To Make Mice Smarter, Add A Few Human Brain Cells

For more than a century, neurons have been the superstars of the brain. Their less glamorous partners, glial cells, can’t send electric signals, and so they’ve been mostly ignored.

Now scientists have injected some human glial cells into the brains of newborn mice. When the mice grew up, they were faster learners. The study, published Thursday in Cell Stem Cell, not only introduces a new tool to study the mechanisms of the human brain, it supports the hypothesis that glial cells — and not just neurons — play an important role in learning.

The scientific obsession with neurons really began at the end of the 19th century. Spanish anatomy professor Santiago Ramon y Cajal used a special dye to stain brain tissue. Under the microscope, neurons were revealed in exquisite detail. “A dense forest,” Ramón y Cajal called it — a field of little branching cells that would soon be named neurons.

With beautiful ink drawings, Ramón y Cajal painstakingly mapped neural networks and slowly developed the theory that neurons are the telegraph lines of thought (an idea later embraced by Schoolhouse Rock). Every idea and memory — every aspect of learning — could be traced back to the electric signals sent between neurons. Ramón y Cajal won the Nobel Prize for his work, and scientists focused on neurons for the next century.

But neurons aren’t the only cells in the brain.

"We’ve overlooked half the brain," says Douglas Fields, a neuroscientist at the National Institutes of Health. "We’ve only been studying one kind of cell in the brain." The other kind of cell — glial cells — are at least as abundant as neurons. But early scientists thought they were so boring they didn’t even merit a singular noun. "Glia is plural — there is no singular," Fields says. "We have ‘neuron’ but we don’t have ‘glion.’ "

Glial cells lacked the ability to send electric signals, and most scientists thought they were housekeeping cells, helping provide nutrients and insulation.

It was only in the last decade or so that scientists realized glial cells were more than that. Special types of glial cells, called astrocytes, which are named for the star-like patterns of their cellular structure, have their own form of chemical signaling. They have the potential to coordinate whole groups of neurons. “Glia are in a position to regulate the flow of information through the brain,” Fields says. “This is all missing from our models.”

And there’s something else. This type of glial cell, these astrocytes, have changed a lot as humans have evolved, while neurons have pretty much stayed the same. A mouse neuron and a human neuron look so much alike, even experienced neuroscientists can’t tell them apart.

"I can’t tell the differences between a neuron from a bird or a mouse or a primate or a human," says Steve Goldman, a neuroscientist at the University of Rochester who has studied brain cells for decades. But Goldman says glial cells are easy to tell apart.

"Human glial cells — human astrocytes — are much larger than those of lower species," he says. "They have more fibers and they send those fibers out over greater distances."

The thought is maybe these glial cells have played a role in making humans smarter. So Goldman teamed up with this wife, Maiken Nedergaard, to test this idea.

They injected some human glial cells into the brains of newborn mice. The mice grew up, and so did the human glial cells. The cells spread through the mouse brain, integrating perfectly with mouse neurons and, in some areas, outnumbering their mouse counterparts. All the while Goldman says the glial cells maintained their human characteristics.

"They very much thought that they were in the human brain, in terms of how they developed and integrated," he says.

So what are these mice like, the ones with brains full of functioning human cells? Their neural circuitry is still just the same, so they act completely normal. They still socialize with other mice and still seem interested in mousey things.

But the researchers say these mice are measurably smarter. In classic maze tests, they learn faster. “They make many fewer errors, and it takes them less time to come to the appropriate answer,” Goldman says.

It might take a normal mouse four or five attempts to learn the correct route, for example. But a mouse with human brain cells could get it on the second try. Glial cells — those boring glial cells — somehow enhance learning.

In fact, they could be changing what it means to be a mouse, and that raises ethical questions for this kind of research.

"Maybe bioethicists have been a little bit too cavalier assuming that a mouse with some human brain cells in it is just your normal old mouse," says Robert Streiffer, a bioethicist from the University of Wisconsin-Madison. "Well, it’s not going to be human, but that doesn’t mean it’s a normal old mouse either."

