Multiple Sclerosis research: the thalamus moves into the spotlight

A growing body of research by multiple sclerosis (MS) investigators at the University at Buffalo and international partners is providing powerful new evidence that the brain’s gray matter reflects important changes in the disease that could allow clinicians to diagnose earlier and to better monitor and predict how the disease will progress.

Over the past three years, the UB researchers and their partners around the world, supported by an active fellowship program at UB’s Buffalo Neuroimaging Analysis Center (BNAC), have published journal papers and given presentations demonstrating that the thalamus region, in particular, is key to a host of issues involving MS.

“The thalamus is providing us with a new window on MS,” says Robert Zivadinov, MD, PhD, UB professor of neurology, BNAC director and leader of the research team. “In our recent studies, we have used large datasets to investigate the evolution of atrophy of the thalamus and its association with clinical impairment in MS, starting with the earliest stages of the disease. The location of the thalamus in the brain, its unique function and its vulnerability to changes wrought by the disease make the thalamus a critical barometer of the damage that MS causes to the brain.”

Zivadinov and UB professor of neurology Ralph Benedict discuss the new research in a video.

At the annual meeting of the American Academy of Neurology today, Zivadinov will discuss a study he performed in collaboration with colleagues from Charles University in Prague. The study found that atrophy of the thalamus, determined with MRI, can help identify which patients with clinically isolated syndrome (CIS), a patient’s first episode of MS, are at risk for developing clinically definite MS. Such a tool would be immensely helpful to clinicians, Zivadinov notes.

“This study, which included more than 200 patients, shows that thalamic atrophy is one of the most important predictors of clinically definite MS,” says Dana Horakova, MD, PhD, the principal investigator at Charles University.

“Therefore, based on these findings, we think MRI should be used to determine which patients are at highest risk for a second attack,” explains Zivadinov.

The neuroscience of finding your lost keys

Ever find yourself racking your brain on a Monday morning to remember where you put your car keys?

When you do find those keys, you can thank the hippocampus, a brain region responsible for storing and retrieving memories of different environments-such as that room where your keys were hiding in an unusual spot.

Now, scientists have helped explain how the brain keeps track of the incredibly rich and complex environments people navigate on a daily basis. They discovered how the dentate gyrus, a subregion of the hippocampus, helps keep memories of similar events and environments separate, a finding they reported March 20 in eLife. The findings, which clarify how the brain stores and distinguishes between memories, may also help identify how neurodegenerative diseases, such as Alzheimer’s disease, rob people of these abilities.

"Everyday, we have to remember subtle differences between how things are today, versus how they were yesterday - from where we parked our car to where we left our cellphone," says Fred H. Gage, senior author on the paper and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease at Salk. "We found how the brain makes these distinctions, by storing separate ‘recordings’ of each environment in the dentate gyrus."

The process of taking complex memories and converting them into representations that are less easily confused is known as pattern separation. Computational models of brain function suggest that the dentate gyrus helps us perform pattern separation of memories by activating different groups of neurons when an animal is in different environments.

However, previous laboratory studies found that in fact the same populations of neurons in the dentate gyrus are active in different environments, and that the way the cells distinguished new surroundings was by changing the rate at which they sent electrical impulses. This discrepancy between theoretical predictions and laboratory findings has perplexed neuroscientists and obscured our understanding of memory formation and retrieval.

To explore this mystery more deeply, the Salk scientists compared the functioning of the mouse dentate gyrus and another region of the hippocampus, known as CA1, using laboratory techniques for tracking the activity of neurons at multiple time points.

First, the researchers took mice from their original chamber and placed them in a novel chamber to learn about a new environment (episode 1). Meanwhile, they recorded which hippocampal neurons were active as the animals responded to their new surroundings. Subsequently, the mice were either returned to that same novel chamber to measure memory recall or to a slightly modified chamber to measure discrimination (episode 2). The active neurons in episode 2 were also labeled in order to determine if the neurons activated in episode 1 were used in the same way for recall and for discrimination of small differences between environments.

When the researchers compared the neural activity during the two episodes, they found that the dentate gyrus and CA1 sub-regions functioned differently. In CA1, the same neurons that were active during the initial learning episode were also active when the mice retrieved the memories. In the dentate gyrus, however, distinct groups of cells were active during the learning episodes and retrieval. Also, exposing the mice to two subtly different environments activated two distinct groups of cells in the dentate gyrus.

