Couch Potatoes May Be Genetically Predisposed to Being Lazy

Studies show 97 percent of American adults get less than 30 minutes of exercise a day, which is the minimum recommended amount based on federal guidelines. New research from the University of Missouri suggests certain genetic traits may predispose people to being more or less motivated to exercise and remain active. Frank Booth, a professor in the MU College of Veterinary Medicine, along with his post-doctoral fellow Michael Roberts, were able to selectively breed rats that exhibited traits of either extreme activity or extreme laziness. They say these rats indicate that genetics could play a role in exercise motivation, even in humans.

“We have shown that it is possible to be genetically predisposed to being lazy,” Booth said. “This could be an important step in identifying additional causes for obesity in humans, especially considering dramatic increases in childhood obesity in the United States. It would be very useful to know if a person is genetically predisposed to having a lack of motivation to exercise, because that could potentially make them more likely to grow obese.”

In their study published in the American Journal of Physiology: Regulatory, Integrative and Comparative Physiology on April 3, 2013, Roberts and Booth put rats in cages with running wheels and measured how much each rat willingly ran on their wheels during a six-day period. They then bred the top 26 runners with each other and bred the 26 rats that ran the least with each other. They repeated this process through 10 generations and found that the line of running rats chose to run 10 times more than the line of “lazy” rats.

Once the researchers created their “super runner” and “couch potato” rats, they studied the levels of mitochondria in muscle cells, compared body composition and conducted thorough genetic evaluations through RNA deep sequencing of each rat.

“While we found minor differences in the body composition and levels of mitochondria in muscle cells of the rats, the most important thing we identified were the genetic differences between the two lines of rats,” Roberts said. “Out of more than 17,000 different genes in one part of the brain, we identified 36 genes that may play a role in predisposition to physical activity motivation.”

Now that the researchers have identified these specific genes, they plan on continuing their research to explore the effects each gene has on motivation to exercise.

Neuroscientists show ’jumping genes’ may contribute to aging-related brain defects

As the body ages, the physical effects are notable; wrinkles in the skin appear, physical exertion becomes harder. But there are also less visible processes going on. Inside aging brains there is another phenomenon at work, which may contribute to age-related brain defects.

In a paper published in the journal Nature Neuroscience CSHL Associate Professor Joshua Dubnau and colleagues show that so-called “jumping genes,” or transposons, increase in abundance and activity in the brains of fruit flies as they age.

Originally discovered at CSHL by Professor Barbara McClintock while working on maize (corn) in the 1940s, transposons are typically repeat DNA sequences that insert themselves into the DNA of an animal or plant.

The moniker “jumping genes” comes from the fact that when activated they can reinsert themselves, or transpose, into another part of the genome. In the course of doing so they are thought to either provide variations in genetic function or, especially in the germline, induce potentially fatal disruptive defects.

Jumping genes in the brains of fruit flies

The median lifespan of a fruit fly can be measured in days. The average fly lives for somewhere between 40-50 days. But they provide a powerful model with which to get at the genetics of things like aging and brain function, including memory.

Dubnau’s interest was piqued by an experiment in which his team showed that when the activity of a protein called Ago2 (Argonaute 2) was perturbed, so was long-term memory—which was tested using a trained Pavolvian response to smell. “This is a neurodegenerative defect that gets profoundly more apparent with age of the flies,” notes Dubnau.

Since Ago2 is known to be involved in protecting against transposon activity in fruit flies, Dubnau and colleagues in his lab, including Wanhe Li and Lisa Prazak, were compelled to look for transposons.

Though transposons have been shown to be active during normal brain development, they are silenced soon afterward. The implication is that they have some functional role in development.

When Dubnau’s group looked for transposons they found that there is a marked increase in transposon levels in the brain cells, or neurons, by 21 days of age in normal fruit flies. The levels were observed to increase steadily with age. These transposons, including one in particular called gypsy, were highly active, jumping from place to place in the genome.

When they blocked Ago2 from being expressed in fruit flies, transposons accumulated at a much younger age. In fact the levels of transposons in young Ago2 “knock-out” flies were equivalent to those in much older normal flies, and increased further still as the Ago2 knock-out flies aged.

Accompanying this transposon accumulation were defects in long-term memory that mirrored those usually seen in much older flies, as well as a much-reduced lifespan. “Essentially the Ago2 knock out flies have no long-term memory by the time they are 20 days old, while normal flies have a normal long-term memory at the same age,” Dubnau reports.