Streiffer says it’s not just that these mice can get through a maze more quickly — they’re better at recognizing things that scare them. And perception of fear is one of the things bioethicists must weigh when they decide the types of experiments you can do on an animal.

"So you have to sort of step back and do some hardcore philosophy," he says. Like, will these types of human-animal hybrids eventually get close enough to humanity that we would feel uncomfortable performing experiments on them?

The researchers in this study say we’re really, really far from that point. And if you want to investigate the role of glial cells, these hybrid mice are the best tools available.

Researchers discover workings of brain’s ‘GPS system’

Just as a global posi­tion­ing sys­tem (GPS) helps find your loca­tion, the brain has an inter­nal sys­tem for help­ing deter­mine the body’s loca­tion as it moves through its surroundings.

A new study from researchers at Prince­ton Uni­ver­sity pro­vides evi­dence for how the brain per­forms this feat. The study, pub­lished in the jour­nal Nature, indi­cates that cer­tain position-tracking neu­rons — called grid cells — ramp their activ­ity up and down by work­ing together in a col­lec­tive way to deter­mine loca­tion, rather than each cell act­ing on its own as was pro­posed by a com­pet­ing theory.

Grid cells are neu­rons that become elec­tri­cally active, or “fire,” as ani­mals travel in an envi­ron­ment. First dis­cov­ered in the mid-2000s, each cell fires when the body moves to spe­cific loca­tions, for exam­ple in a room. Amaz­ingly, these loca­tions are arranged in a hexag­o­nal pat­tern like spaces on a Chi­nese checker board.

“Together, the grid cells form a rep­re­sen­ta­tion of space,” said David Tank, Princeton’s Henry L. Hill­man Pro­fes­sor in Mol­e­c­u­lar Biol­ogy and leader of the study. “Our research focused on the mech­a­nisms at work in the neural sys­tem that forms these hexag­o­nal pat­terns,” he said. The first author on the paper was grad­u­ate stu­dent Cristina Dom­nisoru, who con­ducted the exper­i­ments together with post­doc­toral researcher Amina Kinkhabwala.

Dom­nisoru mea­sured the elec­tri­cal sig­nals inside indi­vid­ual grid cells in mouse brains while the ani­mals tra­versed a computer-generated vir­tual envi­ron­ment, devel­oped pre­vi­ously in the Tank lab. The ani­mals moved on a mouse-sized tread­mill while watch­ing a video screen in a set-up that is sim­i­lar to video-game vir­tual real­ity sys­tems used by humans.

She found that the cell’s elec­tri­cal activ­ity, mea­sured as the dif­fer­ence in volt­age between the inside and out­side of the cell, started low and then ramped up, grow­ing larger as the mouse reached each point on the hexag­o­nal grid and then falling off as the mouse moved away from that point.

This ramp­ing pat­tern cor­re­sponded with a pro­posed mech­a­nism of neural com­pu­ta­tion called an attrac­tor net­work. The brain is made up of vast num­bers of neu­rons con­nected together into net­works, and the attrac­tor net­work is a the­o­ret­i­cal model of how pat­terns of con­nected neu­rons can give rise to brain activ­ity by col­lec­tively work­ing together. The attrac­tor net­work the­ory was first pro­posed 30 years ago by John Hop­field, Princeton’s Howard A. Prior Pro­fes­sor in the Life Sci­ences, Emeritus.

The team found that their mea­sure­ments of grid cell activ­ity cor­re­sponded with the attrac­tor net­work model but not a com­pet­ing the­ory, the oscil­la­tory inter­fer­ence model. This com­pet­ing the­ory pro­posed that grid cells use rhyth­mic activ­ity pat­terns, or oscil­la­tions, which can be thought of as many fast clocks tick­ing in syn­chrony, to cal­cu­late where ani­mals are located. Although the Prince­ton  researchers detected rhyth­mic activ­ity inside most neu­rons, the activ­ity pat­terns did not appear to par­tic­i­pate in posi­tion calculations.

