Posts tagged animal model
Articles and news from the latest research reports.
Mood is Influenced by Immune Cells Called to the Brain in Response to Stress
New research shows that in a dynamic mind-body interaction during the interpretation of prolonged stress, cells from the immune system are recruited to the brain and promote symptoms of anxiety.
The findings, in a mouse model, offer a new explanation of how stress can lead to mood disorders and identify a subset of immune cells, called monocytes, that could be targeted by drugs for treatment of mood disorders.
The Ohio State University research also reveals new ways of thinking about the cellular mechanisms behind the effects of stress, identifying two-way communication from the central nervous system to the periphery – the rest of the body – and back to the central nervous system that ultimately influences behavior.
Unlike an infection, trauma or other problems that attract immune cells to the site of trouble in the body, this recruitment of monocytes that can promote inflammation doesn’t damage the brain’s tissue – but it does lead to symptoms of anxiety.
The research showed that the brain under prolonged stress sends signals out to the bone marrow, calling up monocytes. The cells travel to specific regions of the brain and generate inflammation that causes anxiety-like behavior.
In experiments conducted in mice, the research showed that repeated stress exposure caused the highest concentration of monocytes migrating to the brain. The cells surrounded blood vessels and penetrated brain tissue in several areas linked to fear and anxiety, including the prefrontal cortex, amygdala and hippocampus, and their presence led to anxiety-like behavior in the mice.
“In the absence of tissue damage, we have cells migrating to the brain in response to the region of the brain that is activated by the stressor,” said John Sheridan, senior author of the study, professor of oral biology and associate director of Ohio State’s Institute for Behavioral Medicine Research (IBMR).
“In this case, the cells are recruited to the brain by signals generated by the animal’s interpretation of social defeat as stressful.”
The research appears in the Aug. 21, 2013, issue of The Journal of Neuroscience.
Mice in this study were subjected to stress that might resemble a person’s response to persistent life stressors. In this model of stress, male mice living together are given time to establish a hierarchy, and then an aggressive male is added to the group for two hours. This elicits a “fight or flight” response in the resident mice as they are repeatedly defeated. The experience of social defeat leads to submissive behaviors and the development of anxiety-like behavior.
Mice subjected to zero, one, three or six cycles of this social defeat were then tested for anxiety symptoms. The more cycles of social defeat, the higher the anxiety symptoms; mice took longer to enter an open space and opted for darkness rather than light when given the choice. Anxiety symptoms corresponded to higher levels of monocytes that had traveled to the animals’ brains from the blood.
Additional experiments showed that these cells did not originate in the brain, but traveled there from the bone marrow. In previous studies, this same research group showed that cells in the brain called microglia, the brain’s first line of immune defense, are activated by prolonged stress and are partly responsible for the signals that call up monocytes from the bone marrow.
“There are different moving parts from the central and peripheral components, and what’s novel is them coming together to influence behavior,” said Jonathan Godbout, a senior co-author of the paper and an associate professor of neuroscience at Ohio State.
Exactly what happens at this point in the brain remains unknown, but the research offers clues. The monocytes that travel to the brain don’t respond to natural anti-inflammatory steroids in the body and have characteristics signifying they are in a more inflammatory state. These results indicate that inflammatory gene expression occurs in the brain in response to the stressor.
“The monocytes are coming out of the bone marrow and they are not responsive to steroid regulation, so they overproduce proinflammatory signals when they’re stimulated. We think this is the key to the prolonged anxiety-like disorders that we see in these animals,” Sheridan said.
These findings do not apply to all forms of anxiety, the scientists noted, but they are a game-changer in research on stress-related mood disorders.
“Our data alter the idea of the neurobiology of mood disorders,” said Eric Wohleb, first author of the study and a predoctoral fellow in Ohio State’s Neuroscience Graduate Studies Program. “These findings indicate that a bidirectional system rather than traditional neurotransmitter pathways may regulate some forms of anxiety responses. We’re saying something outside the central nervous system – something from the immune system – is having a profound effect on behavior.”
