Researcher Advancing Motor Neuron Studies

Supported by the commitment of the University of Connecticut and the state to stem cell research, a UConn Health Center researcher is advancing the understanding of the devastating inherited condition known as spinal muscular atrophy.

Xue-Jun Li, assistant professor in the Department of Neuroscience, is corresponding author of a paper published in the prestigious journal Cell Research in December 2012 entitled “Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.” The paper’s other authors are UConn Health Center researcher Zhi-Bo Wang and Xiaoqing Zhang of the Tongji University School of Medicine in Shanghai.

Spinal muscular atrophy (SMA) is a group of inherited diseases that cause muscle damage and debilitation, which progress over time and eventually lead to death. To be affected, a person must inherit the defective gene from both parents. About 1 in 10,000 people have SMA, and most do not survive childhood due to respiratory problems, heart failure and infections.

“There is no effective treatment for spinal muscular atrophy, and one of the roadblocks is not knowing why the spinal motor neuron degenerates,” Li explains. “One of the aspects of our research is to understand how specific types of neurons are specified and degenerated. We are trying to model neurological disorders by using human motor neurons derived from stem cells.”

Establishing human cell models of SMA to mimic motor neuron-specific phenotypes holds the key to understanding this destructive disease, she says. The model described in the journal article provides a unique paradigm for studying how motor neurons degenerate. It also highlights the potential importance of antioxidants for the treatment of SMA.

Understanding how motor neurons are specifically degenerated can lead to effective interventions in the future. “It can help us find some way to rescue the motor neuron degeneration in this disease,” Li points out. “Understanding the role of antioxidants can provide potential clues to finding a treatment.”

In-brain monitoring shows memory network

Working with patients with electrodes implanted in their brains, researchers at the University of California, Davis, and The University of Texas Health Science Center at Houston (UTHealth) have shown for the first time that areas of the brain work together at the same time to recall memories. The unique approach promises new insights into how we remember details of time and place.

"Previous work has focused on one region of the brain at a time," said Arne Ekstrom, assistant professor at the UC Davis Center for Neuroscience. "Our results show that memory recall involves simultaneous activity across brain regions." Ekstrom is senior author of a paper describing the work published Jan. 27 in the journal Nature Neuroscience.

Ekstrom and UC Davis graduate student Andrew Watrous worked with patients being treated for a severe seizure condition by neurosurgeon Dr. Nitin Tandon and his UTHealth colleagues.

To pinpoint the origin of the seizures in these patients, Tandon and his team place electrodes on the patient’s brain inside the skull. The electrodes remain in place for one to two weeks for monitoring.

Six such patients volunteered for Ekstrom and Watrous’ study while the electrodes were in place. Using a laptop computer, the patients learned to navigate a route through a virtual streetscape, picking up passengers and taking them to specific places. Later, they were asked to recall the routes from memory.

Correct memory recall was associated with increased activity across multiple connected brain regions at the same time, Ekstrom said, rather than activity in one region followed by another.

However, the analysis did show that the medial temporal lobe is an important hub of the memory network, confirming earlier studies, he said.

Intriguingly, memories of time and of place were associated with different frequencies of brain activity across the network. For example, recalling, “What shop is next to the donut shop?” set off a different frequency of activity from recalling “Where was I at 11 a.m.?”

Using different frequencies could explain how the brain codes and recalls elements of past events such as time and location at the same time, Ekstrom said.

"Just as cell phones and wireless devices work at different radio frequencies for different information, the brain resonates at different frequencies for spatial and temporal information," he said.

The researchers hope to explore further how the brain codes information in future work.

The neuroscientists analyzed their results with graph theory, a new technique that is being used for studying networks, ranging from social media connections to airline schedules.

"Previously, we didn’t have enough data from different brain regions to use graph theory. This combination of multiple readings during memory retrieval and graph theory is unique," Ekstrom said.

Placing electrodes inside the skull provides clearer resolution of electrical signals than external electrodes, making the data invaluable for the study of cognitive functions, Tandon said. “This work has yielded important insights into the normal mechanisms underpinning recall, and provides us with a framework for the study of memory dysfunction in the future.”

Research Institute Study Shows How Brain Cells Shape Temperature Preferences

While the wooly musk ox may like it cold, fruit flies definitely do not. They like it hot, or at least warm. In fact, their preferred optimum temperature is very similar to that of humans—76 degrees F.