Star-Shaped Glial Cells Act as the Brain’s “Motherboard”

The transistors and wires that power our electronic devices need to be mounted on a base material known as a “motherboard.” Our human brain is not so different — neurons, the cells that transmit electrical and chemical signals, are connected to one another through synapses, similar to transistors and wires, and they need a base material too.

But the cells serving that function in the brain may have other functions as well. PhD student Maurizio De Pittà of Tel Aviv University’s Schools of Physics and Astronomy and Electrical Engineering says that astrocytes, the star-shaped glial cells that are predominant in the brain, not only control the flow of information between neurons but also connect different neuronal circuits in various regions of the brain.

Using models designed to mimic brain signalling, De Pittà’s research, led by his TAU supervisor Prof. Eshel Ben-Jacob, determined that astrocytes are actually “smart” in addition to practical. They integrate all the different messages being transferred through the neurons and multiplexing them to the brain’s circuitry. Published in the journal Frontiers in Computational Neuroscience and sponsored by the Italy-Israel Joint Neuroscience Lab, this research introduces a new framework for making sense of brain communications — aiding our understanding of the diseases and disorders that impact the brain.

Transcending boundaries

"Many pathologies are related to malfunctions in brain connectivity," explains Prof. Ben-Jacob, citing epilepsy as one example. "Diagnosis and the development of therapies rely on understanding the network of the brain and the source of undesirable activity."

Connectivity in the brain has traditionally been defined as point-to-point connections between neurons, facilitated by synapses. Astrocytes serve a protective function by encasing neurons and forming borders between different areas of the brain. These cells also transfer information more slowly, says Prof. Ben-Jacob — one-tenth of a second compared to one-thousandth of a second in neurons — producing signals that carry larger amounts of information over longer distances. Aastrocytes can transfer information regionally or spread it to different areas throughout the brain — connecting neurons in a different manner than conventional synapses.

De Pittà and his fellow researchers developed computational models to look at the different aspects of brain signalling, such as neural network electrical activity and signal transfer by synapses. In the course of their research, they discovered that astrocytes actually take an active role in the way these signals are distributed, confirming theories put forth by leading experimental scientists.

Astrocytes form additional networks to those of the neurons and synapses, operating simultaneously to co-ordinate information from different regions of the brain — much like an electrical motherboard functions in a computer, or a conductor ensuring that the entire orchestra is working in harmony, explains De Pittà.

These findings should encourage neuroscientists to think beyond neuron-based networks and adopt a more holistic view of the brain, he suggests, noting that the two communication systems are actually interconnected, and the breakdown of one can certainly impact the other. And what may seem like damage in one small area could actually be carried to larger regions.

A break in communication

According to Prof. Ben-Jacob, a full understanding of the way the brain sends messages is significant beyond satisfying pure scientific curiosity. Many diseases and disorders are caused by an irregularity in the brain’s communication system or by damage to the glial cells, so more precise information on how the network functions can help scientists identify the cause or location of a breakdown and develop treatments to overcome the damage.

In the case of epilepsy, for example, the networks frequently become overexcited. Alzheimer’s disease and other memory disorders are characterized by a loss of cell-to-cell connection. Further understanding brain connectivity can greatly aid research into these and other brain-based pathologies.

Epigenetics: Neurons remember because they move genes in space

How do neurons store information about past events? In the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw, a mechanism unknown previously of memory traces formation has been discovered. It appears that at least some events are remembered thanks to… geometry.

Neurons are the most important cells of the nervous system. Scientists from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw have shown that during neuron stimulation permanent changes are observed with respect to genes’ arrangement within the cell nucleus. This discovery, reported in the “Journal of Neuroscience”, one of the most prestigious journals in the field of neurobiology, is significant for developing a better understanding of the processes going on in the mind and disorders of the nervous system, especially the brain.

“While conducting experiments on rats after epileptic seizures we have observed that a gene may permanently move deeper into the neuron’s cell nucleus. Since modification of the geometrical structure of the nucleus leads to changes in gene expression, this is how the neuron remembers, what happened”, explains Prof. Grzegorz Wilczyński from the Laboratory of Molecular and Systemic Neuromorphology at the Nencki Institute.