(Source: newswise.com)
New models advance the study of deadly human prion diseases
By directly manipulating a portion of the prion protein-coding gene, Whitehead Institute researchers have created mouse models of two neurodegenerative diseases that are fatal in humans. The highly accurate reproduction of disease pathology seen with these models should advance the study of these unusual but deadly diseases.
“By altering single amino acid codons in the gene coding for the prion protein, in the natural context of the genome—no over expression or other artificial manipulations—we can produce completely different neurodegenerative diseases, each of which spontaneously generates an infectious prion agent,” says Whitehead Member Susan Lindquist. “The work irrefutably establishes the prion hypothesis.”
According to the prion hypothesis, prion proteins infect by passing along their misfolded shape in templated fashion, unlike viruses or bacteria, which depend on DNA or RNA to transmit their information. Certain changes to the prion protein (PrP) create a misshapen structure, which is replicated by contact. The misfolded proteins accumulate, creating clumps that are toxic to surrounding tissue.
PrP is expressed at high levels in the brain, and prion diseases, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, or “mad cow disease”) in cows, and scrapie in sheep, wreak havoc on the brain and other neural tissues. Some prion diseases, like BSE, can be transmitted from feed animals to humans.
The study of these highly unusual but devastating prion diseases has to date been thwarted by a lack of animal models that faithfully mimic the disease processes in humans. However, Walker Jackson, a former postdoctoral researcher in Lindquist’s lab is changing that, creating novel mouse models of human fatal familial insomnia (FFI) and CJD. His research is reported online this week in the Proceedings of the National Academy of Sciences (PNAS).
To generate the models, Jackson created two mutated versions of the PrP-coding gene by changing a single codon—one of the three-nucleotide “words” in genes that code for the various amino acids in proteins. One mutation is known to cause FFI, while the other induces CJD. Unlike previous models that randomly inserted the mutations into the genome, occasionally increasing PrP expression, Jackson’s models faithfully mimic the human disease—from as to disease onset, to PrP production, to infectiousness. In the brain, his FFI mice develop neuronal loss in the thalamus and his CJD mice experience spongiosis in the hippocampus and the cerebellum, reflecting the damage seen in the brains of human patients.
“Walker (Jackson)’s work provides two extraordinary models of neurodegeneration,” says Lindquist, who is also a professor of biology at MIT. “Most mouse models produce pathology that only distantly resembles human diseases. These nail it, for two of the most enigmatic human diseases in the world.”
With the FFI and CJD models in hand, Jackson says he’s excited to investigate how the pathology of these diseases develops.
“Now we have two interesting models that are selectively targeting specific parts of the brain: the thalamus in FFI and the hippocampus in CJD,” says Jackson, who is now a Group Leader at the German Center for Neurodegenerative Disease. “But instead of focusing on areas that are heavily affected by the disease, we’ll be looking at the areas that seem to be resisting the disease to see what they’re doing. The protein is there, but for some reason, it’s not toxic.”
Initial characterization of one of the models (for FFI) was reporter earlier in Neuron.
A New Wrinkle in Parkinson’s Disease Research
The active ingredient in an over-the-counter skin cream might do more than prevent wrinkles. Scientists have discovered that the drug, called kinetin, also slows or stops the effects of Parkinson’s disease on brain cells.
Scientists identified the link through biochemical and cellular studies, but the research team is now testing the drug in animal models of Parkinson’s. The research is published in the August 15, 2013 issue of the journal Cell.
“Kinetin is a great molecule to pursue because it’s already sold in drugstores as a topical anti-wrinkle cream,” says HHMI investigator Kevan Shokat of the University of California, San Francisco. “So it’s a drug we know has been in people and is safe.”
