 copies of a segment of DNA called DUF1220. DUF1220 codes for a protein domain – a specific functionally important segment within a protein. The more copies of a specific DUF1220 subtype a person with autism has, the more severe the symptoms, according to a paper published in the PLoS Genetics.

This association of increasing copy number (dosage) of a gene-coding segment of DNA with increasing severity of autism is a first and suggests a focus for future research into the condition Autism Spectrum Disorder (ASD). ASD is a common behaviorally defined condition whose symptoms can vary widely – that is why the word “spectrum” is part of the name. One federal study showed that ASD affects one in 88 children.

“Previously, we linked increasing DUF1220 dosage with the evolutionary expansion of the human brain,” says James Sikela, PhD, a professor in the Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine. Sikela led the autism study which also involved other members of his laboratory.

“One of the most well-established characteristics of autism is an abnormally rapid brain growth that occurs over the first few years of life. That feature fits very well with our previous work linking more copies of DUF1220 with increasing brain size. This suggests that more copies of DUF1220 may be helpful in certain situations but harmful in others.”

The research team found that not only was DUF1220 linked to severity of autism overall, they found that as DUF1220 copy number increased, the severity of each of three main symptoms of the disorder — social deficits, communicative impairments and repetitive behaviors – became progressively worse.

In 2012, Sikela was the lead scientist of a multi-university team whose research established the link between DUF1220 and the rapid evolutionary expansion of the human brain. The work also implicated DUF1220 copy number in brain size both in normal populations as well as in microcephaly and macrocephaly (diseases involving brain size abnormalities).

Jack Davis, PhD, who contributed to the project while a postdoctoral fellow in the Sikela lab, has a son with autism and thus had a very personal motivation to seek out the genetic factors that cause autism.

The research by Sikela, Davis and colleagues at the Anschutz campus in Aurora, Colo., focused on the presence of DUF1220 in 170 people with autism.

Strikingly, Davis says, DUF1220 is as common in people who do not have ASD as in people who do. So the link with severity is only in people who have the disorder.

“Something else is at work here, a contributing factor that is needed for ASD to manifest itself,” Davis says. “We were only able to look at one of the six different subtypes of DUF1220 in this study, so we are eager to look at whether the other subtypes are playing a role in ASD.” 

Because of the high number of copies of DUF1220 in the human genome, the domain has been difficult to measure. As Sikela says, “To our knowledge DUF1220 copy number has not been directly examined in previous studies of the genetics of autism and other complex human diseases. So the linking of DUF1220 with ASD is also confirmation that there are key parts of the human genome that are still unexamined but are important to human disease.”

New technique classifies retinal neurons into 15 categories, including some previously unknown types.

As we scan a scene, many types of neurons in our retinas interact to analyze different aspects of what we see and form a cohesive image. Each type is specialized to respond to a particular variety of visual input — for example, light or darkness, the edges of an object, or movement in a certain direction.

Neuroscientists believe there are 20 to 30 types of these specialized neurons, known as retinal ganglion cells, but they have yet to come up with a definitive classification system.

A new study from MIT neuroscientists has made some headway on this daunting task. Using a computer algorithm that traces the shapes of neurons and groups them based on structural similarity, the researchers sorted more than 350 mouse retinal neurons into 15 types, including six that were previously unidentified.

This technique, described in the March 24 online edition of Nature Communications, could also be deployed to help identify the huge array of neurons found in the brain’s cortex, says Uygar Sumbul, an MIT postdoc and one of the lead authors of the paper. “This delineates a program that we should be doing for the rest of the retina, and elsewhere in the brain, to robustly and precisely know the cell types,” he says.

The paper’s other lead author is former MIT postdoc Sen Song. Sebastian Seung, a former MIT professor of brain and cognitive sciences and physics who is now at Princeton University, is the paper’s senior author.

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TAU researcher uses DNA therapy in lab mice to improve cochlear implant functionality

One in a thousand children in the United States is deaf, and one in three adults will experience significant hearing loss after the age of 65. Whether the result of genetic or environmental factors, hearing loss costs billions of dollars in healthcare expenses every year, making the search for a cure critical.

Now a team of researchers led by Karen B. Avraham of the Department of Human Molecular Genetics and Biochemistry at Tel Aviv University’s Sackler Faculty of Medicine and Yehoash Raphael of the Department of Otolaryngology–Head and Neck Surgery at University of Michigan’s Kresge Hearing Research Institute have discovered that using DNA as a drug — commonly called gene therapy — in laboratory mice may protect the inner ear nerve cells of humans suffering from certain types of progressive hearing loss.

