July 19, 2012 § Leave a comment
Chemists at LMU Munich have collaborated with colleagues at Berkeley and Bordeaux to perform a series of lab experiments on pain inhibition and pain-sensitive neurons. They have discovered something like a pain switch, allowing the inhibition of the activity of pain-sensitive neurons. Findings were published in February of this year in Nature Methods. The researchers were able to use an agent that acts as a photosensitive switch for the pain sensation. The LMU team, led by Dirk Trauner, Professor of Chemical Biology and Genetics at LMU, developed a system involving a chemical compound called QAQ.
QAQ is a bi-part molecule, with each part containing a quaternary ammonium, connected by a nitrogen double bond (N=N). The bridge between this bond is the pain switch. It is sensitive to light in that when irradiated with light of a certain wavelength, the molecule will flip from a bent to an extended shape. When treated with light of a different color, the effect is reversed.
One of the halves of QAQ resembles Lidocaine, a local anesthetic used by many dentists. The receptors of certain nerve cells in the skin that respond to painful stimuli and transmit signals to the spinal cord are blocked by lidocaine. Neuroreceptors are proteins that cover the outer membrane of nerve cells. They contain pores that open in response to certain stimuli to regulate the flux of electrically charged ions in and out of a cell. The conduit targeted by the lidocaine-like half of QAQ reacts to heat by permitting positively charged sodium ions to enter the cells that come to express it. This changes the electrical capability across the membrane, which conducts the transmission of the nerve impulse.
The researchers conducted an animal experiment, making use of QAQ’s ability to percolate through endogenous ion channels to transfer a molecule into a nerve cell. They would irradiate the lidocaine-like end of QAQ with a 380-nm light, causing the bridge between them to bend. They would then expose it to light with a 500 nm wavelength and the molecule would return to its extended form and reinstate its inhibitory action.
The researchers regard this new irradiation method as a great tool for neurobiological studies, especially for pain research. Timm Fehrentz, one of Dirk Trauner’s PhD students, says that therapeutic applications of this principle are, “a long way off.” One problem to overcome is the fact that the monochromatic light used to isomerize the QAQ molecules does not penetrate through human skin deep enough to reach the neurons, therefore researchers are looking into lights of longer wavelengths.
“An Off Switch For Pain”. (February 22, 2012). Neuroscience News. March 2, 2012. http://neurosciencenews.com/light-controlled-neural-inhibitor-off-switch-pain/.
July 18, 2012 § Leave a comment
A Yale University study, published in the February issue of the Journal of Neuroscience, has revealed a cellular system, stemming from the brain, that controls weight, energy levels, and how much we eat. This group of cells is located in the hypothalamus region of the brain, and they are able to regulate these weight and energy functions by instigating through the nervous system.
The hypothalamus has long been identified as the area of the brain responsible for controlling energy levels. Melanin-Concentrating Hormone (MCH) is a hypothalamic neuron that controls an organism’s food intake and determines energy levels. Scientists are still probing this neuron’s role in these functions. Previous tests on MCH have revealed that it causes test subjects to eat more, sleep more, and have generally less energy.
Contrarily, Thyrotropin-Releasing Hormone (TRH), another hypothalamic neuron, impels an organism to eat less, causing a reduction in body mass, as well as increasing physical activity levels. TRH is an excitatory neurotransmitter, but acts as an inhibitor to MCH. During the study, THR only seemed to inhibit MCH cells by increasing inhibitory synaptic signals. It had little to no effect on other types of neurons involved in appetite, energy, and sleep functions.
The Yale University study revealed that these two neurons work in opposition to maintain a balance in an organism. Therefore both of these neurons are imperative for a healthy balance of hormones. When these hormones are not in equilibrium, an organism is unable to maintain a healthy weight. The study’s senior author Anthony van den Pol, professor of neurosurgery at Yale School of Medicine said, “That these two types of neurons interact at the synaptic level gives us clues as to how the brain controls the amount of food we eat, and how much we sleep.”
This study bolsters previous findings so as to conclude that hormones play a principal role in regulating appetite, energy, fatigue, and, by extension, weight regulation.