In a previous paper the Dubnau lab, in collaboration with CSHL Assistant Professor Molly Hammell, established a connection between transposons and devastating neurodegenerative diseases such ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease) and FTLD (frontotemporal lobar degeneration). The link was the protein TDP-43, which they showed controls transposon activity.

Taken together with the results in his team’s new paper, Dubnau proposes that a “transposon storm” may be responsible for age-related neurodegeneration as well as the pathology seen in some neurodegenerative disorders.

However, his studies so far don’t address whether transposons are the cause or an effect of aging-related brain defects. “The next step will be to activate transposons by genetically manipulating fruit flies and ask whether they are a direct cause of neurodegeneration,” Dubnau says.

Flies Model a Potential Sweet Treatment for Parkinson’s disease

Researchers from Tel Aviv University describe experiments that could lead to a new approach for treating Parkinson’s disease (PD) using a common sweetener, mannitol. This research is presented today at the Genetics Society of America’s 54th Annual Drosophila Research Conference in Washington D.C., April 3-7, 2013.

Mannitol is a sugar alcohol familiar as a component of sugar-free gum and candies. Originally isolated from flowering ash, mannitol is believed to have been the “manna” that rained down from the heavens in biblical times. Fungi, bacteria, algae, and plants make mannitol, but the human body can’t. For most commercial uses it is extracted from seaweed although chemists can synthesize it. And it can be used for more than just a sweetener.

The Food and Drug Administration approved mannitol as an intravenous diuretic to flush out excess fluid. It also enables drugs to cross the blood-brain barrier (BBB), the tightly linked cells that form the walls of capillaries in the brain. The tight junctions holding together the cells of these tiniest blood vessels come slightly apart five minutes after an infusion of mannitol into the carotid artery, and they stay open for about 30 minutes.

Mannitol has another, less-explored talent: preventing a sticky protein called α-synuclein from gumming up the substantia nigra part of the brains of people with PD and Lewy body dementia (LBD), which has similar symptoms to PD. In the disease state, the proteins first misfold, then form sheets that aggregate and then extend, forming gummy fibrils.

Certain biochemicals, called molecular chaperones, normally stabilize proteins and help them fold into their native three-dimensional forms, which are essential to their functions. Mannitol is a chemical chaperone. So like a delivery person who both opens the door and brings in the pizza, mannitol may be used to treat Parkinson’s disease by getting into the brain and then restoring normal folding to α-synuclein.

Daniel Segal, PhD, and colleagues at Tel Aviv University investigated the effects of mannitol on the brain by feeding it to fruit flies with a form of PD that has highly aggregated α-synuclein.

The researchers used a “locomotion climbing assay” to study fly movement. Normal flies scamper right up the wall of a test tube, but flies whose brains are encumbered with α-synuclein aggregates stay at the bottom, presumably because they can’t move normally. The percentage of flies that climb one centimeter in 18 seconds assesses the effect of mannitol.

An experimental run tested flies daily for 27 days. After that time, 72% of normal flies climbed up, in comparison to 38% of the PD flies. Their lack of ascension up the sides of the test tube indicated “severe motor dysfunction.”

In contrast, were flies bred to harbor the human mutant α-synuclein gene, who as larvae feasted on mannitol that sweetened the medium at the bottoms of their vials. These flies fared much better — 70% of them could climb after 27 days. And slices of their brains revealed a 70% decrease in accumulated misfolded protein compared to the brains of mutant flies raised on the regular medium lacking mannitol.

It’s a long way from helping climbing-impaired flies to a new treatment for people, but the research suggests a possible novel therapeutic direction. Dr. Segal, however, cautioned that people with PD or similar movement disorders should not chew a ton of mannitol-sweetened gum or sweets; that will not help their current condition. The next step for researchers is to demonstrate a rescue effect in mice, similar to improved climbing by flies, in which a rolling drum (“rotarod”) activity assesses mobility.

“Until and if mannitol is proven to be efficient for PD on its own, the more conservative and possibly more immediate use can be the conventional one, using it as a BBB disruptor to facilitate entrance of other approved drugs that have problems passing through the BBB,” Dr. Segal said. A preliminary clinical trial of mannitol on a small number of volunteers might follow if results in mice support those seen in the flies, he added, but that is still many research steps away.

(Image: Wikimedia Commons)

Flies with personality

Fruit flies may have more individuality and personality than we imagine.