Scientists have known that a type of brain cell circuit helps regulate a variety of innate and learned behavior in animals, including their temperature preferences. What has been a mystery is whether or not this behavior stems from a specific set of neurons (brain cells) or overlapping sets.

Now, a new study from The Scripps Research Institute (TSRI) shows that a complex set of overlapping neuronal circuits work in concert to drive temperature preferences in the fruit fly Drosophila by affecting a single target, a heavy bundle of neurons within the fly brain known as the mushroom body. These nerve bundles, which get their name from their bulbous shape, play critical roles in learning and memory.

The study, published in the January 30, 2013 edition of the Journal of Neuroscience, shows that dopaminergic circuits—brain cells that synthesize dopamine, a common neurotransmitter—within the mushroom body do not encode a single signal, but rather perform a more complex computation of environmental conditions.

“We found that dopamine neurons process multiple inputs to generate multiple outputs—the same set of nerves process sensory information and reward-avoidance learning,” said TSRI Assistant Professor Seth Tomchik. “This discovery helps lay the groundwork to better understand how information is processed in the brain. A similar set of neurons is involved in behavior preferences in humans—from basic rewards to more complex learning and memory.”

Using imaging techniques that allow scientists to visualize neuron activity in real time, the study illuminated the response of dopaminergic neurons to changes in temperature. The behavioral roles were then examined by silencing various subsets of these neurons. Flies were tested using a temperature gradient plate; the flies moved from one place to another to express their temperature preferences.

As it turns out, genetic silencing of dopaminergic neurons innervating the mushroom body substantially reduces cold avoidance behavior. “If you give the fly a choice, it will pick San Diego weather every time,” Tomchik said, “but if you shut down those nerves, they suddenly don’t mind being in Minnesota.”

The study also showed dopaminergic neurons respond to cooling with sudden a burst of activity at the onset of a drop in temperature, before settling down to a lower steady-state level. This initial burst of dopamine could function to increase neuronal plasticity—the ability to adapt—during periods of environmental change when the organism needs to acquire new associative memories or update previous associations with temperature changes.

(Image: ALAMY)

Discovering the Missing “LINC” to Deafness

Because half of all instances of hearing loss are linked to genetic mutations, advanced gene research is an invaluable tool for uncovering causes of deafness — and one of the biggest hopes for the development of new therapies. Now Prof. Karen Avraham of the Sackler Faculty of Medicine at Tel Aviv University has discovered a significant mutation in a LINC family protein — part of the cells of the inner ear — that could lead to new treatments for hearing disorders.

Her team of researchers, including Dr. Henning Horn and Profs. Colin Stewart and Brian Burke of the Institute of Medical Biology at A*STAR in Singapore, discovered that the mutation causes chaos in a cell’s anatomy. The cell nucleus, which contains our entire DNA, moves to the top of the cell rather than being anchored to the bottom, its normal place. Though this has little impact on the functioning of most of the body’s cells, it’s devastating for the cells responsible for hearing, explains Prof. Avraham. “The position of the nucleus is important for receiving the electrical signals that determine proper hearing,” she explains. “Without the ability to receive these signals correctly, the entire cascade of hearing fails.”

This discovery, recently reported in the Journal of Clinical Investigation, may be a starting point for the development of new therapies. In the meantime, the research could lead towards work on a drug that is able to mimic the mutated protein’s anchoring function, and restore hearing in some cases, she suggests.

Altering eye cells may one day restore vision

Doctors may one day treat some forms of blindness by altering the genetic program of the light-sensing cells of the eye, according to scientists at Washington University School of Medicine in St. Louis.

Working in mice with retinitis pigmentosa, a disease that causes gradual blindness, the researchers reprogrammed the cells in the eye that enable night vision. The change made the cells more similar to other cells that provide sight during daylight hours and prevented degeneration of the retina, the light-sensing structure in the back of the eye. The scientists now are conducting additional tests to confirm that the mice can still see.

“We think it may be significantly easier to preserve vision by modifying existing cells in the eye than it would be to introduce new stem cells,” says senior author Joseph Corbo, MD, PhD, assistant professor of pathology and immunology. “A diseased retina is not a hospitable environment for transplanting stem cells.”

The study is available in the early online edition of Proceedings of the National Academy of Sciences.

Mutations in more than 200 genes have been linked to various forms of blindness. Efforts are underway to develop gene therapies for some of these conditions.