In the study, doctoral student Shaked Shivatzki created a mouse population possessing the gene that produces the most prevalent form of hearing loss in humans: the mutated connexin 26 gene. Some 30 percent of American children born deaf have this form of the gene. Because of its prevalence and the inexpensive tests available to identify it, there is a great desire to find a cure or therapy to treat it.

"Regenerating" neurons

Prof. Avraham’s team set out to prove that gene therapy could be used to preserve the inner ear nerve cells of the mice. Mice with the mutated connexin 26 gene exhibit deterioration of the nerve cells that send a sound signal to the brain. The researchers found that a protein growth factor used to protect and maintain neurons, otherwise known as brain-derived neurotrophic factor (BDNF), could be used to block this degeneration. They then engineered a virus that could be tolerated by the body without causing disease, and inserted the growth factor into the virus. Finally, they surgically injected the virus into the ears of the mice. This factor was able to “rescue” the neurons in the inner ear by blocking their degeneration.

"A wide spectrum of people are affected by hearing loss, and the way each person deals with it is highly variable," said Prof. Avraham. "That said, there is an almost unanimous interest in finding the genes responsible for hearing loss. We tried to figure out why the mouse was losing cells that enable it to hear. Why did it lose its hearing? The collaborative work allowed us to provide gene therapy to reverse the loss of nerve cells in the ears of these deaf mice."

Although this approach is short of improving hearing in these mice, it has important implications for the enhancement of sound perception with a cochlear implant, used by many people whose connexin 26 mutation has led to impaired hearing.

Embryonic hearing?

Inner ear nerve cells facilitate the optimal functioning of cochlear implants. Prof. Avraham’s research suggests a possible new strategy for improving implant function, particularly in people whose hearing loss gets progressively worse with time, such as those with profound hearing loss as well as those with the connexin gene mutation. Combining gene therapy with the implant could help to protect vital nerve cells, thus preserving and improving the performance of the implant.

More research remains. “Safety is the main question. And what about timing? Although over 80 percent of human and mouse genes are similar, which makes mice the perfect lab model for human hearing, there’s still a big difference. Humans start hearing as embryos, but mice don’t start to hear until two weeks after birth. So we wondered, do we need to start the corrective process in utero, in infants, or later in life?” said Prof. Avraham.

"Practically speaking, we are a long way off from treating hearing loss during embryogenesis. But we proved what we set out to do: that we can help preserve nerve cells in the inner ears of the mouse," Prof. Avraham continued. "This already looks very promising."

Researchers from The University of Manchester have discovered a new mechanism that governs how body clocks react to changes in the environment.

And the discovery, which is being published in Current Biology, could provide a solution for alleviating the detrimental effects of chronic shift work and jet-lag.

The team’s findings reveal that the enzyme casein kinase 1epsilon (CK1epsilon) controls how easily the body’s clockwork can be adjusted or reset by environmental cues such as light and temperature.

Internal biological timers (circadian clocks) are found in almost every species on the planet. In mammals including humans, circadian clocks are found in most cells and tissues of the body, and orchestrate daily rhythms in our physiology, including our sleep/wake patterns and metabolism.

Dr David Bechtold, who led The University of Manchester’s research team, said: “At the heart of these clocks are a complex set of molecules whose interaction provides robust and precise 24 hour timing. Importantly, our clocks are kept in synchrony with the environment by being responsive to light and dark information.” 

This work, funded by the Biotechnology and Biological Sciences Research Council, was undertaken by a team from The University of Manchester in collaboration with scientists from Pfizer led by Dr Travis Wager.

The research identifies a new mechanism through which our clocks respond to these light inputs. During the study, mice lacking CK1epsilon, a component of the clock, were able to shift to a new light-dark environment (much like the experience in shift work or long-haul air travel) much faster than normal.

The research team went on to show that drugs that inhibit CK1epsilon were able to speed up shift responses of normal mice, and critically, that faster adaption to the new environment minimised metabolic disturbances caused by the time shift.

Dr Bechtold said: “We already know that modern society poses many challenges to our health and wellbeing - things that are viewed as commonplace, such as shift-work, sleep deprivation, and jet lag disrupt our body’s clocks. It is now becoming clear that clock disruption is increasing the incidence and severity of diseases including obesity and diabetes.

“We are not genetically pre-disposed to quickly adapt to shift-work or long-haul flights, and as so our bodies’ clocks are built to resist such rapid changes. Unfortunately, we must deal with these issues today, and there is very clear evidence that disruption of our body clocks has real and negative consequences for our health.”

He continues: “As this work progresses in clinical terms, we may be able to enhance the clock’s ability to deal with shift work, and importantly understand how maladaptation of the clock contributes to diseases such as diabetes and chronic inflammation.”