And it might all be down to a bit of genetic shuffling in nerve cells that makes every fly brain unique, suggest Oxford University scientists.

Their new study has found that small genetic elements called ‘transposons’ are active in neurons in the fly brain. Transposons are also known as 'jumping genes', as these short scraps of DNA have the ability to move, cutting themselves out from one position in the genome and inserting themselves somewhere else.

The inherent randomness of the process is likely to make every fly brain unique, potentially providing behavioural individuality – or ‘fly personality’. So says Professor Scott Waddell, who led the work at the University of Oxford Centre for Neural Circuits and Behaviour: ‘We have known for some time that individual animals that are supposed to be genetically identical behave differently.

'The extensive variation between fly brains that this mechanism could generate might demystify why some behave while others misbehave,' he suggests.

The Oxford researchers, along with US colleagues at the University of Massachusetts Medical School and Howard Hughes Medical Institute, were able to deep-sequence the DNA from small numbers of nerve cells in the brains of Drosophila fruit flies.

They identified many transposons that were inserted in a number of important memory-related genes. Whether this is detrimental or advantageous to the fly remains an open question, the researchers say.

Scott Waddell notes that neural transposition has been described in rodent and human brains, and transposons have historically been considered to be problematic parasites. New insertions of transposons can on occasion disrupt genes (as was found in this study), and transposons have been associated to some human disorders such as schizophrenia.

However, it is also possible that organisms have harnessed transposition to generate variation within cells, and by extension create variation between individual animals that may turn out to be favourable.

Scott Waddell wants next to determine whether neural transposition provides an explanation for variation in fruit fly behaviour by finding ways of halting the process in flies in his lab.

Brain cell signal network genes linked to schizophrenia risk in families

New genetic factors that predispose to schizophrenia have been uncovered in five families with several affected relatives. The psychiatric disorder can disrupt thinking, feeling, and acting, and blur the border between reality and imagination.

Dr. Debby W. Tsuang, professor of psychiatry and behavioral sciences, and Dr. Marshall S. Horwitz, professor of pathology, both at the University of Washington in Seattle, led the multi-institutional study. Tsuang is also a staff physician at the Puget Sound Veterans Administration Health Care System.

The results are published in the April 3 online edition of the JAMA Psychiatry.

Loss of brain nerve cell integrity occurs in schizophrenia, but scientists have not worked out the details of when and how this happens. In all five families in the present study, the researchers found rare variants in genes tied to the networking of certain signal receptors on nerve cells distributed throughout the brain. These N-methyl-D-aspartate, or NMDA, receptors are widespread molecular control towers in the brain. They regulate the release of chemical messages that influence the strength of brain cell connections and the ongoing remodeling of the networks.

These receptors respond to glutamate, one of the most common nerve-signaling chemicals in the brain, and they are also found on brain circuits that manage dopamine release. Dopamine is a nerve signal associated with reward-seeking, movement and emotions. Deficits in glutamate and dopamine function have both been implicated in schizophrenia but most of the medications that have been developed to treat schizophrenia have targeted dopamine receptors.

Tsuang and her groups’ discovery of gene variations that disturb N-methyl-D-aspartate receptor networking functions supports the hypothesis that decreased NMDA receptor-mediated nerve-signal transmissions contributes to some cases of schizophrenia.

Tsuang pointed out that several hallucinogenic drugs, such as ketamine and phencyclidine (PCP, or angel dust), block N-methyl-D-aspartate receptors and can produce symptoms similar to schizophrenia. These are the strongest evidence implicating these receptors in schizophrenia. The drugs sometimes induce psychosis and terrifying sensory detachment. Reports of such effects in recreational drug users fingered faulty NMDA receptor networks as suspects in schizophrenia.

In all five of their study families, Tsuang’s team detected rare protein-altering variants in one of three genes involved with the N-methyl-D-aspartate receptor network. One of the genes, GRM5, is directly linked with glutamate signaling. In the other two genes, the links are indirect and connected through other proteins synthesized in brain cells. One of these proteins, PPEF2, appears to affect the levels of certain brain nerve-cell signaling mediators, and the other altered protein, LRP1B, may compete with a normal protein for a binding spot on a subunit of the NMDA receptor.

These discoveries provide additional clues to the molecular disarray that might occur in the brain nerve cells of some patients with schizophrenia, and suggest new targets for therapy for certain patients. In a disease occurring in about 1 percent of the population, the picture of how and why schizophrenia arises in all these people is far from complete.