"This finding supported the predictions of theoretical models that different groups of cells are activated during exposure to similar, but distinct, environments," says Wei Deng, a Salk postdoctoral research and first author on the paper. "This contrasts with the findings of previous laboratory studies, possibly because they looked at different sub-populations of neurons in the dentate gyrus."

The Salk researchers’ findings suggest that recalling a memory-such as the location of missing keys-does not always involve reactivation of the same neurons that were active during encoding. More importantly, the results indicate that the dentate gyrus performs pattern separation by using distinct populations of cells to represent similar but non-identical memories.

The findings help clarify the mechanisms that underpin memory formation and shed light on systems that are disrupted by injuries and diseases of the nervous system.

How Serotonin Receptors Can Shape Drug Effects from LSD to Migraine Medication

A team including scientists from The Scripps Research Institute (TSRI), the University of North Carolina at Chapel Hill and the Chinese Academy of Sciences has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor. The new findings help explain why some drugs that interact with these receptors have had unexpectedly complex and sometimes harmful effects.

“Understanding the structure-function of these receptors allows us to discover new biology of serotonin signaling and also gives us better ideas about what biological questions to probe in a more intelligent manner,” said TSRI Professor Raymond Stevens, who was a senior investigator for the new research. The studies were published in two papers on March 21, 2013 in Science Express [1 , 2], the advance online version of the journal Science.

Pioneering Important Molecular Structures

Stevens’s laboratory at TSRI has pioneered the development of techniques for determining the 3D atomic structures of cellular receptors—particularly the large receptor class known as G protein-coupled receptors (GPCRs). GPCRs sit in the cell membrane and sense various molecules outside cells. When certain molecules bind to them, the receptor’s respond in a way to transmit a signal inside the cell.

“Because G protein-coupled receptors are the targets of nearly 50 percent of medicines, they are the focus of several major National Institutes of Health (NIH) initiatives,” said Jean Chin of the NIH’s National Institute of General Medical Sciences, which partly funded the work through the Protein Structure Initiative. “These detailed molecular structures of two serotonin receptor subfamilies bound to antimigraines, antipsychotics, antidepressants or appetite suppressants will help us understand how normal cellular signaling is affected by these drugs and will offer a valuable framework for designing safer and more effective medicines.”

In the past several years, using X-ray crystallography, the Stevens laboratory has determined the high-resolution structures of 10 of the most important GPCRs for human health—including the β2 adrenergic receptor, the A2a adenosine receptor (the target of caffeine), HIV related CXCR4 receptor, the pain-mediating nociceptin receptor, S1P1 receptor important for inflammatory diseases, H1 histamine receptor (antihistamine medications) and the D3 dopamine receptor which is involved in mood, motivation and addiction.

Serotonin receptors are no less important. “Nearly all psychiatric drugs affect serotonin receptors to some extent, and these receptors also mediate a host of effects outside the brain, for example on blood coagulation, smooth muscle contraction and heart valve growth,” said Bryan Roth, a collaborator on both studies who is professor of pharmacology at the University of North Carolina (UNC).

Untangling Two Serotonin Receptors

Roth’s laboratory teamed up with Stevens’s as part of the National Institute of General Medical Sciences (NIGMS) Protein Structure Initiative. For this project the two labs also worked with the laboratories of Professors Eric Xu and Hualiang Jiang at the Shanghai Institute of Materia Medica, part of the Chinese Academy of Sciences. “By collaborating with the Chinese teams we were able to complete a much more thorough study and get the most out of our fundamental structural results,” said Stevens.

In the first of the new studies, co-lead author Chong Wang, a graduate student in the Stevens laboratory, and his colleagues determined the structure of the serotonin receptor subtype 5-HT_1B, the principal target of several drug classes. (5-HT, or 5-hydroxytryptamine, is a technical term for serotonin.) The team produced the 5-HT_1B receptor while it was bound by either ergotamine or dihydroergotamine—two old-line anti-migraine drugs that work in part by activating 5-HT_1B receptors.