Parkinson’s disease is a degenerative disease that causes the death of neurons in the brain. Initially, the disease affects one’s movement and causes tremors, difficulty walking, and slurred speech. Later stages of the disease can cause dementia and broader health problems. In 2004, researchers studying an Italian family with a high prevalence of early-onset Parkinson’s disease discovered mutations in a protein called PINK1 associated with the inherited form of the disease.
Since then, studies have shown that PINK1 normally wedges into the membrane of damaged mitochondria inside cells that causes another protein, Parkin, to be recruited to the mitochondria, which are organelles responsible for energy generation. Neurons require high levels of energy production, therefore when mitochondrial damage occurs, it can lead to neuronal death. However, when Parkin is present on damaged mitochondria, studding the mitochondrial surface, the cell is able to survive the damage. In people who inherit mutations in PINK1, however, Parkin is never recruited to the organelles, leading to more frequent neuronal death than usual.
Shokat and his colleagues wanted to develop a way to turn on or crank up PINK1 activity, therefore preventing an excess of cell death, in those with inherited Parkinson’s disease. But turning on activity of a mutant enzyme is typically more difficult than blocking activity of an overactive version.
“When we started this project, we really thought that there would be no conceivable way to make something that directly turns on the enzyme,” says Shokat. “For any enzyme we know that causes a disease, we have ways to make inhibitors but no real ways to turn up activity.”
His team expected it would have to find a less direct way to mimic the activity of PINK1 and recruit Parkin. In the hopes of more fully understanding how PINK1 works, they began investigating how PINK1 binds to ATP, the energy molecule that normally turns it on. In one test, instead of adding ATP to the enzymes, they added different ATP analogues, versions of ATP with altered chemical groups that slightly change its shape. Scientists typically must engineer new versions of proteins to be able to accept these analogs, since they don’t fit into the typical ATP binding site. But to Shokat’s surprise, one of the analogs—kinetin triphosphate, or KTP—turned on the activity of not only normal PINK1, but also the mutated version, which doesn’t bind ATP.
“This drug does something that chemically we just never thought was possible,” says Shokat. “But it goes to show that if you find the right key for the right lock, you’ll be able to open the door.”
To test whether the binding of KTP to PINK1 led to the same consequences as the usual ATP binding, Shokat’s group measured the activity of PINK1 directly, as well as the downstream consequences of this activity, including the amount of Parkin recruited to the mitochondrial surface, and the levels of cell death. Adding the precursor of KTP, kinetin, to cells—both those with PINK1 mutations and those with normal physiology—amplified the activity of PINK1, increased the level of Parkin on damaged mitochondria, and decreased levels of neuron death, they found.
“What we have here is a case where the molecular target has been shown to be important to Parkinson’s in human genetic studies,” says Shokat. “And now we have a drug that specifically acts on this target and reverses the cellular causes of the disease.”
The similar results in cells with and without PINK1 mutations suggest that kinetin, which is a precursor to KTP, could be used to treat not only Parkinson’s patients with a known PINK1 mutation, but to slow progression of the disease in those without a family history by decreasing cell death.
Shokat is now performing experiments on the effects of kinetin in mice with various forms of Parkinson’s disease. However, the usefulness of animal models in Parkinson’s research has been debated, and therefore the positive results from the cellular data, he says, is as good an indicator as results in animals that this drug has potential to treat Parkinson’s in humans. Initial human studies will likely focus on the small population of patients with PINK1 mutations, and if successful in that group the drug could later be tested in a wider array of Parkinson’s patients.
(Source: hhmi.org)
Electrical signatures of consciousness in the dying brain
A University of Michigan animal study shows high electrical activity in the brain after clinical death
The “near-death experience” reported by cardiac arrest survivors worldwide may be grounded in science, according to research at the University of Michigan Health System.
Whether and how the dying brain is capable of generating conscious activity has been vigorously debated.
But in this week’s PNAS Early Edition, a U-M study shows shortly after clinical death, in which the heart stops beating and blood stops flowing to the brain, rats display brain activity patterns characteristic of conscious perception.
