Manipulating memory with light: Scientists erase specific memories in mice

Manipulating memory with light: Scientists erase specific memories in mice

  8:13:00 PM    Science Lover

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Just look into the light: not quite, but researchers at the UC Davis Center for Neuroscience and Department of Psychology have used light to erase specific memories in mice, and proved a basic theory of how different parts of the brain work together to retrieve episodic memories.

During memory retrieval, cells in the hippocampus
connect to cells in the brain cortex.

Credit: Photo illustration by Kazumasa Tanaka and 
Brian Wiltgen/UC Davis

Optogenetics, pioneered by Karl Diesseroth at Stanford University, is a new technique for manipulating and studying nerve cells using light. The techniques of optogenetics are rapidly becoming the standard method for investigating brain function.

Kazumasa Tanaka, Brian Wiltgen and colleagues at UC Davis applied the technique to test a long-standing idea about memory retrieval. For about 40 years, Wiltgen said, neuroscientists have theorized that retrieving episodic memories -- memories about specific places and events -- involves coordinated activity between the cerebral cortex and the hippocampus, a small structure deep in the brain.

"The theory is that learning involves processing in the cortex, and the hippocampus reproduces this pattern of activity during retrieval, allowing you to re-experience the event," Wiltgen said. If the hippocampus is damaged, patients can lose decades of memories.

But this model has been difficult to test directly, until the arrival of optogenetics.

Wiltgen and Tanaka used mice genetically modified so that when nerve cells are activated, they both fluoresce green and express a protein that allows the cells to be switched off by light. They were therefore able both to follow exactly which nerve cells in the cortex and hippocampus were activated in learning and memory retrieval, and switch them off with light directed through a fiber-optic cable.

They trained the mice by placing them in a cage where they got a mild electric shock. Normally, mice placed in a new environment will nose around and explore. But when placed in a cage where they have previously received a shock, they freeze in place in a "fear response."

Tanaka and Wiltgen first showed that they could label the cells involved in learning and demonstrate that they were reactivated during memory recall. Then they were able to switch off the specific nerve cells in the hippocampus, and show that the mice lost their memories of the unpleasant event. They were also able to show that turning off other cells in the hippocampus did not affect retrieval of that memory, and to follow fibers from the hippocampus to specific cells in the cortex.

"The cortex can't do it alone, it needs input from the hippocampus," Wiltgen said. "This has been a fundamental assumption in our field for a long time and Kazu’s data provides the first direct evidence that it is true."

They could also see how the specific cells in the cortex were connected to the amygdala, a structure in the brain that is involved in emotion and in generating the freezing response.

Co-authors are Aleksandr Pevzner, Anahita B. Hamidi, Yuki Nakazawa and Jalina Graham, all at the Center for Neuroscience. The work was funded by grants from the Whitehall Foundation, McKnight Foundation, Nakajima Foundation and the National Science Foundation.

Story Source:
The above story is based on materials provided by University of California - Davis. Note: Materials may be edited for content and length.

Journal Reference:
Kazumasa Z. Tanaka, Aleksandr Pevzner, Anahita B. Hamidi, Yuki Nakazawa, Jalina Graham, Brian J. Wiltgen. Cortical Representations Are Reinstated by the Hippocampus during Memory Retrieval. Neuron, 2014 DOI: 10.1016/j.neuron.2014.09.037

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The Link Between Circadian Rhythms and Aging: Gene Associated With Longevity Also Regulates the Body's Circadian Clock

The Link Between Circadian Rhythms and Aging: Gene Associated With Longevity Also Regulates the Body's Circadian Clock

  12:39:00 AM    Science Lover

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Human sleeping and waking patterns are largely governed by an internal circadian clock that corresponds closely with the 24-hour cycle of light and darkness. This circadian clock also controls other body functions, such as metabolism and temperature regulation.

A new study finds that a gene associated with longevity also regulates the body’s circadian clock. (Credit: iStockphoto)

Studies in animals have found that when that rhythm gets thrown off, health problems including obesity and metabolic disorders such as diabetes can arise. Studies of people who work night shifts have also revealed an increased susceptibility to diabetes.

A new study from MIT shows that a gene called SIRT1, previously shown to protect against diseases of aging, plays a key role in controlling these circadian rhythms. The researchers found that circadian function decays with aging in normal mice, and that boosting their SIRT1 levels in the brain could prevent this decay. Conversely, loss of SIRT1 function impairs circadian control in young mice, mimicking what happens in normal aging.