New clues to causes of peripheral nerve damage

Anyone whose hand or foot has “fallen asleep” has an idea of the numbness and tingling often experienced by people with peripheral nerve damage. The condition also can cause a range of other symptoms, including unrelenting pain, stinging, burning, itching and sensitivity to touch.

Although peripheral neuropathies afflict some 20 million Americans, their underlying causes are not completely understood. Much research has focused on the breakdown of cellular energy factories in nerve cells as a contributing factor.

Now, new research at Washington University School of Medicine in St. Louis points to a more central role in damage to energy factories in other cells: Schwann cells, which grow alongside neurons and enable nerve signals to travel from the spinal cord to the tips of the fingers and toes.

The finding may lead to new therapeutic strategies to more effectively treat symptoms of this highly variable disorder, the scientists report March 6 in the journal Neuron.

“We found that a toxic substance builds up in Schwann cells that have disabled energy factories, leading to the same kind of nerve damage seen in patients with neuropathies,” says senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor of Genetics and head of the Department of Genetics. “Now, we’re evaluating whether drugs can block the buildup of that toxin, which could lead to a new treatment for the condition.”

The most common cause of peripheral neuropathy is diabetes, which accounts for about half of all cases. The condition also can occur in cancer patients treated with chemotherapy, which can damage nerves.

In the body, Schwann cells wrap tightly around nerve axons, the fibers that relay nerve signals. Graduate student and first author Andreu Viader and colleagues in Milbrandt’s lab studied Schwann cells in mice with genetically disabled mitochondria, or cellular energy factories. Under normal conditions, these mitochondria produce fuel and intermediates of energy metabolism that allow nerve cells to function.

The researchers showed that the crippled mitochondria activated a stress response in the Schwann cells. Instead of synthesizing fatty acids, a key component of Schwann cells, the cells burned fatty acids for fuel.

Over time, inefficient burning of fatty acids by the crippled mitochondria leads to a build up of acylcarnitines, a toxic substance, in the Schwann cells. The researchers found levels of acylcarnitines up to 100-fold higher in these mutant Schwann cells than in healthy Schwann cells.

And the bad news doesn’t end there. Eventually, the toxin leaks out of the Schwann cells and onto the nerve axons. Studying neurons in petri dishes, the researchers showed that acylcarnitines damage nerve axons and disrupt the ability of nerves to relay signals.

“The toxin leaking out of the Schwann cells and onto the adjacent nerve axons causes damage that results in pain, numbness, tingling and other symptoms,” Milbrandt says. “We think that is a likely mechanism to explain the degeneration of axons that is known to occur in peripheral neuropathies.”

The new research suggests that drugs that inhibit the buildup of acylcarnitines may block axonal degeneration. Milbrandt and his team now are evaluating the drugs in mice with disabled Schwann cells to see if they can slow or alleviate the decay of axons.

Obesity makes fat cells act like they’re infected

The inflammation of fat tissue is part of a spiraling series of events that leads to the development of type 2 diabetes in some obese people. But researchers have not understood what triggers the inflammation, or why.

In Cell Metabolism this month (cover), scientists from The Methodist Hospital report fat cells themselves are at least partly to blame — high calorie diets cause the cells to make major histocompatibility complex II, a group of proteins usually expressed to help the immune system fight off viruses and bacteria. In overweight mice and humans the fat cells, or adipocytes, are issuing false distress signals — they are not under attack by pathogens. But this still sends local immune cells into a tizzy, and that causes inflammation.

"We did not know fat cells could instigate the inflammatory response," said principal investigator and Methodist Diabetes & Metabolism Institute Director Willa Hsueh, M.D. "That’s because for a very long time we thought these cells did little else besides store and release energy. But what we have learned is that adipocytes don’t just rely on local resident immune cells for protection — they play a very active role in their own defense. And that’s not always a good thing."

In pinpointing major histocompatibility complex II (MHCII) as a cause of inflammation, the researchers may have also identified a new drug target for the treatment of obesity. Blocking the MHCII response of adipocytes wouldn’t cure obesity, Hsueh said, “but it could make it possible for doctors to alleviate some of obesity’s worst consequences while the condition itself is treated.”