University of Bonn psychologists prove genetic variation is underlying factor in higher incidence of forgetfulness

Misplaced your keys? Can’t remember someone’s name? Didn’t notice the stop sign? Those who frequently experience such cognitive lapses now have an explanation. Psychologists from the University of Bonn have found a connection between such everyday lapses and the DRD2 gene. Those who have a certain variant of this gene are more easily distracted and experience a significantly higher incidence of lapses due to a lack of attention. The scientific team will probably report their results in the May issue of “Neuroscience Letters,” which is already available online in advance.

Most of us are familiar with such everyday lapses; can’t find your keys, again! Or you walk into another room but forgot what you actually went there for. Or you are on the phone with someone and cannot remember their name. “Such short-term memory lapses are very common, but some people experience them particularly often,” said Prof. Dr. Martin Reuter from the department for Differential and Biological Psychology at the University of Bonn. Mistakes occurring due to such short-term lapses can become a hazard in cases where, e.g., a person overlooks a stop sign at an intersection. And in the workplace, a lack of attention can also become a problem–so for example when it results in forgetting to save essential data.

A gene “directing” your brain

"A familial clustering of such lapses suggests that they are subject to genetic effects," explained Dr. Sebastian Markett, the principal author and a member of Prof. Reuter’s team. In lab experiments, the group of scientists had already found indications earlier that the so-called dopamine D2 receptor gene (DRD2) plays a part in forgetfulness. DRD2 has an essential function in signal transmission within the frontal lobes. "This structure can be compared to a director coordinating the brain like an orchestra," Dr. Markett added. In this simile, the DRD2 gene would correspond to the baton, because it plays a part in dopamine transmission in the brain. If the baton skips a beat, the orchestra gets confused.

The psychologists from the University of Bonn tested a total of 500 women and men by taking a saliva sample and examining it using methods from molecular biology. All humans carry the DRD2 gene, which comes in two variants that are distinguished by only one letter within the genetic code. The one variant has C (cytosine) in one locus, which is displaced by T (thymine) in the other. According to the research team’s analyses, about a quarter of the subjects exclusively had the DRD2 gene with the cytosine nucleobase, while three quarters were the genotype with at least one thymine base.

The scientists then wanted to find out whether this difference in the genetic code also had an effect on everyday behavior. By means of a self-assessment survey they asked the subjects to state how frequently they experience these lapses–how often they forgot names, misplaced their keys. The survey also included questions regarding certain impulsivity-related factors, such as how easily a subject was distracted from actual tasks at hand, and how long they were able to maintain their concentration.

Lapses can clearly be tied to the gene variant

The scientists used statistical methods to check whether it was possible to associate the forgetfulness symptoms elicited by means of the surveys to one of the DRD2 gene variants. The results showed that functions such as attention and memory are less clearly expressed in persons who carry the thymine variant of the gene than in the cytosine type. “The connection is obvious; such lapses can partially be attributed to this gene variant,” reported Dr. Markett. According to their own statements, the subjects with the thymine DRD2 variant more frequently “fall victim” to forgetfulness or attention deficits. And vice versa, the cytosine type seems to be protected from that. “This result matches the results of other studies very well,” added Dr. Markett.

Carriers of the gene variant linked to forgetfulness may now find solace in the fact that they are not responsible for their genes, and that this is just their fate….but Dr. Markett doesn’t agree. “There are things you can do to compensate for forgetfulness; writing yourself notes or making more of an effort to put your keys down in a specific location–and not just anywhere.” Those who develop such strategies for the different areas of their lives are better able to handle their deficit.

Why do neurodegenerative diseases such as Alzheimer’s affect only the elderly? Why do some people live to be over 100 with intact cognitive function while others develop dementia decades earlier?

Image: A new study shows that a gene regulator called REST, dormant in the brains of young people (left), switches on in normal aging brains (center) to protect against various stresses, including abnormal proteins associated with neurodegenerative diseases. REST is lost in critical brain regions of people with Alzheimer’s (right). Credit: Yankner Lab

More than a century of research into the causes of dementia has focused on the clumps and tangles of abnormal proteins that appear in the brains of people with neurodegenerative diseases. However, scientists know that at least one piece of the puzzle has been missing because some people with these abnormal protein clumps show few or no signs of cognitive decline.

A new study offers an explanation for these longstanding mysteries. Researchers have discovered that a gene regulator active during fetal brain development, called REST, switches back on later in life to protect aging neurons from various stresses, including the toxic effects of abnormal proteins. The researchers also showed that REST is lost in critical brain regions of people with Alzheimer’s and mild cognitive impairment.

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