Since the SIRT1 protein itself was found to decline with aging in the normal mice, the findings suggest that drugs that enhance SIRT1 activity in humans could have widespread health benefits, says Leonard Guarente, the Novartis Professor of Biology at MIT and senior author of a paper describing the findings in the June 20 issue of Cell.

"If we could keep SIRT1 as active as possible as we get older, then we'd be able to retard aging in the central clock in the brain, and health benefits would radiate from that," Guarente says.

Staying on schedule

In humans and animals, circadian patterns follow a roughly 24-hour cycle, directed by the circadian control center of the brain, called the suprachiasmatic nucleus (SCN), located in the hypothalamus.

"Just about everything that takes place physiologically is really staged along the circadian cycle," Guarente says. "What's now emerging is the idea that maintaining the circadian cycle is quite important in health maintenance, and if it gets broken, there's a penalty to be paid in health and perhaps in aging."

Last year, Guarente found that a robust circadian period correlated with longer lifespan in mice. That got him wondering what role SIRT1, which has been shown to prolong lifespan in many animals, might play in that phenomenon. SIRT1, which Guarente first linked with aging more than 15 years ago, is a master regulator of cell responses to stress, coordinating a variety of hormone networks, proteins and genes to help keep cells alive and healthy.

To investigate SIRT1's role in circadian control, Guarente and his colleagues created genetically engineered mice that produce different amounts of SIRT1 in the brain. One group of mice had normal SIRT1 levels, another had no SIRT1, and two groups had extra SIRT1 -- either twice or 10 times as much as normal.

Mice lacking SIRT1 had slightly longer circadian cycles (23.9 hours) than normal mice (23.6 hours), and mice with a 10-fold increase in SIRT1 had shorter cycles (23.1 hours).

In mice with normal SIRT1 levels, the researchers confirmed previous findings that when the 12-hour light/dark cycle is interrupted, younger mice readjust their circadian cycles much more easily than older ones. However, they showed for the first time that mice with extra SIRT1 do not suffer the same decline in circadian control as they age.

The researchers also found that SIRT1 exerts this control by regulating the genes BMAL and CLOCK, the two major keepers of the central circadian clock.

Enhancing circadian function

A growing body of evidence suggests that being able to respond to large or small disruptions of the light/dark cycle is important to maintaining healthy metabolic function, Guarente says.

"Essentially we experience a mini jet lag every day because the light cycle is constantly changing. The critical thing for us is to be able to adapt smoothly to these jolts," Guarente says. "Many studies in mice say that while young mice do this perfectly well, it's the old mice that have the problem. So that could well be true in humans."

If so, it could be possible to treat or prevent diseases of aging by enhancing circadian function -- either by delivering SIRT1 activators in the brain or developing drugs that enhance another part of the circadian control system, Guarente says.

"I think we should look at every aspect of the machinery of the circadian clock in the brain, and any intervention that can maintain that machinery with aging ought to be good," he says. "One entry point would be SIRT1, because we've shown in mice that genetic maintenance of SIRT1 helps maintain circadian function."

Some SIRT1 activators are now being tested against diabetes, inflammation and other diseases, but they are not designed to cross the blood-brain barrier and would likely not be able to reach the SCN. However, Guarente believes it could be possible to design SIRT1 activators that can get into the brain.

Roman Kondratov, an associate professor of biology at Cleveland State University, says the study raises several exciting questions regarding the potential to delay or reverse age-related changes in the brain through rejuvenation of the circadian clock with SIRT1 enhancement.

"The importance of this study is that it has both basic and potentially translational applications, taking into account the fact that pharmacological modulators of SIRT1 are currently under active study," Kondratov says.

Researchers in Guarente's lab are now investigating the relationship between health, circadian function and diet. They suspect that high-fat diets might throw the circadian clock out of whack, which could be counteracted by increased SIRT1 activation.

The research was funded by the National Institutes of Health and the Glenn Foundation for Medical Research.

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Alzheimer's: 'Cleansing' Brain of Plaques

Alzheimer's: 'Cleansing' Brain of Plaques

  8:08:00 PM    Science Lover

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New molecular tools developed at the University of Michigan show promise for "cleansing" the brain of amyloid plaques, implicated in Alzheimer's disease.