“Disorders like schizophrenia are likely to have many underlying causes,” Tsuang noted. She added that it might eventually make sense to divide schizophrenia into categories based, for example, on which biochemical pathways in the brain are disrupted. Treatments might be developed to correct the exact malfunctioning mechanisms underlying various forms of the disease.

Tsuang gave an example: Agents that stimulate N-methyl-D-aspartate receptor-mediated nerve-signal transmissions include glycine-site blockers and glycine-transport inhibitors have shown some encouraging results in pre-clinical drug trials, but mostly in adjunctive treatment in addition to standard antipsychotic therapy.

“But perhaps the data we have generated will help pharmaceutical companies target specific subunits of the NMDA receptors and pathways,” Tsuang said. She added, however, that effective treatments may lag by many years after these kinds of discoveries. Someday it may make sense to initiate such treatments in people at high genetic risk when early symptoms, such as apathy and lack of motivation, appear, and before brain dysfunction is severe.

Also, possessing the newly discovered gene mutations does not always mean that a person will become schizophrenic. In the recent family study, three of the five families had relatives with the protein-altering variants who did not have schizophrenia.

“This isn’t surprising,” Tsuang observed, “Given that schizophrenia is such a complex disorder, we would expect that not everyone who carries the variants would develop the disease.” In the future, researchers will be seeking what triggers the gene variants into causing problems, other mutations within affected individuals’ genetic profile that might promote or protect against disease, as well as non-genetic factors in the onset of the illness in genetically susceptible people.

The researchers also utilized a strategy and selected more distant relatives of affected individuals for genetic sequencing. Distant kin share, a smaller proportion of genes compared to closely related family members. For example,siblings typically on the average share about 50 percent of their genes whereas cousins on the average share 12.5 percent of their genes. The researhers also hypothesized that the causative mutation within each family would be the same variant.

This strategy helped the researchers decrease the number of genetic variants that were detected by sequencing and thereby concentrate only on the remaining strongest candidates. The researchers also filtered their results against the many publicly available sequencing databases. This allowed them to pick out genetic variants not seen in individuals without psychiatric illness.

According to Tsuang, the research team was excited by recent advances in technology enabled them to uncover unknown, rare genetic variants not previously found in large populations without psychiatric condition. The ability to rapidly sequence only those portions of the genome that code for proteins made this experiment possible.

The next step for the researchers will be to screen for the newly discovered genetic variants in a large sample of unrelated cases of schizophrenia compared to controls. They want to determine if the variants are statistically associated with the disease.

Smoking genes predict risk

Your DNA may play a significant role in determining whether or not you end up a smoker – and how easy you find it to kick the habit.

Many large studies have identified particular gene variants that are more common in smokers than other people, suggesting the they play a role in nicotine dependence.

Now an international team of researchers have used these genetic clues develop a ‘genetic risk profile’, and to see how accurate it is, they have road-tested it on the on a well known sample of Kiwis: the Dunedin Birth Cohort.

Researchers analysed data from the long-term study of 1,000 New Zealanders to identify whether individuals at high genetic risk got hooked on cigarettes more quickly as teens and whether, as adults, they had a harder time quitting.

The results, published in JAMA Psychiatry, showed that a person’s genetic risk profile did not predict whether he or she would try cigarettes. But for those who did try cigarettes, having a high-risk genetic profile predicted increased likelihood of heavy smoking and nicotine dependence.

This link was most apparent for teenagers; Among teens who tried cigarettes, those with a high-risk genetic profile were 24 percent more likely to become daily smokers by age 15 and 43 percent more likely to become pack-a-day smokers by age 18.

As adults, those with high-risk genetic profiles were 22 percent more likely to fail in their attempts at quitting.

“The effects of genetic risk seem to be limited to people who start smoking as teens,” said author Daniel Belsky, a post-doctoral research fellow at Duke University.

“This suggests there may be something special about nicotine exposure in the adolescent brain, with respect to these genetic variants.”

The authors noted that their genetic risk profile isn’t yet accurate enough to be used for targeted interventions to prevent at-risk teens smoking, but it does highlight the critical adolescent period in addiction development.

“Public health policies that make it harder for teens to become regular smokers should continue to be a focus in antismoking efforts,” Belsky said.