“Molecular Duo Dictate Weight and Energy Levels”. (February 28, 2012). Neuroscience News. March 2, 2012. http://neurosciencenews.com/melanin-thyrotropin-hormones-weight-loss-energy-levels/
July 18, 2012 § Leave a comment
A study published in the February edition of the medical journal of the American Academy of Neurology called Neurology reveals that a diet deficient in omega-3 fatty acids may cause the brain to age more rapidly, as well as lose a decent portion of its memory and thinking abilities.
Omega-3 fatty acids include the nutrients called docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). They are typically found in fish, marine and plant oils, eggs, turkey, and some beans and grains.
The study involved 1,575 people free of dementia at an average age of 67 who underwent brain scans, tests to measure mental function, body mass and omega-3 fatty acid levels in their blood. Results showed that people with DHA levels in the bottom 25% had a lower brain volume than those with a higher DHA level. Also those with the lower levels of omega-3 fatty acid levels scored lower on tests for visual memory, and executive functions such as multi-tasking, abstract thinking, and problem solving.
The author of the study is Zaldy S. Tan, M.D., M.P.H., of the Eastern Center for Alzheimer’s Disease Research and the Division of Geriatrics, University of California in Los Angeles. He says, “People with lower blood levels of omega-3 fatty acids had lower brain volumes that were equivalent to about two years of structural brain aging.”
This study was funded by the Framingham Heart Study’s National Heart, Lung, and Blood Institute as well as the National Institute on Aging.
“Low Levels of Omega-3 Fatty Acids May Cause Memory Problems”. (February 28, 2012). Neuroscience News. March 4, 2012. http://neurosciencenews.com/omega-3-fatty-acids-low-levels-memory-problems/.
July 17, 2012 § Leave a comment
Thomas Park, biologist at the University of Illinois in Chicago, along with colleagues at UIC and the University of Texas Health Science Center in San Antonio believe that naked mole rats demonstrate how the brain can adapt to oxygen deprivation. This may shed light on possible treatments for heart attack and stroke victims.
Park explains, “Normally, calcium in brain cells does wonderful things, including forming memories. But too much calcium makes things go haywire.” He goes on to explain that too much calcium in a cell is unhealthy and that brain cells deprived of oxygen are unable to regulate calcium entry. Heart attacks and strokes prevent oxygen from entering the brain, resulting in brain damage and sometimes death.
Naked mole rat brain cells are better able to regulate their intake of calcium. They are tolerant to oxygen deprivation (hypoxia), just as human newborns are, because their brain cells possess calcium conduits that close off during oxygen deprivation. This closure protects the cells from a calcium overload.
As the body ages the calcium channels naturally lose their ability to close off because oxygen deprivation is not a normal occurrence that the body must adapt to after birth. The body does not anticipate a heart attack. Because of the naked mole rat’s subterranean lifestyle, in which it often confronts situations of oxygen deprivation, it retains its tolerance for oxygen deprivation into adulthood.
Park and his colleagues already knew the rat’s brain was similar to that of newborns, but they wanted to know if they used the same strategy to prevent calcium entry. The researchers measured the entry of calcium into the brain of rats that had been kept in oxygen-poor conditions. Park thinks they may have found a new way for protecting the human adult brain from oxygen deprivation. They reported their findings online in February in PLoS One.
Park says, “Developing this target into a clinical application is our next goal. We need to find a way to rapidly up-regulate the infant-type of calcium channels. Adult humans actually have some of these channels already, but far fewer than infants.” He believes his studies on naked mole rats could reveal much more about evolutionary adaptation. For instance, the naked more rats live in conditions of high carbon dioxide and ammonia, which would make most animals ill. These remarkable rats can suppress both pain and even cancer. He advocates further studies of these creatures. “The more we study these creatures,” said Park, “the more we learn.”
“Naked Mole Rats Bear Lifesaving Clues”. (February 24, 2012). Neuroscience News. March 4, 2012. http://neurosciencenews.com/naked-mole-rats-bear-lifesaving-clues/.
July 17, 2012 § Leave a comment
It has heretofore been a great mystery as to how the brain is able to both store new memories while also maintaining older ones. Researchers at the RIKEN-MIT Center for Neural Circuit Genetics will be publishing a study in the March 30th issue of Cell that links memory formation to the birth of new neurons.