With the help of the special fusion protein, nicknamed BRIL (apocytochrome b562RIL), Wang and colleagues were able to stabilize these structures and coax them to line up in a regular ordering known as a crystal. X-ray crystallography revealed, at high resolution, an atomic structure of 5-HT_1B with a main binding pocket and a separate, extended binding pocket.

Harmful Off-Target Effects

In the second study, TSRI graduate student and lead author Daniel Wacker and colleagues used similar techniques to determine the structure of the 5-HT_2B receptor bound to ergotamine. The 5-HT_2B receptor was chiefly of interest because drug developers want to avoid activating it.

“Drugs that are meant to target other serotonin receptors in the brain can have harmful off-target effects on 5-HT_2B receptors, which are found abundantly on heart valves, for example,” said Roth. The weight-loss drug fenfluramine and closely related dexfenfluramine were withdrawn from the US market in 1997 after being linked to heart valve disease. Roth’s laboratory later showed that this side effect was mediated by heart valve 5-HT_2B receptors.

Analyses of the 5-HT_1B and 5-HT_2B receptor structures revealed a subtle difference between them. “Although their main binding pockets look very similar, their extended binding pockets are not as similar—the one for 5-HT_2B is narrower and in a slightly different position,” said Wang.

With the two receptor structures in hand, the Xu and Jiang team simulated the bindings of various drugs. They showed, for example, that anti-migraine drugs called triptans should bind well to 5-HT_1B receptors but poorly to 5-HT_2B receptor structures, in which the extended binding pocket is less accessible. Similarly, the team’s calculations confirmed that fenfluramine’s active metabolite should bind very tightly to the 5-HT_2B receptor.

Delving Deeper

In the second study, the researchers used the 5-HT_2B and 5-HT_1B structural data to better understand a recently discovered GPCR signaling pathway.

When a neurotransmitter such as serotonin binds to its GPCR receptor and triggers the primary, G protein-mediated activation signal, it also usually triggers another signal, often mediated by a protein called β-arrestin. This second signaling cascade may simply have the effect of “arresting” or inhibiting the primary, G protein-mediated signaling. But it can also have other effects on the cell, and although most molecules bind to their target GPCRs in a way that activates these primary and secondary signals equally, others preferentially activate one or the other. “Such functional selectivity, as we call it, adds another layer of complexity to drug effects on GPCRs,” said Roth, a co-senior author of the study.

Roth’s laboratory produced several 5-HT receptor subtypes in test cells, and compared the strength of G-protein and β-arrestin signaling when these receptors were bound by ergotamine or various other drugs, including the ergotamine-derived hallucinogen LSD (lysergic acid diethylamide). Most of the tested drugs showed no bias. However, ergotamine, LSD and some of their relatives turned out to be clearly biased in favor of β-arrestin signaling at the 5-HT_2B receptor. Comparison of the ergotamine-bound 5-HT_2B structure with the ergotamine-bound 5-HT_1B structure revealed the likely reason. “We could see that when ergotamine is bound to the 5-HT_2B receptor it stabilizes the receptor structure in a conformation that interferes with G protein signaling,” said Wacker.

The findings allow scientists to start probing this arrestin-mediated signaling pathway and its downstream effects in a more targeted manner. “These structural data are teaching us to ask better questions about receptor biology,” said Stevens.

Robot-Delivered Speech and Physical Therapy

In one of the earliest experiments using a humanoid robot to deliver speech and physical therapy to a stroke patient, researchers at the University of Massachusetts Amherst saw notable speech and physical therapy gains and significant improvement in quality of life.

Regarding the overall outcome, speech language pathologist and study leader Yu-kyong Choe says, “It’s clear from our study of a 72-year-old male stroke client that a personal humanoid robot can help people recover by delivering therapy such as word-retrieval games and arm movement tasks in an enjoyable and engaging way.”

A major focus of this case study was to assess how therapy interventions in one domain, speech, affected interventions in another, physical therapy, in two different delivery scenarios. Despite the importance of working with other professionals, the authors point out, until now it has been “largely unknown how interventions by one type of therapy affects progress in others.”

The client, with aphasia and physical disability on one side, completed a robot-mediated program of only speech therapy for five weeks followed by only physical therapy for five weeks in the sole condition, but for the sequential condition he attended back-to-back speech and physical therapy sessions for five weeks.