Innate ability to vocalize: Deaf or not, courting male mice make same sounds

Scientists have long thought mice might be a model for how humans learn to vocalize. But new research led by scientists at Washington State University Vancouver has found that, unlike humans and songbirds, mice do not learn to vocalize.

The results, published in the Journal of Neuroscience, point the way to a more finely focused, genetic tool for teasing out the mysteries of speech and its disorders.

To see if mice learn to vocalize, WSU neurophysiologist Christine Portfors destroyed the ear hair cells in more than a dozen newborn male mice. The cells convert sound waves into electrical signals processed by the brain, making hearing possible.

The deaf mice were then raised with hearing mice in a normal social environment.

Portfors and her fellow researchers, including WSU graduate student Elena Mahrt, used males because they are particularly exuberant vocalizers in the presence of females.

"We can elicit vocalization behavior in males really easily by just putting them with a female,” Portfors said. "They vocalize like crazy.”

And it turned out that it didn’t matter if the mouse was deaf or not. The researchers catalogued essentially the same suite of ultrasonic sounds from both the deaf and hearing mice. “It means that they don’t need to hear to be able to produce their sounds, their vocalizations,” Portfors said. “Basically, they don’t need to hear themselves. They don’t need auditory feedback. They don’t need to learn.”

The finding means mice are out as a model to study vocal learning. However, scientists can now focus on the mouse to learn the genetic mechanism behind communication disorders.

"If you don’t have learning as a variable, you can look at the genetic control of these things,” Portfors said. "You can look at the genetic control of the output of the signal. It’s not messed up by an animal that’s been in a particular learning situation.”

(Image: Fotolia)

Alterations in brain activity in children at risk of schizophrenia predate onset of symptoms

Research from the University of North Carolina has shown that children at risk of developing schizophrenia have brains that function differently than those not at risk.

Brain scans of children who have parents or siblings with the illness reveal a neural circuitry that is hyperactivated or stressed by tasks that peers with no family history of the illness seem to handle with ease.

Because these differences in brain functioning appear before neuropsychiatric symptoms such as trouble focusing, paranoid beliefs, or hallucinations, the scientists believe that the finding could point to early warning signs or “vulnerability markers” for schizophrenia.

“The downside is saying that anyone with a first degree relative with schizophrenia is doomed. Instead, we want to use our findings to identify those individuals with differences in brain function that indicate they are particularly vulnerable, so we can intervene to minimize that risk,” said senior study author Aysenil Belger, PhD, associate professor of psychiatry at the UNC School of Medicine.

The UNC study, published online on March 6, 2013, in the journal Psychiatry Research: Neuroimaging, is one of the first to look for alterations in brain activity associated with mental illness in individuals as young as nine years of age.

Individuals who have a first degree family member with schizophrenia have an 8-fold to 12-fold increased risk of developing the disease. However, there is no way of knowing for certain who will become schizophrenic until symptoms arise and a diagnosis is reached. Some of the earliest signs of schizophrenia are a decline in verbal memory, IQ, and other mental functions, which researchers believe stem from an inefficiency in cortical processing – the brain’s waning ability to tackle complex tasks.

In this study, Belger and her colleagues sought to identify what if any functional changes occur in the brains of adolescents at high risk of developing schizophrenia. She performed functional magnetic resonance imaging (fMRI) on 42 children and adolescents ages 9 to 18, half of which had relatives with schizophrenia and half of which did not. Study participants each spent an hour and a half playing a game where they had to identify a specific image – a simple circle – out of a lineup of emotionally evocative images, such as cute or scary animals. At the same time, the MRI machine scanned for changes in brain activity associated with each target detection task.

Belger found that the circuitry involved in emotion and higher order decision making was hyperactivated in individuals with a family history of schizophrenia, suggesting that the task was stressing out these areas of the brain in the study subjects.

“This finding shows that these regions are not activating normally,” she says. “We think that this hyperactivation eventually damages these specific areas in the brain to the point that they become hypoactivated in patients, meaning that when the brain is asked to go into high gear it no longer can.”

Belger is currently exploring what kind of role stress plays in the changing mental capacity of adolescents at high risk of developing schizophrenia. Though only a fraction of these individuals will be diagnosed with schizophrenia, Belger thinks it is important to pinpoint the most vulnerable people early to explore interventions that may stave off the mental illness.

“It may be as simple as understanding that people are different in how they cope with stress,” says Belger. “Teaching strategies to handle stress could make these individuals less vulnerable to not just schizophrenia but also other neuropsychiatric disorders.”