“This study, performed in animals, is the first dealing with what happens to the neurophysiological state of the dying brain,” says lead study author Jimo Borjigin, Ph.D., associate professor of molecular and integrative physiology and associate professor of neurology at the University of Michigan Medical School.
“It will form the foundation for future human studies investigating mental experiences occurring in the dying brain, including seeing light during cardiac arrest,” she says.
Approximately 20 percent of cardiac arrest survivors report having had a near-death experience. These visions and perceptions have been called “realer than real,” according to previous research, but it remains unclear whether the brain is capable of such activity after cardiac arrest.
“We reasoned that if near-death experience stems from brain activity, neural correlates of consciousness should be identifiable in humans or animals even after the cessation of cerebral blood flow,” she says.
Researchers analyzed the recordings of brain activity called electroencephalograms (EEGs) from nine anesthetized rats undergoing experimentally induced cardiac arrest.
Within the first 30 seconds after cardiac arrest, all of the rats displayed a widespread, transient surge of highly synchronized brain activity that had features associated with a highly aroused brain.
Furthermore, the authors observed nearly identical patterns in the dying brains of rats undergoing asphyxiation.
“The prediction that we would find some signs of conscious activity in the brain during cardiac arrest was confirmed with the data,” says Borjigin, who conceived the idea for the project in 2007 with study co-author neurologist Michael M. Wang, M.D., Ph.D., associate professor of neurology and associate professor of molecular and integrative physiology at the U-M.
“But, we were surprised by the high levels of activity,” adds study senior author anesthesiologist George Mashour, M.D., Ph.D., assistant professor of anesthesiology and neurosurgery at the U-M. “ In fact, at near-death, many known electrical signatures of consciousness exceeded levels found in the waking state, suggesting that the brain is capable of well-organized electrical activity during the early stage of clinical death.”
The brain is assumed to be inactive during cardiac arrest. However the neurophysiological state of the brain immediately following cardiac arrest had not been systemically investigated until now.
The current study resulted from collaboration between the labs of Borjigin and Mashour, with U-M physicist UnCheol Lee, Ph.D., playing a critical role in analysis.
“This study tells us that reduction of oxygen or both oxygen and glucose during cardiac arrest can stimulate brain activity that is characteristic of conscious processing,” says Borjigin. “It also provides the first scientific framework for the near-death experiences reported by many cardiac arrest survivors.”
Researchers find caffeine during pregnancy negatively impacts mice brains
A team of European researchers has found that mice who consume caffeine while pregnant give birth to pups with negative changes to their brains. In their paper published in the journal Science Translational Medicine, the team reports on their findings after examining the brains of mice pups whose mothers were given caffeine during pregnancy.
Medical researchers have shown that drugs such as cocaine, heroin or even marijuana can have a negative impact on fetal development—in contrast most believe that moderate amounts of caffeine consumption during pregnancy is “safe” meaning it has little or no adverse impact on fetal development. This new study doesn’t change that view, but it does suggest that perhaps more research needs to be done.
In their study, the researchers administered the equivalent of 4 or 5 cups of coffee a day to pregnant mice—afterwards they studied the brains of the pups that were born. In so doing, they found that GABA neurons didn’t migrate during brain development to their proper location in the Hippocampus at the same rate as untreated mice. GABA neurons are responsible for controlling the flow of information in the brain. Subsequent tests found the treated pups to be more susceptible to seizures.
The team also found that if they allowed the treated pups to grow to adulthood, they tended to demonstrate problems with memory—instead of playing with new objects placed in their cages, for example, they were satisfied with playing with objects they already knew—a trait that is uncommon for mice. Autopsies of adult brains also showed fewer neurons in the Hippocampus.
The researchers point out that their results in mice are not necessarily applicable to humans and to reinforce that point another team of researchers also published a Focus piece in the same journal pointing out that there are significant differences in the developmental process of humans and mice fetuses and thus the study with mice has no real bearing on whether caffeine may or may not cause developmental problems with human babies.