Small Molecules for Metal-Amyloid Species in the Brain. 
(Credit: Mi Hee Lim and Joseph J. Braymer)

A hallmark of Alzheimer's disease -- a neurodegenerative disease with no cure -- is the aggregation of protein-like bits known as amyloid-beta peptides into clumps in the brain called plaques. These plaques and their intermediate messes can cause cell death, leading to the disease's devastating symptoms of memory loss and other mental difficulties.

The mechanisms responsible for the formation of these misfolded proteins and their associations with Alzheimer's disease are not entirely understood, but it's thought that copper and zinc ions are somehow involved.

The research, led by assistant professor Mi Hee Lim, was published online Dec. 3 in the Proceedings of the National Academy of Science.
 
In earlier work, Lim and her team developed dual-purpose molecular tools that both grab metal ions and interact with amyloid-beta. The researchers went on to show that in solutions with or without living cells, the molecules were able to regulate copper-induced amyloid-beta aggregation, not only disrupting the formation of clumps, but also breaking up clumps that already had formed.

Building upon that first generation of compounds, Lim and lab members Jung-Suk Choi and Joseph Braymer now report a second generation of compounds that are more stable in biological environments. The researchers tested one of those compounds, described in the PNAS paper, in homogenized brain tissue samples from Alzheimer's disease patients.

"We found that our compound is capable of disassembling the misfolded amyloid clumps to form smaller amyloid pieces, which might be 'cleansed' from the brain more easily, demonstrating a therapeutic application of our compound," said Lim, who has joint appointments in the Life Sciences Institute and the Department of Chemistry. In addition, preliminary tests show that the bi-functional small molecules have a strong potential to cross the blood-brain barrier, the barricade of cells that separates brain tissue from circulating blood, protecting the brain from harmful substances in the bloodstream.

"Crossing this barrier is essential for any treatment like this to be successful," Lim said.

Next steps include more intensive testing of the new compounds for diagnostic and therapeutic properties.

Lim and her team collaborated with Ayyalusamy Ramamoorthy, professor of chemistry and biophysics on this work, with funding from the U-M Horace H. Rackham School of Graduate Studies, the Alzheimer's Art Quilt Initiative, and the National Institutes of Health.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment.

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Do Brain's 'Traffic Lights' Direct Our Actions?

Do Brain's 'Traffic Lights' Direct Our Actions?

  1:42:00 PM    Science Lover

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In every waking minute, we have to make decisions -- sometimes within a split second. Neuroscientists at the Bernstein Center Freiburg have now discovered a possible explanation how the brain chooses between alternative options. The key lies in extremely fast changes in the communication between single nerve cells.

The timing of exciting (red curve) and inhibiting 
(blue curve) signals could be a way to control the 
"traffic flow" of activity in the brain. (Illustration: 
Bernstein Center Freiburg) (Credit: Illustration 
courtesy of Bernstein Center Freiburg)

The traffic light changes from green to orange -- should I push down the accelerator a little bit further or rather hit the brakes? Our daily lives present a long series of decisions we have to make, and sometimes we only have a split second at our disposal. Often the problem of decision-making entails the selection of one set of brain processes over multiple others seeking access to same resources. Several mechanisms have been suggested how the brain might solve this problem. However, up to now, it is a mystery what exactly happens when during a rapid choice between two options.

In the current issue of the Journal of Neuroscience, Jens Kremkow, Arvind Kumar, and Ad Aertsen from the Bernstein Center Freiburg propose a mechanism how the brain can choose between possible actions -- already at the level of single nerve cells.

As the structure and activity of the brain are just too complex to answer this question through a simple biological experiment, the scientists constructed a network of neurons in the computer. An important aspect of the model in this context is the property of nerve cells to influence the activity of other nerve cells, either in an excitatory or inhibitory manner. In the constructed network, two groups of neurons acted as the senders of two different signals. Further downstream in the network, another group of neurons, the "gate" neurons, were to control which of the signals would be transmitted onward.

As the cells within the network were connected both with exciting and inhibiting neurons, the signals reached the gate as excitatory and, after a short delay, inhibitory activity. In their simulations, the scientists found that the key for the gate neurons' "decision" in favour of one signal over the other was the time delay of the inhibitory signal relative to the excitatory signal. If the delay was set to be very small, the activity of the cells in the gate was quenched too quickly for the signal to be propagated.

