Neuroscience
Month
In a study published in Nature Neuroscience, neurobiologists from the Friedrich Miescher Institute for Biomedical Research have been linking synapse formation in the hippocampus to distinct learning steps. They show how different regions of the hippocampus have specific and sequential functions in the mastery of a complex task.
The setup is natural. The mouse finds herself in the water and is looking for a dry place. But how does she solve this task? And what happens if she finds herself in the same situation again? Here is what the scientists observed: At the beginning, the mouse swims all around the little pool, randomly searching for the platform. After two days, there is a change in search approach: The mouse has learned where about the platform is and will start to search right away in the area of the platform. Finally, after another five days, the mouse knows exactly where the platform is and swims directly for it. What is astonishing is that every mouse behaves same way and all the mice learn to find the platform in about the same time, through the same trial and error search strategy stages.
Pico Caroni, senior group leader at the Friedrich Miescher Institute for Biomedical Research, and his team not only described for the first time how mice learn to master such a complex task step by step, but they have also been able to show how one region of the brain, the hippocampus, is engaged in these learning processes. The hippocampus is the region of the brain that is the relay station for a lot of sensory information. In this function, the hippocampus is extremely important for learning and the consolidation of memory. The hippocampus can be divided into three areas termed ventral (vH), intermediate (iH) and dorsal hippocampus (dH). Even though the composition of the neuronal networks in each area is comparable, they differ in gene expression, connectivity, tuning and function.
Caroni and his team could now show that this difference has functional implications in learning. It has been known that during learning new synapses are formed in the hippocampus by so called mossy fibers. In their study published in Nature Neuroscience the scientists show that each search strategy, each level of learning, is associated with a different region of the hippocampus. First, mossy fiber synapses are formed in vH. With the first change in search strategy, mossy fiber formation moves to iH. The mice now have a clear understanding of the relative position of the platform, e.g. distance from the pool wall. Finally, synapse formation moves to dH. By now the mouse has a clear map of the pool, the platform and her position in these surroundings. From now on the mouse will always know where the platform is and will directly head for it.
"We believe that many complex learning tasks are achieved through sub-tasks and that the three areas of the hippocampus are involved in similar ways," comments Caroni. "Our experiments indicate further that this approach is innate, which indicates that similar processes may play as we learn to bike or become proficient in playing tennis."
Diseases that progressively destroy nerve cells in the brain or spinal cord, such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), are devastating conditions with no cures.
Now, a team that includes a University of Iowa researcher has identified a new class of small molecules, called the P7C3 series, which block cell death in animal models of these forms of neurodegenerative disease. The P7C3 series could be a starting point for developing drugs that might help treat patients with these diseases. These findings are reported in two new studies published the week of Oct. 1 in the online early edition of the Proceedings of the National Academy of Sciences (PNAS).
“We believe that our strategy for identifying and testing these molecules in animal models of disease gives us a rational way to develop a new class of neuroprotective drugs, for which there is a great, unmet need,” says Andrew Pieper, M.D., Ph.D., associate professor of psychiatry at the UI Carver College of Medicine, and senior author of the two studies.
About six years ago, Pieper, then at the University of Texas Southwestern Medical Center, and his colleagues screened thousands of compounds in living mice in search of small, drug-like molecules that could boost production of neurons in a region of the brain called the hippocampus. They found one compound that appeared to be particularly successful and called it P7C3.
“We were interested in the hippocampus because new neurons are born there every day. But, this neurogenesis is dampened by certain diseases and also by normal aging,” Pieper explains. “We were looking for small drug-like molecules that might enhance production of new neurons and help maintain proper functioning in the hippocampus.”
However, when the researchers looked more closely at P7C3, they found that it worked by protecting the newborn neurons from cell death. That finding prompted them to ask whether P7C3 might also protect existing, mature neurons in other regions of the nervous system from dying as well, as occurs in neurodegenerative disease.
Using mouse and worm models of PD and a mouse model of ALS, the research team has now shown that P7C3 and a related, more active compound, P7C3A20, do in fact potently protect the neurons that normally are destroyed by these diseases. Their studies also showed that protection of the neurons correlates with improvement of some disease symptoms, including maintaining normal movement in PD worms, and coordination and strength in ALS mice.
Two proteins previously found to contribute to ALS, also known as Lou Gehrig’s disease, have divergent roles. But a new study, led by researchers at the Department of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine, shows that a common pathway links them.