Still, the results do indicate that perhaps more research should be done to find out if caffeine does indeed have an unknown negative impact on human fetal development.
Putting the brakes on pain
Neuropathic pain — pain that results from a malfunction in the nervous system — is a daily reality for millions of Americans. Unlike normal pain, it doesn’t go away after the stimulus that provoked it ends, and it also behaves in a variety of other unusual and disturbing ways. Someone suffering from neuropathic pain might experience intense discomfort from a light touch, for example, or feel as though he or she were freezing in response to a slight change in temperature.
A major part of the answer to the problem of neuropathic pain, scientists believe, is found in spinal nerve cells that release a signaling chemical known as GABA. These GABA neurons act as a sort of brake on pain impulses; it’s thought that when they die or are disabled the pain system goes out of control. If GABA neurons could be kept alive and healthy after peripheral nerve or tissue injury, it’s possible that neuropathic pain could be averted.
Now, University of Texas Medical Branch at Galveston researchers have found a way to, at least partially, accomplish this objective. The key, they determined, is stemming the biochemical assault by reactive oxygen species that are generated in the wake of nerve injury.
"GABA neurons are particularly susceptible to oxidative stress, and we hypothesized that reactive oxygen species contribute to neuropathic sensitization by promoting the loss of GABA neurons as well as hindering GABA functions," said UTMB professor Jin Mo Chung, senior author of a paper on the research now online in the journal Pain.
To test this hypothesis — and determine whether GABA neurons could be saved — the researchers conducted a series of experiments in mice that had been surgically altered to simulate the conditions of neuropathic pain. In one key experiment, mice treated with an antioxidant compound for a week after surgery were compared with untreated mice. The antioxidant mice showed less pain-associated behavior and were found to have far more GABA neurons than the untreated mice.
"So by giving the antioxidant we lowered the pain behavior, and when we look at the spinal cords we see the GABA neuron population is almost the same as normal," Chung said. "That suggested we prevented those neurons from dying, which is a big thing."
One complication, Chung noted, is a “moderate quantitative mismatch” between the behavioral data and the GABA-neuron counts. While the anti-oxidant mice displayed less pain behavior, their behavioral improvement wasn’t as substantial as their high number of GABA neurons would suggest. One possibility is that the surviving neurons were somehow impaired — a hypothesis supported by electrophysiological data.
Although no clinical trials are planned in the immediate future, Chung believes anti-oxidants have great potential as a treatment for neuropathic pain. “If this is true and it works in humans — well, any time you can salvage neurons, it’s a good thing,” he said. “Neuropathic pain is very difficult to treat, and I think this is a possibility, a good possibility.”
(Source: eurekalert.org)
Statins Suppress Rett Syndrome Symptoms in Mice
Statins, a class of cholesterol-lowering drugs found in millions of medicine cabinets, may help treat Rett Syndrome, according to a study published today in Nature Genetics. The Rett Syndrome Research Trust (RSRT) funded this work with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation.
Rett Syndrome is a neurological disorder that affects girls. A seemingly typical toddler begins to miss developmental milestones. A regression follows as young girls lose speech, mobility, and hand use. Many girls have seizures, orthopedic and severe digestive problems, as well as breathing and other autonomic impairments. Most live into adulthood and require total, round-the-clock care. Rett Syndrome affects about 1 in 10,000 girls born in the U.S. each year.
The new study screened for randomly induced mutations in genes that modify the effect of the Rett gene, MECP2 (methyl-CpG-binding protein 2), in a mouse model. MECP2 turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes.
The challenge of treating Rett Syndrome is what drove senior author Monica Justice, Ph.D., Professor in the Departments of Molecular and Human Genetics and Molecular Physiology and Biophysics at the Baylor College of Medicine, to look beyond MECP2, hoping to find new drug targets that might improve symptoms or even reverse the course of the disease. In 2007, Adrian Bird, Ph.D., Buchanan Professor of Genetics at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, showed that symptoms in mice are reversible regardless of the age of the animal.