Could the inflammation caused by a high fat diet serve any purpose, or is it a senseless response to an unnaturally caloric diet?

"The expression of MHCII in adipocytes does not seem to be helpful to the body," said co-lead author Christopher Lyon, Ph.D. "It is not at all clear what the advantage would be, given all the negative long-term consequences of fat tissue inflammation in people who are obese, including insulin resistance and, eventually, full diabetes. This just appears to be a runaway immune response to a modern high calorie diet."

Hsueh added, “The bottom line is, you’re feeding and feeding these fat cells and they’re turning around and biting you back. They’re doing the thing they’re supposed to do — storing energy — but reacting negatively to too much of it.”

The scientists studied fat cells from obese, female humans (via biopsy) and overfed male mice. The researchers said that while they expect similar MHCII expression to occur in overweight male humans and female mice, further studies are needed to establish this.

The immunology of adipocyte inflammation is complex. It begins with the import of excess nutrients from the bloodstream, which are converted and stored as fat and stimulate the production of the hormone leptin. Excess leptin, spurred by a high calorie diet, excites CD4 T cells to produce a second signaling molecule, interferon gamma, which causes adipocytes to produce MHCII. This dialogue between adipocytes and T cells appears to initiate the inflammatory response to high fat diet — Hsueh and her group found that overfed mice lacking MHCII experienced less inflammation.

Interferon gamma from T cells exacerbates the inflamed adipocytes’ behavior and causes another type of immune cell, M2 macrophages, to be converted to their pro-inflammatory (M1) version.

"It was known that macrophages and T cells are major players," said lead author Tuo Deng, Ph.D. "But no one knew what the start signals were to ignite inflammation.

RNA was extracted from adipocytes purified from fat tissue biopsies and subjected to microarray analysis, which allowed the researchers to see what genes were increased in overweight subjects. The researchers found high expression of most MHCII complex and MHCII antigen processing genes. Similar gene expression patterns were observed in mice within two weeks of starting a high-fat diet, and this mirrored pro-inflammatory changes in fat tissue CD4 T cells. Hsueh says her group plans to investigate whether the inflammatory response in overfed mice can be blocked when MHCII expression is specifically reduced in adipocytes.

Hsueh says that if she and her group can identify the antigen(s) that MHCII is presenting to T cells in fat tissue, medical researchers would have a new approach to target adipose inflammation in obese patients. The hypothesis is that if a treatment can interfere with the production or MHCII presentation of these antigens, this would reduce the activation of fat tissue immune cells and thus reduce inflammation. Determining the MHCII antigen(s) involved in the inflammatory response of fat tissue to weight gain is one of her group’s next goals, she says.

Use It or Lose It

"Use it or lose it." The saying could apply especially to the brain when it comes to protecting against Alzheimer’s disease. Previous studies have shown that keeping the mind active, exercising and social interactions may help delay the onset of dementia in Alzheimer’s disease.

Now, a new study led by Dennis Selkoe, MD, co-director of the Center for Neurologic Diseases in the Brigham and Women’s Hospital (BWH) Department of Neurology, provides specific pre-clinical scientific evidence supporting the concept that prolonged and intensive stimulation by an enriched environment, especially regular exposure to new activities, may have beneficial effects in delaying one of the key negative factors in Alzheimer’s disease.

The study will be published online on March 6, 2013 in Neuron.

Alzheimer’s disease occurs when a protein called amyloid beta accumulates and forms “senile plaques” in the brain. This protein accumulation can block nerve cells in the brain from properly communicating with one another. This may gradually lead to an erosion of a person’s mental processes, such as memory, attention, and the ability to learn, understand and process information.

The BWH researchers used a wild-type mouse model when evaluating how the environment might affect Alzheimer’s disease. Unlike other pre-clinical models used in Alzheimer’s disease research, wild-type mice tend to more closely mimic the scenario of average humans developing the disease under normal environmental conditions, rather than being strongly genetically pre-disposed to the disease.