The discovery reveals a small set of target genes that could be used to measure the health of motor neurons, and provides a useful tool for development of new pharmaceuticals to treat the devastating disorder, which currently has no treatment or cure.
Funded in part by the National Institutes of Health and the California Institute for Regenerative Medicine (CIRM), the study will be published in the advance online edition of Nature Neuroscience on September 30.
ALS is an adult-onset neurodegenerative disorder characterized by premature degeneration of motor neurons, resulting in a progressive, fatal paralysis in patients.
The two proteins that contribute to the disease – FUS/TLS and TDP-43 – bind to ribonucleic acid (RNA), intermediate molecules that translate genetic information from DNA to proteins. In normal cells, both TDP-43 and FUS/TLS are found in the nucleus where they help maintain proper levels of RNA. In the majority of ALS patients, however, these proteins instead accumulate in the cell’s cytoplasm – the liquid that separates the nucleus from the outer membrane, and thus are excluded from the nucleus, which prevents them from performing their normal duties.
Since the proteins are in the wrong location in the cell, they are unable to perform their normal function, according to the study’s lead authors, Kasey R. Hutt, Clotilde Lagier-Tourenne and Magdalini Polymenidou. “In diseased motor neurons where TDP-43 is cleared from the nucleus and forms cytoplasmic aggregates,” the authors wrote, “we saw lower protein levels of three genes regulated by TDP-43 and FUS/TLS. We predicted that this, based on our mouse studies, and found the same results in neurons derived from human embryonic stem cells.”
In 2011, this team of UC San Diego scientists discovered that more than one-third of the genes in the brains of mice are direct targets of TDP-43, affecting the functions of these genes. In the new study, they compared the impact of the FUS/TLS protein to that of TDP-43, hoping to find a large target overlap.
“Surprisingly, instead we saw a relatively small overlap, and the common RNA targets genes contained exceptionally long introns, or non-coding segments. The set is comprised of genes that are important for synapse function,” said principal investigator Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine and the Institute for Genomic Medicine at UC San Diego and a visiting professor at the Molecular Engineering Laboratory in Singapore. “Loss of this common overlapping set of genes is evidence of a common pathway that appears to contribute to motor neuron degeneration.”
In an effort to understand the normal function of these two RNA binding proteins, the scientists knocked down the proteins in brains of mice to mimic nuclear clearance, using antisense oligonucleotide technology developed in collaboration with ISIS Pharmaceuticals. The study resulted in a list of genes that are up or down regulated, and the researchers duplicated the findings in human cells.
“If we can somehow rescue the genes from down regulation, or being decreased by these proteins, it could point to a drug target for ALS to slow or halt degeneration of the motor neurons,” said Yeo.
These proteins also look to be a central component in other neurodegenerative conditions. For example, accumulating abnormal TDP-43 and FUS/TLS in neuronal cytoplasm has been documented in frontotemporal lobar dementia, a neurological disorder that has been shown to be genetically and clinically linked to ALS, and which is the second most frequent cause of dementia after Alzheimer’s disease.
Using the new science of optogenetics, scientists can activate or shut down neural pathways, altering behavior and heralding a true cure for psychiatric disease.
Stopped at a red light on his drive home from work, Karl Deisseroth contemplates one of his patients, a woman with depression so entrenched that she had been unresponsive to drugs and electroshock therapy for years. The red turns to green and Deisseroth accelerates, navigating roads and intersections with one part of his mind while another part considers a very different set of pathways that also can be regulated by a system of lights. In his lab at Stanford University’s Clark Center, Deisseroth is developing a remarkable way to switch brain cells off and on by exposing them to targeted green, yellow, or blue flashes. With that ability, he is learning how to regulate the flow of information in the brain.
Deisseroth’s technique, known broadly as optogenetics, could bring new hope to his most desperate patients. In a series of provocative experiments, he has already cured the symptoms of psychiatric disease in mice. Optogenetics also shows promise for defeating drug addiction. When Deisseroth exposed a set of test mice to cocaine and then flipped a switch, pulsing bright yellow light into their brains, the expected rush of euphoria—the prelude to addiction—was instantly blocked. Almost miraculously, they were immune to the cocaine high; the mice left the drug den as uninterested as if they had never been exposed.
Most people know the frustration of having a word on the “tip of your tongue” that they simply can’t remember. But that passing nuisance can be an everyday occurrence for someone with aphasia, a communication disorder caused by a stroke or other brain damage that impairs the ability to process language.