Exploring cholesterol metabolism in neurological diseases is an emerging area, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. But it hadn’t been on the radar for Rett Syndrome. “Our screen was to see if we could suppress the symptoms to reveal alternative pathways to treatment. The cholesterol hit was a big one,” Dr. Justice said. The screen was unbiased – the researchers were looking for any gene that would interact with MECP2 in a useful way, rather than employing a candidate gene approach based on hypotheses.
Dr. Justice and her team injected healthy male mice with a chemical called ENU (a form of nitrosourea) that mutates sperm stem cells randomly, then mated the males to Rett females. The researchers then looked for offspring that should have developed the syndrome (according to their genes), but didn’t (according to their good health).
Key to the investigation was being able to tell sick mice from healthy ones. Fortunately this turned out to be easy. The rescued mice didn’t develop the characteristic tremor, trouble breathing, poor limb-clasping, and general scruffiness of their affected cage-mates. They moved around more, performed better on mobility tests and lived longer.
Once the rescued mice had been identified the random gene mutations from the 24,000 genes that make up the mouse genome had to be pinpointed. “With next generation DNA sequencing, we are finding mutations so easily and quickly. It’s amazing,” said Dr. Justice, compared to the old days of setting up many more generations of crosses to narrow down a part of the genome harboring a gene of interest.
“We are only15% of the way through the screen, and so far we have identified 5 modifiers. The most drug-targetable is a gene called squalene epoxidase (Sqle), which encodes a rate-limiting enzyme in the cholesterol biosynthetic pathway. Frankly, this discovery was a surprise,” Dr. Justice said. It’s important to note that this enzyme is different from the rate-limiting enzyme (HMG CoA reductase) influenced by statin drugs.
Cholesterol is of course best known for its negative effects on the cardiovascular system, but the lipid has multiple roles in the brain: it helps to form the myelin insulation on neurons and takes part in membrane trafficking, dendrite remodeling, synapse formation, signal transduction, and neuropeptide synthesis.
The next step was to test several statins (fluvastatin and lovastatin) on Rett mice. Like the Sqle mutation, the drugs improved symptoms. Treated mice performed well on mobility and gross motor tests, had better overall health scores and lived longer. The drugs didn’t, however, improve breathing.
“When we saw the mutation in a cholesterol pathway enzyme, we immediately thought of statin drugs. Now that our eyes have opened to what is going on, we have a multitude of drugs that modulate lipid metabolism that we can try in addition to statins,” said first author Christie Buchovecky, graduate student in the Justice lab.
With additional RSRT funding, pediatric neurologist and Director of the Tri-State Rett Syndrome Center in the Bronx Dr. Sasha Djukic undertook a detailed review of lipid data in girls with Rett Syndrome. She found that a subset have elevated cholesterol levels which normalize as they age. These data are not included in the Nature Genetics publication but will be part of a subsequent paper. Dr. Djukic is now planning a clinical trial.
Drs. Justice and Djukic caution that carefully designed and rigorously executed clinical trials are essential to test whether what works in mice will also work in girls with Rett Syndrome. Clinical trials should also determine the most effective timeframe for treatment, ways to identify which girls are most likely to respond, (for example, will statins help girls with Rett who do not have elevated cholesterol?), which drugs to trial and what dosages are effective but not toxic.
“Although statins are blockbuster drugs taken by a large percentage of the population they are not without risks and side-effects, and data on statins in the general pediatric population are quite limited. One of the key objectives of the clinical trial will be to determine correct dosages for Rett symptoms. It’s important to note that the mice in Dr. Justice’s study received very low doses of statins. I urge parents to resist any temptation to medicate their children with off-label statins,” cautions Dr Djukic. “The only way to know if this class of drugs will be efficacious in Rett is through controlled trials. Working with Dr. Justice and RSRT we will be bringing families additional information as soon as possible.”