Conversely, a larger delay caused the gate to open for the signal. Results from neurophysiological experiments have already shown that a change in delay properties is possible in real neurons. These findings therefore support the hypothesis of Kremkow and colleagues that such temporal gating can form the basis for selecting one of several alternative options in our brain.

Admin's Note: This article is not intended to provide medical advice, diagnosis or treatment.

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Carbon Nanostructures: Elixir or Poison?

Carbon Nanostructures: Elixir or Poison?

  1:15:00 AM    Science Lover

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A Los Alamos National Laboratory toxicologist and a multidisciplinary team of researchers have documented potential cellular damage from "fullerenes" -- soccer-ball-shaped, cage-like molecules composed of 60 carbon atoms. The team also noted that this particular type of damage might hold hope for treatment of Parkinson's disease, Alzheimer's disease, or even cancer.

Los Alamos National Laboratory toxicologist Jun Gao works in his laboratory using a protective fume hood. (Credit: Photo by James R. Rickman)

The research recently appeared in Toxicology and Applied Pharmacology and represents the first-ever observation of this kind for spherical fullerenes, also known as buckyballs, which take their names from the late Buckminster Fuller because they resemble the geodesic dome concept that he popularized.

Engineered carbon nanoparticles, which include fullerenes, are increasing in use worldwide. Each buckyball is a skeletal cage of carbon about the size of a virus. They show potential for creating stronger, lighter structures or acting as tiny delivery mechanisms for designer drugs or antibiotics, among other uses. About four to five tons of carbon nanoparticles are manufactured annually.

"Nanomaterials are the 21st century revolution," said Los Alamos toxicologist Rashi Iyer, the principal research lead and coauthor of the paper. "We are going to have to live with them and deal with them, and the question becomes, 'How are we going to maximize our use of these materials and minimize their impact on us and the environment?'"

Iyer and lead author Jun Gao, also a Los Alamos toxicologist, exposed cultured human skin cells to several distinct types of buckyballs. The differences in the buckyballs lay in the spatial arrangement of short branches of molecules coming off of the main buckyball structure. One buckyball variation, called the "tris" configuration, had three molecular branches off the main structure on one hemisphere; another variation, called the "hexa" configuration, had six branches off the main structure in a roughly symmetrical arrangement; the last type was a plain buckyball.

The researchers found that cells exposed to the tris configuration underwent premature senescence -- what might be described as a state of suspended animation. In other words, the cells did not die as cells normally should, nor did they divide or grow. This arrest of the natural cellular life cycle after exposure to the tris-configured buckyballs may compromise normal organ development, leading to disease within a living organism. In short, the tris buckyballs were toxic to human skin cells.

Moreover, the cells exposed to the tris arrangement caused unique molecular level responses suggesting that tris-fullerenes may potentially interfere with normal immune responses induced by viruses. The team is now pursuing research to determine if cells exposed to this form of fullerenes may be more susceptible to viral infections.

Ironically, the discovery could also lead to a novel treatment strategy for combating several debilitating diseases. In diseases like Parkinson's or Alzheimer's, nerve cells die or degenerate to a nonfunctional state. A mechanism to induce senescence in specific nerve cells could delay or eliminate onset of the diseases. Similarly, a disease like cancer, which spreads and thrives through unregulated replication of cancer cells, might be fought through induced senescence. This strategy could stop the cells from dividing and provide doctors with more time to kill the abnormal cells.

Because of the minute size of nanomaterials, the primary hazard associated with them has been potential inhalation -- similar to the concern over asbestos exposure.

"Already, from a toxicological point of view, this research is useful because it shows that if you have the choice to use a tris- or a hexa-arrangement for an application involving buckyballs, the hexa-arrangement is probably the better choice," said Iyer. "These studies may provide guidance for new nanomaterial design and development."

These results were offshoots from a study (Shreve, Wang, and Iyer) funded to understand the interactions between buckyballs and biological membranes. Los Alamos National Laboratory has taken a proactive role by initiating a nanomaterial bioassessmnet program with the intention of keeping its nanomaterial workers safe while facilitating the discovery of high-function, low-bioimpact nanomaterials with the potential to benefit national security missions. In addition to Gao and Iyer, the LANL program includes Jennifer Hollingsworth, Yi Jiang, Jian Song, Paul Welch, Hsing Lin Wang, Srinivas Iyer, and Gabriel Montaño.