Selkoe and his team found that prolonged exposure to an enriched environment activated certain adrenalin-related brain receptors which triggered a signaling pathway that prevented amyloid beta protein from weakening the communication between nerve cells in the brain’s “memory center,” the hippocampus. The hippocampus plays an important role in both short- and long-term memory.

The ability of an enriched, novel environment to prevent amyloid beta protein from affecting the signaling strength and communication between nerve cells was seen in both young and middle-aged wild-type mice.

"This part of our work suggests that prolonged exposure to a richer, more novel environment beginning even in middle age might help protect the hippocampus from the bad effects of amyloid beta, which builds up to toxic levels in one hundred percent of Alzheimer patients," said Selkoe.

Moreover, the scientists found that exposing the brain to novel activities in particular provided greater protection against Alzheimer’s disease than did just aerobic exercise. According to the researchers, this observation may be due to stimulation that occurred not only physically, but also mentally, when the mice moved quickly from one novel object to another.

"This work helps provide a molecular mechanism for why a richer environment can help lessen the memory-eroding effects of the build-up of amyloid beta protein with age," said Selkoe. "They point to basic scientific reasons for the apparent lessening of AD risk in people with cognitively richer and more complex experiences during life."

Alzheimer’s risk gene discovered using imaging method that screens brain’s connections

Scientists at UCLA have discovered a new genetic risk factor for Alzheimer’s disease by screening people’s DNA and then using an advanced type of scan to visualize their brains’ connections.

Alzheimer’s disease, the most common cause of dementia in the elderly, erodes these connections, which we rely on to support thinking, emotion and memory. With no known cure for the disease, the 20 million Alzheimer’s sufferers worldwide lack an effective treatment. And we are all at risk: Our chance of developing Alzheimer’s doubles every five years after age 65.

The UCLA researchers discovered a common abnormality in our genetic code that increases the risk of Alzheimer’s. To find the gene, they used a new imaging method that screens the brain’s connections — the wiring, or circuitry, that communicates information. Switching off such Alzheimer’s risk genes (nine of them have been implicated over the last 20 years) could stop the disorder in its tracks or delay its onset by many years.

The research is published in the March 4 online edition of the journal Proceedings of the National Academy of Sciences.

"We found a change in our genetic code that boosts our risk for Alzheimer’s disease," said the study’s senior author, Paul Thompson, a UCLA professor of neurology and a member of the UCLA Laboratory of Neuro Imaging. "If you have this variant in your DNA, your brain connections are weaker. As you get older, faulty brain connections increase your risk of dementia."

The researchers, Thompson said, screened more than a thousand people’s DNA to find the common “spelling errors” in the genetic code that might heighten their risk for the disease later in life. The new study was the first of its kind to also give each person a “connectome scan,” a special type of scan that measures water diffusion in the brain, allowing scientists to map the strength of the brain’s connections.

The new scan reveals the brain’s circuitry and how information is routed around the brain, in order to discover risk factors for disease. The researchers then combined these connectivity scans with the extensive genomic screening to pinpoint what causes faulty wiring in the brain.

Hundreds of computers, calculating for months, sifted through more than 4,000 brain connections and the entire genetic code, comparing connection patterns in people with different genetic variations. In people whose genetic code differed in one specific gene called SPON1, weaker connections were found between brain centers controlling reasoning and emotion. The rogue gene also affects how senile plaques build up in the brain — one of the hallmarks of Alzheimer’s disease.

"Much of your risk for disease is written in your DNA, so the genome is a good place to look for new drug targets," said Thompson, who in 2009 founded a research network known as Project ENIGMA to pool brain scans and DNA from 26,000 people worldwide. "If we scan your brain and DNA today, we can discover dangerous genes that will undermine your ability to think and plan and will make you ill in the future. If we find these genes now, there is a better chance of new drugs that can switch them off before you or your family get ill."

Developing new therapeutics for Alzheimer’s is a hot area for pharmaceutical research, Thompson said.

It has also been found that the SPON1 gene can be manipulated to develop new treatments for the devastating disease, Thompson noted. When the rogue gene was altered in mice, it led to cognitive improvements and fewer plaques building up in the brain. Alzheimer’s patients show an accumulation of these senile plaques, which are made of a sticky substance called amyloid and are thought to kill brain cells, causing irreversible memory loss and personality changes.