“The biggest finding is the discovery that this pathway is so important to the pathology of the disorder; it suggests new directions for trying to learn more about Rett Syndrome,” Dr. Justice explains. “Emerging evidence from both mice and humans suggest that Rett Syndrome may have a component of disease that is metabolic. Certainly, this study will further clarify our data, and may suggest avenues for treatment that were previously unexplored.”
(Source: rsrt.org)
Neurons in the rat brain use a preexisting set of firing sequences to encode future navigational experiences
Specialized neurons called place cells, located in the hippocampus region of the brain, fire when an animal is in a particular location in its environment, and it is the linear sequence of their firing that encodes in the brain movement trajectories from one location to another. Building on previous work, George Dragoi and Susumu Tonegawa from the RIKEN–MIT Center for Neural Circuit Genetics have now shown that place cells have a preexisting inventory of firing sequences that they can use to encode multiple novel routes of exploration.
Specific sequences of place cells are known to encode spatial experiences, but it has been debated whether such sequences are formed during a new experience or preformed and adapted to specific experiences when required. Dragoi and Tonegawa recently showed that ‘future’ place cells fire in sequence while the animal is asleep, prior to experiencing a novel environment, and that animals use this preexisting neuronal firing pattern to rapidly learn how to navigate their surroundings.
To confirm and investigate this mechanism further, the researchers first recorded the neuronal activity of place cells in rats during one hour of sleep. Next, they monitored this activity during movement along a track that the rat had not previously explored, and later recorded it during movement along the same track with two additional lengths separated by right-angle turns. They then correlated the temporal pattern of place cell activity recorded during sleep with the spatial pattern of activity recorded while the animals were freely exploring the longer track.
The researchers found that the sequences of place cell activity were unique for each of the three lengths of the track and matched those recorded during sleep. “We had observed the same sequences as independent clusters of correlated temporal sequences during the preceding sleep period,” explains Dragoi.
The results suggest that rapid encoding of particular trajectories within novel environments is achieved during exploration by selecting from a set of preexisting temporal sequences that fired during sleep. In other words, hippocampal place cells appear to be prearranged into sets of sequential firing cells that can be adapted rapidly to encode for multiple spatial trajectories that the animal could undertake in its surroundings. Based on their data, Dragoi and Tonegawa predict that the sets of hippocampal place cells could encode for at least 15 unique future spatial experiences. In addition, their findings could explain the role that the hippocampus plays in humans in imagining future encounters within our own complex environment.
Analysis of 26 networked autism genes suggests functional role in the cerebellum
A team of scientists has obtained intriguing insights into two groups of autism candidate genes in the mammalian brain that new evidence suggests are functionally and spatially related. The newly published analysis identifies two networked groupings from 26 genes associated with autism that are overexpressed in the cerebellar cortex, in areas dominated by neurons called granule cells.
The team, composed of neuroscientists and computational biologists, worked from a database providing expression levels of individual genes throughout the mouse brain, as complied in the open-source Allen Mouse Brain Atlas. To promote reproducibility, the scientists surveyed expression data of over 3000 genes, about three-fourths of all the genes listed in the Atlas for which two independent sets of data have been complied.
The work was led by Professor Partha Mitra of Cold Spring Harbor Laboratory (CSHL) and scientists from MindSpec, a nonprofit research organization, founded by Dr. Sharmila Banerjee-Basu.
Despite obvious genetic and neuroanatomical differences between mouse and human, the team explains, mouse models are extremely effective in dissecting out the role of specific genes, pathways, neuronal subtypes and brain regions in specific abnormal behaviors manifested in both mice and people.
Based on years of studies in both species, scientists now know of mutations affecting more than 300 genes whose occurrence correlates with autism susceptibility; more are certain to be identified. Some of these candidate genes are more strongly correlated with the illness than others, although correlation is not the same thing as direct evidence of causation.