About 1 million Americans — roughly one in every 250 — are affected by aphasia, which can also impact reading and writing skills. But how they acquire the problem and how long they’ll endure it differ from person to person, explained Ellayne Ganzfried, a speech-language pathologist and executive director of the National Aphasia Association.
"No two people with aphasia are alike because everyone’s brain responds to the injury in a different way," Ganzfried said. "About half of people who have aphasia recover quickly, within the first few days. If the symptoms of aphasia last longer than two or three months, a complete recovery is unlikely … [though] some people continue to improve over a period of years and even decades."
Strokes are the most common cause, followed by head injuries, tumors, migraines or other neurological issues. Depending on the damage to the brain regions controlling language, which are typically in the left hemisphere, the resulting aphasia can be broken into four broad categories:
"Processing language requires the collaboration of lots of different parts or systems of the brain," explained Karen Riedel, director of speech-language pathology at the Rusk Institute of Rehabilitation Medicine at NYU Langone Medical Center in New York City. "The whole brain ‘talks’ — the whole brain has something to do with the use of language."
Because of this, a variety of therapies are used to help people regain as much speech and language as possible. But regardless of the injury, people with aphasia have the best chances for recovery when language therapy begins immediately, Riedel said.
Because aphasia is so variable, a therapy that helps one person might not help another, she noted. Tried-and-true techniques include melodic intonation therapy, which uses melody and rhythm to help improve the ability to retrieve words, and constraint-induced therapy, which forces people to use speech over other communication methods.
But technology, Riedel said, has introduced new language-improvement techniques into the mix over the last few years that are both exciting and fun. Several apps available for iPhone or iPad involve synthetic speech that helps engage those with aphasia in yet another realm of communication.
"Our patients have much more access to different kinds of programs that are computer-based," she said. "There’s always something new around the corner."
What remains a constant concern, however, is the misunderstanding many people have of those with language difficulties and how to treat them, Ganzfried and Riedel agreed.
"Many people with aphasia will become socially isolated because of their communication difficulties, which can lead to depression," Ganzfried said. "There are also many misconceptions about aphasia, including that the person is mentally unstable or under the influence of drugs or alcohol. It’s also extremely frustrating. Imagine knowing what you want to say in your head but you can’t get the words out."
Researchers at Brigham and Women’s Hospital have found that melatonin supplementation significantly improved sleep in hypertensive patients taking beta-blockers
Over 20 million people in the United States take beta-blockers, a medication commonly prescribed for cardiovascular issues, anxiety, hypertension and more. Many of these same people also have trouble sleeping, a side effect possibly related to the fact that these medications suppress night-time melatonin production. Researchers at Brigham and Women’s Hospital (BWH) have found that melatonin supplementation significantly improved sleep in hypertensive patients taking beta-blockers.
The study will be electronically published on September 28, 2012 and will be published in the October print issue of SLEEP (Title: A mechanism for upper airway stability during slow wave sleep).
"Beta-blockers have long been associated with sleep disturbances, yet until now, there have been no clinical studies that tested whether melatonin supplementation can improve sleep in these patients," explained Frank Scheer, PhD, MSc, an associate neuroscientist at BWH, and principal investigator on this study. "We found that melatonin supplements significantly improved sleep."
The research team analyzed 16 hypertensive patients who regularly took beta-blockers as treatment for their hypertension. The study participants were given either a melatonin supplement or placebo to take each night before bed. To avoid bias, neither the participants nor the researchers knew which pill they were taking. During the three week study, the participants spent two separate four-day visits in lab. While in the lab, the researchers assessed the participants’ sleep patterns and found a 37-minute increase in the amount of sleep in the participants who received the melatonin supplement compared to those who received placebo. They also found an eight percent improvement of sleep efficiency and a 41 minute increase in the time spent in Stage 2 sleep, without a decrease in slow wave sleep or REM sleep.
"Over the course of three weeks, none of the study participants taking the melatonin showed any of the adverse effects that are often observed with other, classic sleep aids. There were also no signs of ‘rebound insomnia’ after the participants stopped taking the drug," explained Scheer, who is also an assistant professor of Medicine at Harvard Medical School. "In fact, melatonin had a positive carry-over effect on sleep even after the participants had stopped taking the drug."
The researchers caution that while this data is promising for hypertensive patients taking beta-blockers, more research is needed to determine whether patients taking beta-blockers for causes other than hypertension could also benefit from melatonin supplementation.