Screening genomes has led to many new drug targets in the treatment of cancer, heart disease, arthritis and brain disorders such as epilepsy. But the UCLA team’s approach — screening genomes and performing brain scans of the same people — promises a faster and more efficient search.

"With a brain scan that takes half an hour and a DNA scan from a saliva sample, we can search your genes for factors that help or harm your brain’s connections," Thompson said. "This opens up a new landscape of discovery in medical science."

Study stops stress-based drug relapse in rats

All too often, stress turns addiction recovery into relapse, but years of basic brain research have provided scientists with insight that might allow them develop a medicine to help. A new study in the journal Neuron pinpoints the neural basis for stress-related relapse in rat models to an unprecedented degree. The advance could accelerate progress toward a medicine that prevents stress from undermining addiction recovery.

In the paper published March 6, researchers at Brown University and the University of Pennsylvania demonstrated specific steps in the sequence of neural events underlying stress-related drug relapse and showed that they take place within a brain region called the ventral tegmental area (VTA), which helps reinforce behaviors related to fulfilling basic needs. They also showed that a closely related neural process believed to be crucial to stress-related relapse may not be involved after all.

Moreover, this new understanding allowed the researchers to prevent relapse to drug seeking in the animal model. When they treated rats that had recovered from cocaine addiction with a chemical that blocks the “kappa opioid receptors” that stress activates in the VTA, the rats did not relapse to cocaine use under stress. Untreated rats who had also recovered from addiction did relapse after the same stress.

The chemical that helped the rats, “nor-BNI,” may be one that would someday be tried in humans, said study senior author Julie Kauer, professor of biology in Brown’s Department of Molecular Pharmacology, Physiology, and Biotechnology. By deepening scientists’ understanding of the stress-related relapse mechanism, she and her co-authors hope to identify multiple possible targets for eventual patient treatments.

“If we understand how kappa opioid receptor antagonists are interfering with the reinstatement of drug seeking we can target that process,” Kauer said. “We’re at the point of coming to understand the processes and possible therapeutic targets. Remarkably, this has worked.”

The neural crux of relapse

Exactly how stress acts in the brain to trigger relapse is a complicated sequence that is still not fully understood, but the new study focuses on and elucidates three key players at the crux of the phenomenon in the VTA: GABA-releasing neurons, dopamine-releasing neurons, and the kappa opioid receptors that affect their connections.

Fulfilling natural needs such as hunger or thirst results in a rewarding release of dopamine from the VTA’s dopamine neurons, Kauer said. Unfortunately, so does using drugs of abuse.

In normal brain function, GABA applies the brakes on the rewarding dopamine release, slowing it back to a normal level. It achieves this by forging and then strengthening the connections, called synapses, with the dopamine neuron. The strengthening process is called long-term potentiation (LTP).

In the first of their experiments, the team at Brown, including lead author Nicholas Graziane, showed that stress interrupts the LTP process, hindering GABA’s ability to slam the brakes on dopamine release.

Previous research implicated kappa opioid receptors as one of many neural entities that could have a role in stress-related relapse. Kauer, Graziane, and co-author Abigail Polter investigated that directly by blocking the receptors in some rats with a treatment of nor-BNI in the VTA and leaving others untreated. Then they subjected the rats to a standardized five-minute stress exercise. After 24 hours they looked at the cells in the VTA and found that LTP was hindered in the untreated rats but still present and underway in the rats whose receptors had been blocked with nor-BNI.

With the role of stress and the receptors in the GABA-dopamine dynamic both confirmed and then mitigated, the question remained: Could this knowledge be used to prevent relapse?

To answer that, Penn co-authors Lisa Briand and Christopher Pierce performed the experiment demonstrating that nor-BNI delivered directly to the VTA prevented stressed rats from relapsing to cocaine seeking, while untreated rats subjected to the same stress did relapse.

“Our results indicate that the kappa receptors within the VTA critically control stress-induced drug seeking in animals,” the authors wrote in Neuron.