Nevertheless, “the key question as yet unanswered,” notes Dr. Mitra, “concerns the way or ways in which particular mutations, singly or in combination, cause pathologies that result in the complex combination of symptoms that characterizes autism in children.” It is assumed that autism pathologies are the result of insults — genetic, environmental, or most likely both — sustained at the time of conception and early in development.
Dr. Idan Menashe, now of Ben-Gurion University of the Negev in Israel, and Dr. Pascal Grange, a postdoctoral researcher in the Mitra lab, demonstrated that co-expression of 26 autism genes was “significantly higher” than would occur by chance. “This suggests that these 26 genes have common neuro-functional properties,” says Dr. Menashe.
The team found two co-expressed networks or “cliques” of genes that are significantly enriched with autism genes. They then asked where in the mouse brain these cliques are expressed. Notably, genes in both groups showed significant overexpression in the cerebellar cortex, and particularly in regions in which granule cells predominate. “This result supports prior studies pointing to involvement of the cerebellum in autism,” says Dr. Grange. Specifically, a recent neuroimaging study highlighted functional subregions in the cerebellum as playing a role in both motor and cognitive tasks. Other genes associated with autism have been shown in other studies to play a role in the development of this brain region.
“Our study provides insights into co-expression properties of genes associated with autism and suggests specific brain regions implicated in pathology. Complementing these findings with additional genomic and neuroimaging analyses from both mouse and human brains will help in obtaining a broader picture of the autistic brain,” the team concludes.
Choline intake improves memory and attention-holding capacity
An experimental study in rats has shown that consuming choline, a vitamin B group nutrient found in foodstuffs like eggs and chicken or beef liver, soy and wheat germ, helps improve long-term memory and attention-holding capacity. The study, conducted by scientists at the University of Granada (Spain) Simón Bolívar University, (Venezuela) and the University of York (United Kingdom), has revealed that choline is directly involved in attention and memory processes and helps modulate them.
Researchers studied the effects of dietary supplements of choline in rats in two experiments aimed at analysing the influence of vitamin B intake on memory and attention processes during gestation and in adult specimens.
In the first experiment, scientists administered choline to rats during the third term of gestation in order to determine the effect of prenatal choline on the memory processes of their offspring. Three groups of pregnant rats were fed choline-rich, standard or choline-deficient diets. When their offspring had reached adult age, a sample of 30 was selected: 10 were female offspring of dams fed a choline-supplement, 10 had followed a choline-deficient diet and the other 10, a standard diet, acting as a control group.
Long-term memory
This sample of adult offspring underwent an experiment to measure their memory retention: 24 hours after being shown an object all the offspring (whether in the choline-supplement group or not) remembered it and it was familiar to them However, after 48 hours, the rats of dams fed a prenatal choline-rich diet recognized the object better than those in the standard diet group, while the choline-deficient group could not recognize it. Thus, the scientists concluded that prenatal choline intake improves long-term memory in the resulting offspring once they reach adulthood.
In the second experiment, the researchers measured changes in attention that occurred in adult rats fed a choline supplement for 12 weeks, versus those with no choline intake. They found that the rats which had ingested choline maintained better attention that the others when presented with a familiar stimulus. The control group, fed a standard diet, showed the normal learning delay when this familiar stimulus acquired a new meaning. However, the choline-rich intake rats showed a fall in attention to the familiar stimulus, rapidly learning its new meaning.
The study has been undertaken by University of Granada Department of Experimental Psychology researchers Isabel De Brugada-Sauras and Hayarelis Moreno-Gudiño (also on the research staff of Simón Bolívar University together with Diamela Carias); Milagros Gallo-Torre, researcher in the University of Granada Department of Psychobiology and Director of the “Federico Olóriz” University Research Institute for Neuroscience; and Geoffrey Hall, of the Department of Psychology of the University of York. Their study has recently given rise to publications in Nutritional Neuroscience and Behavioural Brain Research.