Los Alamos National Laboratory researchers will continue to attempt to understand the potential effects of exposure to nanomaterials in much the same way that Los Alamos was a worldwide leader in understanding the effects of radiation during the Lab's early history. Los Alamos workers using nanomaterials will continue to follow protocols that provide the highest degree of protection from potential exposure.

Meantime, Los Alamos research into nanomaterials provides a cautionary tale for nanomaterial use, as well as early foundations for worker protection. Right now, there are no federal regulations for the use of nanomaterials. Disclosure of use by companies or individuals is voluntary. As nanomaterial use increases, understanding of their potential hazards should also increase.

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Surprise! Neural Mechanism May Underlie an Enhanced Memory for the Unexpected

Surprise! Neural Mechanism May Underlie an Enhanced Memory for the Unexpected

  9:06:00 AM    Science Lover

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The human brain excels at using past experiences to make predictions about the future. However, the world around us is constantly changing, and new events often violate our logical expectations.

The element of surprise appears to have a big effect on our ability to remember. Researchers have discovered that unexpected stimuli enhanced an early and a late electrical potential in the hippocampus and the late signal was associated with a memory for the unexpected picture. (Credit: iStockphoto/Rosemarie Gearhart)

"We know these unexpected events are more likely to be remembered than predictable events, but the underlying neural mechanisms for these effects remain unclear," says lead researcher, Dr. Nikolai Axmacher, from the University of Bonn in Germany.

Dr. Axmacher and colleagues, whose new study is published by Cell Press in the February 25 issue of the journal Neuron, investigated the relationship between novelty processing and memory formation in two key brain structures, the hippocampus, and the nucleus accumbens. The hippocampus plays a key role in memory formation while the nucleus accumbens is involved in processing rewards and novel information. Previous work had suggested that information transfer between these structures may be associated with enhanced memory for unexpected items or events.

Obtaining direct information on the electrical activity of these structures deep in the brain is usually impossible in humans. However, the researchers used the opportunity to record from two groups of patients with electrodes implanted in these regions: Epilepsy patients awaiting surgical treatment of severe epilepsy, and patients with treatment-resistant depression undergoing deep-brain stimulation. Both groups of participants studied pictures of faces and houses in grayscale that were usually presented on a red or green background, respectively. Occasionally, a picture would have an "unexpected" configuration, such as a face on a green background. Subjects were subsequently tested for their memory of the expected and unexpected items.

The researchers discovered that unexpected stimuli enhanced an early and a late electrical potential in the hippocampus and the late signal was associated with a memory for the unexpected picture. In the nucleus accumbens, there was only a late potential which was larger during exposure to unexpected items. "Our findings support the idea that hippocampal activity may initially signal the occurrence of an unexpected event and that the nucleus accumbens may influence subsequent processing which serves to promote memory encoding," explains Dr. Axmacher.

The authors are careful to point out that one limitation of their study is that the recordings from the hippocampus and nucleus accumbens came from two separate groups of subjects, so their data provide an indirect measure of the functional connectivity between these two brain areas. However, their findings do provide fascinating new insight into this complex brain circuit. "Taken together, these are the first results that speak to the relative timing of expectation effects in different regions of the human brain, and they support models of accumbens-hippocampus interactions during encoding of unexpected events," concludes Dr. Axmacher.

The researchers include Nikolai Axmacher, University of Bonn, Bonn, Germany, University of California, Davis, Davis, CA; Michael X. Cohen, University of Amsterdam, Amsterdam, The Netherlands, University of Arizona, Tucson, AZ; Juergen Fell, University of Bonn, Bonn, Germany; Sven Haupt, University of Bonn, Bonn, Germany; Matthias Dumpelmann, Epilepsy Center, University Hospital Freiburg, Freiburg, Germany; Christian E. Elger, University of Bonn, Bonn, Germany, University of California, Davis, Davis, CA; Thomas E. Schlaepfer, University of Bonn, Bonn, Germany, The Johns Hopkins University, Baltimore, MD; Doris Lenartz, University of Cologne, Koln, Germany; Volker Sturm, University of Cologne, Koln, Germany; and Charan Ranganath, University of California, Davis, Davis, CA.

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