Over the course of the experiment, the client made “notable gains in the frequency and range of the upper-limb movements,” the authors say. He also made positive gains in verbal expression. Interestingly, his improvements in speech and physical function were much greater when he engaged in only one therapy than when the two therapies were paired in sessions immediately following each other. The authors summarize that in such a sequential schedule “speech and physical functions seemed to compete for limited resources” in the brain. Their work is described in the current issue of the journal Aphasiology.

Choe and computer science researcher and robot expert Rod Grupen, director of the Laboratory for Perceptual Robotics at UMass Amherst, are in the second year of a $109,251 grant from the American Heart Association to investigate the effect of stroke rehabilitation delivered by a humanoid robot, uBot-5. It is a child-sized unit with arms and a computer screen through which therapists interact with the client.

Choe, Grupen and colleagues are seeking ways to bring more and longer-term therapy and social contact to people recovering from stroke. It’s estimated that 3 million Americans daily experience the debilitating effects of stroke. But even after years, they can recover significant function with intensive rehabilitation, says Choe. The bad news is that this is rarely available or accessible due to a shortage of therapists and lack of coverage for long-term treatment. Many people are left with chronic low function, which can lead to social isolation and depression.

While some may object to robots delivering therapy, the need is great and definitely not being met now, especially in rural areas, Grupen and Choe point out. They hope to aid human-to-human interaction, so a robot can temporarily take the therapist’s place. Grupen says, “In addition to improving quality of life, if we can support a client in the home so they can delay institutionalization, we can improve outcomes and make a huge impact on the cost of elder care. There are 70 million baby boomers beginning to retire now.”

“Stroke rehabilitation is such a monumental financial problem everywhere in the world, that’s where it can pay for itself,” he adds. “A personal robot could save billions of dollars in elder care while letting people stay in their own homes and communities. We’re hoping for a win-win where our elders live better, more independent and productive lives and our overtaxed healthcare resources are used more effectively.”

Humanoid robot helps train children with autism

“Aiden, look!” piped NAO, a two-foot tall humanoid robot, as it pointed to a flat-panel display on a far wall. As the cartoon dog Scooby Doo flashed on the screen, Aiden, a young boy with an unruly thatch of straw-colored hair, looked in the direction the robot was pointing.

Aiden, who is three and a half years old, has been diagnosed with autism spectrum disorder (ASD). NAO (pronounced “now”) is the diminutive “front man” for an elaborate system of cameras, sensors and computers designed specifically to help children like Aiden learn how to coordinate their attention with other people and objects in their environment. This basic social skill is called joint attention. Typically developing children learn it naturally. Children with autism, however, have difficulty mastering it and that inability can compound into a variety of learning difficulties as they age.

An interdisciplinary team of mechanical engineers and autism experts at Vanderbilt University have developed the system and used it to demonstrate that robotic systems may be powerful tools for enhancing the basic social learning skills of children with ASD. Writing in the March issue of the IEEE Transactions on Neural Systems and Rehabilitation Engineering, the researchers report that children with ASD paid more attention to the robot and followed its instructions almost as well as they did those of a human therapist in standard exercises used to develop joint attention skill.

The finding indicates that robots could play a crucial role in responding to the “public health emergency” that has been created by the rapid growth in the number of children being diagnosed with ASD. Today, one in 88 children (one in 54 boys) are being diagnosed with ASD. That is a 78 percent increase in just four years. The trend has major implications for the nation’s healthcare budget because estimates of the lifetime cost of treating ASD patients ranges from four to six times greater than for patients without autism.

“This is the first real world test of whether intelligent adaptive systems can make an impact on autism,” said team member Zachary Warren, who directs the Treatment and Research Institute for Autism Spectrum Disorders (TRIAD) at Vanderbilt’s Kennedy Center.

How two brain areas interact to trigger divergent emotional behaviors

New research from the University of North Carolina School of Medicine for the first time explains exactly how two brain regions interact to promote emotionally motivated behaviors associated with anxiety and reward.

The findings could lead to new mental health therapies for disorders such as addiction, anxiety, and depression. A report of the research was published online by the journal, Nature, on March 20, 2013.