Along the way, the team also discovered evidence that another stress-affected synapse in the VTA – one that excites dopamine release rather than inhibits it – does not play a role in the stress-related relapse as many researchers have thought. The nor-BNI treatment that prevented stress-related relapse, for example, did not affect those synapses.

Kauer emphasized that her lab’s findings of therapeutic potential are the product of more than a decade of essential basic research on the importance of how changes in synapses relate to behaviors including addiction.

“If we can figure out how not only stress, but the whole system works, then we’ll potentially have a way to tune it down in a person who needs that,” she said.

Portion of Hippocampus Found to Play Role in Modulating Anxiety

Columbia University Medical Center (CUMC) researchers have found the first evidence that selective activation of the dentate gyrus, a portion of the hippocampus, can reduce anxiety without affecting learning. The findings suggest that therapies that target this brain region could be used to treat certain anxiety disorders, such as panic disorder and post-traumatic stress syndrome (PTSD), with minimal cognitive side effects. The study, conducted in mice, was published in the online edition of the journal Neuron.

The dentate gyrus is known to play a key role in learning. Some evidence suggests that the structure also contributes to anxiety. “But until now no one has been able to figure out how the hippocampus could be involved in both processes,” said senior author Rene Hen, PhD, professor of neuroscience and pharmacology (in psychiatry) at CUMC.

“It turns out that different parts of the dentate gyrus have somewhat different functions, with the dorsal portion largely dedicated to learning and the ventral portion dedicated to anxiety,” said lead author Mazen A. Kheirbek, PhD, a postdoctoral fellow in neuroscience at CUMC.

To examine the role of the dentate gyrus in learning and anxiety, the investigators used a state-of-the-art technique called optogenetics, in which light-sensitive proteins, or opsins, are genetically inserted into neurons in the brains of mice. Neurons with these genes can then be selectively activated or silenced through the application of light (via a fiber-optic strand), allowing researchers to study the function of the cells in real time. Previously, the only way to study the dentate gyrus was to silence portions of it using such long-term manipulations as drugs or lesions, techniques that yielded conflicting results.

In the current study, opsins were inserted into dentate gyrus granule cells (the principal cells of the dentate gyrus). The researchers then activated or silenced the ventral or dorsal portions of the dentate gyrus for three minutes at a time, while the mice were subjected to two well-validated anxiety tests (the elevated plus maze and the open field test).

“Our main findings were that elevating cell activity in the dorsal dentate gyrus increased the animals’ desire to explore their environment. But this also disrupted their ability to learn. Elevating activity in the ventral dentate gyrus lowered their anxiety, but had no effect on learning,” said Dr. Kheirbek. The effects were completely reversible — that is, when the stimulation was turned off, the animals returned to their previous anxiety levels.

“The therapeutic implication is that it may be possible to relieve anxiety in people with anxiety disorders by targeting the ventral dentate gyrus, perhaps with medications or deep-brain stimulation, without affecting learning,” said Dr. Hen, who is also director of the Division of Integrative Neuroscience, the New York State Psychiatric Institute, and a member of The Kavli Institute for Brain Science. “Given the immediate behavioral impact of such manipulations, these strategies are likely to work faster than current treatments, such as serotonin reuptake inhibitors.”

According to Dr. Hen, such an intervention would probably work best in people with panic disorder or PTSD. “There is evidence that people with these anxiety disorders tend to have a problem with pattern separation — the ability to distinguish between similar experiences,” he said. “In other words, they overgeneralize, perceiving minor threats to be the same as major ones, leading to a heightened state of anxiety. Such patients could conceivably benefit from therapies that fine-tune hippocampal activity.”

Dr. Hen and his team are currently exploring strategies aimed at modulating the activity of the ventral dentate gyrus by stimulating neurogenesis in the ventral dentate gyrus. “Indeed the dentate gyrus is one of the few areas in the adult brain where neurons are continuously produced, a phenomenon termed adult hippocampal neurogenesis,” added Dr. Hen.

(Image: Catherine E. Myers, Memory Loss and the Brain)