A specific type of neuron in the brain, dentate gyrus, plays a discrete role in memory formation. This apparently depends on the age of the neural stem cells that produced them. An imbalance between old and new brain neurons can actually disrupt memory formation while an individual is aging or has post-traumatic stress disorder. Senior author of the study Susumu Tonegawa, 1987 Nobel Laureate and director of the RIKEN-MIT Center, said that, “In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging.”
The study involved the testing of mice in two different types of pattern development memory processes: pattern separation and pattern completion. Pattern separation is the process by which the brain distinguishes between similar events or experiences, such as two hamburgers with different tastes. Pattern completion is used to recall the distinct content of memories based on clues of association surrounding the development of that memory, such as recalling whom one was with during the experience of the hamburger.
So whereas pattern separation forms memories based on differences between similar experiences, pattern completion retrieves memories by discerning similarities. Individuals with brain trauma have trouble recalling people that they see every day, and those with post-traumatic stress disorder are unable to forget disturbing events. Tonegawa explains, “Impaired pattern separation due to the loss of young neurons may shift the balance in favor of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients.”
Neuroscientists thought these two opposing processes occurred in separate neural circuits. Pattern separation was though to be engaged by the dentate gyrus. Pattern completion was thought to occur in the CA3 region. But the study found that dentate gyrus neurons might perform either pattern separation or completion, depending on the age of cells.
Two types of mice were involved in the study: normal mice and those lacking either young or old neurons. During the study, in the portion involving pattern separation, mice were taught to distinguish between two similar chambers. One was “safe” and the other was “unsafe” as it was associated with an unpleasant foot shock. In the portion of the study designed to test pattern completion abilities, mice were given partial cues to escape a maze that they had previously learned to navigate.
Depending on which set of neurons were removed, the mice demonstrated defects in either of the memory pattern processes. Co-author Toshiaki Nakashiba explains their findings in detail, “We found that old neurons were dispensable for pattern separation, whereas young neurons were required for it. Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons.”
These findings could lead to a whole new class of drugs aimed at treating memory disorders. The work thus far has been supported by the RIKEN-MIT Center, the Howard Hughes Medical Institute, Ostuka Maryland Research Institute, Picower Foundation and the National Institutes of Health.
“Memory Formation Triggered by Stem Cell Development”. (February 23, 2012). Neuroscience News. February 25, 2012. http://neurosciencenews.com/memory-stem-cells-dentate-gyrus/.
July 4, 2012 § 2 Comments
Parkinson’s Disease is a neurological disorder that affects millions of people worldwide. Although many effective treatments have been developed, none have proven successful in slowing its progression.
The cause of Parkinson’s is as of yet unknown, but a protein called α-synuclein is thought to be the culprit. This protein is found in all Parkinson’s patients. Its tendency to collect together in the brain forms toxic clumps that destroy brain neurons.
In an experiment published in the online edition of the journal Neurotherapeutics, scientists at UCLA have discovered a way to break up these aggregates and prevent the proteins from clumping in the first place. Jeff Bronstein, UCLA professor of neurology, along with Gal Bitan, associate UCLA professor of neurology, and their colleagues, have developed a new compound that they call a “molecular tweezer”.
The UCLA tweezer compound is able to prevent the protein clumps from forming, stop them from becoming toxic, and are also able to break up the clumps that have already accumulated, all without hampering normal brain function.
Protein aggregation is the cause of many diseases for which there is no cure. Alzheimer’s, Parkinson’s, and Type 2 Diabetes are all the result of protein aggregation. If doctors are able to prevent the clumping altogether, they can prevent these diseases from forming, without having to find a cure. The difficulty with finding a therapy that targets only protein aggregates is due to the natural ubiquity of α-synuclein all through the brain. The aggregation and toxicity of α-synuclein must be prevented, but not α-synuclein’s regular functioning. Bronstein believes this protein aids communication between neurons, but this is mere speculation.
The compound developed through the Bronstein-Bitan collaboration – CLR01 – was very successful at attacking the targeted aggregates and leaving other normal brain functions untouched. Bronstein explains, “The most surprising aspect of the work is that despite the ability of the compound to bind to many proteins, it did not show toxicity or side effects to normal, functioning brain cells.” Bitan added, “We call this unique mechanism ‘process-specific,’ rather than the common protein-specific inhibition.”