Located deep in the brain’s temporal lobe are tightly packed clusters of brain cells in the almond shaped amygdala that are important for processing memory and emotion. When animals or people are in stressful situations, neurons in an extended portion of the amygdala called the bed nucleus of the stria terminalis, or BNST, become hyperactive.

But, almost paradoxically, neurons in the BNST, which modulate fear and anxiety, reach into a portion of the midbrain that’s involved in behavioral responses to reward, the ventral tegmental area, or VTA.

“For many years it’s been known that dopamine neurons in the VTA are involved in reward processing and motivation. For example, they’re activated during exposure to drugs of abuse and naturally rewarding experiences,” says study senior author Garret Stuber, PhD, assistant professor in the departments of Psychiatry and Cell Biology and Physiology, and the UNC Neuroscience Center.  “On the one hand, you have this area of the brain – the BNST – that’s associated with aversion and anxiety, but it’s in direct communication with a brain reward center. We wanted to figure out exactly how these two brain regions interact to promote different types of behavioral responses related to anxiety and reward.”

In the past, researchers have tried to get a glimpse into the inner workings of the brain using electrical stimulation or drugs, but those techniques couldn’t quickly and specifically change only one type of cell or one type of connection. But optogenetics, a technique that emerged about seven years ago, can.

In the technique, scientists transfer light-sensitive proteins called “opsins” – derived from algae or bacteria that need light to grow – into the mammalian brain cells they wish to study. Then they shine laser beams onto the genetically manipulated brain cells, either exciting or blocking their activity with millisecond precision.

Brain Mapping Reveals Neurological Basis of Decision-Making in Rats

Scientists at UC San Francisco have discovered how memory recall is linked to decision-making in rats, showing that measurable activity in one part of the brain occurs when rats in a maze are playing out memories that help them decide which way to turn. The more they play out these memories, the more likely they are to find their way correctly to the end of the maze.

In their study, reported this week in the journal Neuron, the UCSF researchers implanted electrodes directly on a region of the rat brain known as the hippocampus, which is already known to play a key role in the formation and recall of memory. This same region is active when animals are learning, and it is damaged in people who have Alzheimer’s and post-traumatic stress disorder.

The study showed that when the rats paused before an upcoming choice, sometimes the hippocampus was more active and sometimes it was less active. When it was more active it did a better job of recalling memories of places the animal could go next, and the animal was more likely to go to the right place.

“We know that considering possibilities is important for decision-making, but we haven’t really known how this happens in the brain,” said neuroscientist Loren Frank, PhD, who led the research. Frank is an associate professor of physiology and a member of the UCSF Center for Integrative Neuroscience at UCSF.

The work builds upon several years of investigations in Frank’s laboratory that have shown how activity in the hippocampus is a fundamental constituent of memory retrieval. Their recent work shows that this activity is not just about remembering the past – it is also important for thinking about the future. When the brain does a better job of thinking about future possibilities, it makes better decisions.

Next, the team wants to tease out why sometimes the hippocampus does not do a good job of playing out future options. Problems with memory and decision-making are central to age-related cognitive decline, and a deeper understanding of how this works could pave the way for interventions that make the brain work better.

Sleep consolidates memories for competing tasks

Sleep plays an important role in the brain’s ability to consolidate learning when two new potentially competing tasks are learned in the same day, research at the University of Chicago demonstrates.

Other studies have shown that sleep consolidates learning for a new task. The new study, which measured starlings’ ability to recognize new songs, shows that learning a second task can undermine the performance of a previously learned task. But this study is the first to show that a good night’s sleep helps the brain retain both new memories.

Starlings provide an excellent model for studying memory because of fundamental biological similarities between avian and mammalian brains, scholars wrote in the paper, “Sleep Consolidation of Interfering Auditory Memories in Starlings,” published in the current online edition of Psychological Science.

“These observations demonstrate that sleep consolidation enhances retention of interfering experiences, facilitating daytime learning and the subsequent formation of stable memories,” the authors wrote.

The paper was written by Timothy Brawn, a graduate researcher in psychology at UChicago; Howard Nusbaum, professor of psychology; and Daniel Margoliash, professor of psychology, organismal biology and anatomy. Nusbaum is a leading expert on learning, and Margoliash is a pioneer in the research of brain function and its development in birds.