Rather than seek treatments tailored to individual mutations, Corbo hopes to develop therapies that can alleviate many forms of visual impairment. To make that possible, he studies the genetic factors that allow cells in the developing eye to take on the specialized roles necessary for vision.

Tests conducted on Israel’s Ariel Sharon reveal significant brain activity

A team of American and Israeli brain scientists tested former Israeli Prime Minister Ariel Sharon to assess his brain responses, using functional magnetic resonance imaging (fMRI). Surprisingly, Sharon showed significant brain activity.

The team consisted of Martin Monti, an assistant professor of psychology and neurosurgery at UCLA, professors Alon Friedman, Galia Avidan and Tzvi Ganel of the Zlotowski Center for Neuroscience at Israel’s Ben-Gurion University of the Negev, and Dr. Ilan Shelef, head of medical imaging at Israel’s Soroka University Medical Center.

The 84-year-old Sharon, presumed to be in a vegetative state since suffering a brain hemorrhage in 2006, was scanned last week to assess the extent and quality of his brain processing, using methods recently developed by Monti and his colleagues. The test lasted approximately two hours.

The scientists showed Sharon pictures of his family, had him listen to his son’s voice and used tactile stimulation to assess the extent to which his brain responded to external stimuli.

To their surprise, significant brain activity was observed in each test, in specific brain regions, indicating appropriate processing of these stimulations, Monti said.

The scientists conducted three tests to assess Sharon’s level of consciousness. They asked him to imagine he was hitting a tennis ball and to imagine he was walking through the rooms of his home. They also showed him a photograph of a face superimposed on a photo of a house, asking him to focus first on the face and then on the house. The scientists found encouraging, but subtle, signs of consciousness.

"Information from the external world is being transferred to the appropriate parts of Mr. Sharon’s brain. However, the evidence does not as clearly indicate whether Mr. Sharon is consciously perceiving this information," Monti said. "We found faint brain activity indicating that he was complying with the tasks. He may be minimally conscious, but the results were weak and should be interpreted with caution."

Tzvi Ganel, who initiated the project, stressed that Sharon’s family wished to employ these new techniques not only for the benefit of the former prime minister but also for other families in a similar situation.

New research uncovers the neural mechanism underlying drug cravings

Addiction may result from abnormal brain circuitry in the frontal cortex, the part of the brain that controls decision-making. Researchers from the RIKEN Center for Molecular Imaging Science in Japan collaborating with colleagues from the Montreal Neurological Institute of McGill University in Canada report today that the lateral and orbital regions of the frontal cortex interact during the response to a drug-related cue and that aberrant interaction between the two frontal regions may underlie addiction. Their results are published today in the journal Proceedings of the National Academy of Sciences of the USA.

Cues such as the sight of drugs can induce cravings and lead to drug-seeking behaviors and drug use. But cravings are also influenced by other factors, such as drug availability and self-control. To investigate the neural mechanisms involved in cue-induced cravings the researchers studied the brain activity of a group of 10 smokers, following exposure to cigarette cues under two different conditions of cigarette availability. In one experiment cigarettes were available immediately and in the other they were not. The researchers combined a technique called transcranial magnetic stimulation (TMS) with functional magnetic resonance imaging (fMRI).

The results demonstrate that in smokers the orbitofrontal cortex (OFC) tracks the level of craving while the dorsolateral prefrontal cortex (DPFC) is responsible for integrating drug cues and drug availability. Moreover, the DPFC has the ability to suppress activity in the OFC when the cigarette is unavailable. When the DPFC was inactivated using TMS, both craving and craving-related signals in the OFC became independent of drug availability.

The authors of the study conclude that the DLPFC incorporates drug cues and knowledge on drug availability to modulate the value signals it transmits to the OFC, where this information is transformed into drug-seeking action.

"We demonstrate that in smokers, cravings build up in the OFC upon processing of cigarette cues and availability by the DFPC. What is surprising is that this is a neural circuit involved in decision making and self-control, that normally guides individuals to optimal behaviors in daily life." Explains Dr. Hayashi, from RIKEN, who designed and conducted the fMRI and TMS experiments.

"This research uncovers the brain circuitry responsible for self-control during reward-seeking choices. It is also consistent with the view that drug addiction is a pathology of decision making." According to Dr. Alain Dagher, a neurologist at the Montreal Neurological Institute.

These findings will help understand the neural basis of addiction and may contribute to a therapeutic approach for addiction.

(Image: New Jersey Addiction Assistance)