The next step for the researchers was to try the compound in a living organism. They tested it on the zebrafish. This fish is common for animal research because it can be easily genetically manipulated, develops rapidly, and it is transparent, making observation and measurement a simple task.
The researchers used a transgenic zebrafish and used fluorescent proteins to track the added CLR01’s effects on the aggregates. Indeed, the tweezer prevented α-synuclein aggregation and, by extension, neural death. This halted the progression of Parkinson’s in the live animal model. Bronstein says, “CLR01 holds great promise as a new drug that can slow or stop the progression of Parkinson’s and related disorders. This takes us one step closer to a cure.”
Researchers are currently studying the CLR01 in a mouse model of Parkinson’s. Each new animal species trial takes them one step closer to human clinical trials, along the path to finding a cure.
“Parkinson’s Disease Stopped in Animal Model”. (March 2, 2012). Neuroscience News. March 8, 2012. http://neurosciencenews.com/parkinsons-disease-stopped-animal-model-clr01/.
July 4, 2012 § Leave a comment
Alzheimer’s affects 5.4 million Americans. This number is expected to double every 20 years. Neuroscientists at MIT have discovered the culprit of memory impairment associated with Alzheimer’s disease. The findings were published in the February online edition of Nature, lead by author Johannes Gräff, postdoctoral at the Picower Institute.
The overproduction of a blockading enzyme in the brain of Alzheimer’s patients thwarts the formation of new memories. The enzyme is known as HDAC2. MIT researchers observed that by inhibiting the enzyme in mice, a reversal of the symptoms of Alzheimer’s occurs. The findings suggest that therapeutic drugs aimed at this enzyme could better treat the disease.
The leader of the research team is Li-Huei Tsai, director of the Picower Institute for Learning and Memory at MIT. Tsai says that the enzyme inhibitors could achieve this goal, but that it could take up to 10 years to develop and test the drugs. However, she strongly advocates a program to develop the agents. She says, “The disease is so devastating and affects so many people, so I would encourage more people to think about this.”
HDACs are a group of 11 enzymes that regulate genes by modifying histones. Histones are proteins that DNA reels around, forming chromatin. Through a process called deacetylation, HDACs alter histones, causing the chromatin to tighten its DNA and histone spool, making it less likely for the genes in this region to be expressed. The HDAC inhibitors loosen the spools, allowing for DNA expression. Tsai explains, “With such a blockade, the brain really loses the ability to quickly respond to stimulation. You can imagine that this creates a huge problem in terms of learning and memory functions, and perhaps other cognitive functions.”
During the study, researchers discovered that mice with Alzheimer’s symptoms had an overabundance of HDAC2 in the hippocampus. This is the site of new memory formation. This enzyme was clinging to the genes implicated in synaptic plasticity – the brain’s capacity for strengthening and weakening connections between neurons, which is critical for memory formation. Afflicted mice had less expression in these genes, due to tightening effect of the high concentration of the HDAC2 enzymes.
Using a molecule called short hairpin RNA – the molecule that carried genetic instructions from DNA to the cell – researchers shut off the HDAC2 in the afflicted mice. Histone acetylation recommenced and genes responsible for synaptic plasticity and learning memory processes were able to express. Normal cognitive function was redeemed in the treated mice.
Beta-amyloid protein clearing drugs are the treatment option most commonly used. The results are modest at best. These proteins cluster in the brains of Alzheimer’s patients and this causes an interference with the cell receptors required for synaptic plasticity. This new study revealed that beta amyloid stimulates the production of the HDAC2 enzyme.
Tsai explains, “We think that once this epigenetic blockade of gene expression is in place, clearing beta amyloid may not be sufficient to restore the active configuration of the chromatin.” He says that the HDAC2 inhibitors could reverse the symptoms of Alzheimer’s even after the blockade is created.
Before the drug can be entered into clinical trials, many more tests and development steps must be taken. Tsai believes clinical trials could be as many as 5 years away and approval will take as many as 10 years. To treat Alzheimer’s, the process of testing inhibitors must be extremely selective and precise.
“Reversing Alzheimer’s Gene Blockade Can Restore Memory, Other Cognitive Functions”. (February 29, 2012). Neuroscience News. March 3, 2012. http://neurosciencenews.com/reversing-alzheimers-gene-blockade-restores-memory-function/.