Wiring of retina reveals how eyes sense motion

Online gamers helped researchers map neuron connections involved in detecting direction of moving objects.

A vast project to map neural connections in the mouse retina may have answered the long-standing question of how the eyes detect motion. With the help of volunteers who played an online brain-mapping game, researchers showed that pairs of neurons positioned along a given direction together cause a third neuron to fire in response to images moving in the same direction.

It is sometimes said that we see with the brain rather than the eyes, but this is not entirely true. People can only make sense of visual information once it has been interpreted by the brain, but some of this information is processed partly by neurons in the retina. In particular, 50 years ago researchers discovered that the mammalian retina is sensitive to the direction and speed of moving images. This showed that motion perception begins in the retina, but researchers struggled to explain how.

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Functioning of aged brains and muscles in mice made younger

Harvard Stem Cell Institute (HSCI) researchers have shown that a protein they previously demonstrated can make the failing hearts in aging mice appear more like those of young health mice, similarly improves brain and skeletal muscle function in aging mice.

In two separate papers given early online release today by the journal Science—which is publishing the papers this coming Friday, Professors Amy Wagers, PhD, and Lee Rubin, PhD, of Harvard’s Department of Stem Cell and Regenerative Biology (HSCRB), report that injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human, and also improved the function of the olfactory region of the brains of the older mice—they could detect smell as younger mice do.

Rubin, and Wagers, who also has a laboratory at the Joslin Diabetes Center, each said that, baring unexpected developments, they expect to have GDF11 in initial human clinical trials within three to five years.

Postdoctoral fellow Lida Katsimpardi, PhD, is the lead author on the Rubin group’s paper, and postdocs Manisha Sinha, PhD, and Young Jang, PhD, are the lead authors on the paper from the Wagers group.

Both studies examined the effect of GDF11 in two ways. First, by using what is called a parabiotic system, in which two mice are surgically joined and the blood of the younger mouse circulates through the older mouse. And second, by injecting the older mice with GDF11, which in an earlier study by Wagers and Richard Lee, MD, of Brigham and Women’s Hospital who is also an author on the two papers released today, was shown to be sufficient to reverse characteristics of aging in the heart.

Doug Melton, PhD, co-chair of HSCRB and co-director of HSCI, reacted to the two papers by saying that he couldn’t “recall a more exciting finding to come from stem cell science and clever experiments. This should give us all hope for a healthier future. We all wonder why we were stronger and mentally more agile when young, and these two unusually exciting papers actually point to a possible answer: the higher levels of the protein GDF11 we have when young. There seems to be little question that, at least in animals, GDF11 has an amazing capacity to restore aging muscle and brain function,” he said.

Melton, Harvard’s Xander University Professor, continued, saying that the ongoing collaboration between Wagers, a stem cell biologist whose focus has been on muscle, Rubin, whose focus is on neurodegenerative diseases and using patient generated stem cells as targets for drug discovery, and Lee, a practicing cardiologist and researcher, “is a perfect example of the power of the Harvard Stem Cell Institute as an engine of truly collaborative efforts and discovery, bringing together people with big, unique ideas and expertise in different biological areas.”

As Melton noted, GDF11 is naturally found in much higher concentrations in young mice than in older mice, and raising its levels in the older mice has improved the function of every organ system thus far studied.

Wagers first began using the parabiotic system in mice 14 years ago as a postdoctoral fellow at Stanford University, when she and colleagues Thomas Rando, MD, PhD, of Stanford, Irina Conboy, PhD, of the University of California, Berkley, and Irving Weissman, MD, of Stanford, observed that the blood of young mice circulating in old mice seemed to have some rejuvenating effects on muscle repair after injury.

Last year, she and Richard Lee published a paper in which they reported that when exposed to the blood of young mice, the enlarged, weakened hearts of older mice returned to a more youthful size, and their function improved. And then working with a Colorado firm, the pair reported that GDF11 was the factor in the blood apparently responsible for the rejuvenating effect. That finding has raised hopes that GDF11 may prove, in some form, to be a possible treatment for diastolic heart failure, a fatal condition in the elderly that now is irreversible, and fatal.

“From the previous work it could have seemed that GD11 was heart specific,” said Wagers, “but this shows that it is active in multiple organs and cell types. Prior studies of skeletal muscle and the parabiotic effect really focused on regenerative biology. Muscle was damaged and assayed on how well it could recover,” Wagers explained.

She continued: “The additional piece is that while prior studies of young blood factors have shown that we achieve restoration of muscle stem cell function and they repair the muscle better, in this study, we also saw repair of DNA damage associated with aging, and we got it in association with recovery of function, and we saw improvements in unmanipulated muscle. Based on other studies, we think that the accumulation of DNA damage in muscle stem cells might reflect an inability of the cells to properly differentiate to make mature muscle cells, which is needed for adequate muscle repair.”

Wagers noted that there is still a great deal to be learned about the mechanics of aging in muscle, and its repair. “I don’t think we fully understand how this happening or why. We might say that the damage is modification to the genetic material; the genome does have breaks in it. But whether it’s damaging, or a necessary part of repair, we don’t know yet.”

Rubin, whose primary research focus is on developing treatment for neurodegenerative diseases, particularly in children, said that when his group began its GDF11 experiments, “we knew that in the old mouse things were bad in the brain, there is a reduced amount of neurogenesis (the development of neurons), and it’s well known that cognition goes down. It wasn’t obvious to me that those things that can be repaired in peripheral tissue could be fixed in the brain.”

Rubin said that postdoctoral fellow Lida Katsimpardi, the lead author on his group’s paper, was taught the parabiotic experimental technique by Wagers, but conducted the Rubin group’s experiments independently of the Wagers group, and “she saw an increase in neural stem cells, and increased development of blood vessels in the brain.” Rubin said that 3D reconstruction of the brain, and magnetic resonance imaging (MRI) of the mouse brain showed “more new blood vessels and more blood flow,” both of which are normally associated with younger, healthier brain tissue.”

Younger mice, Rubin said, “have a keen sense of olfactory discrimination,” they can sense fine differences in odor. “When we tested the young mice, they avoided the smell of mint; the old mice didn’t. But the old mice exposed to the blood of the young mice, and those treated with GDF11 did.”

“We think an effect of GDF11 is the improved vascularity and blood flow, which is associated with increased neurogenesis,” Rubin said. “However, the increased blood flow should have more widespread effects on brain function. We do think that, at least in principle, there will be a way to reverse some of the cognitive decline that takes place during aging, perhaps even with a single protein. It could be that a molecule like GDF11, or GDF11 itself, could” reverse the damage of aging.

“It isn’t out of question that GDF11,” or a drug developed from it, “might be capable of slowing some of the cognitive defects associated with Alzheimer’s disease, a disorder whose main risk factor is aging itself,” Rubin said. It is even possible that this could occur without directly changing the “plaque and tangle burden” that are the pathological hallmarks of Alzheimer’s. Thus, a future treatment for this disease might be a combination of a therapeutic that reduces plaques and tangles, such as an antibody directed against the β-amyloid peptide, with a potential cognition enhancer like GDF11.

Wagers said that the two research groups are in discussions with a venture capital group to obtain funding to “be able to do the additional preclinical work” necessary before moving GDF11 into human trials.

“I would wager that the results of this work, together with the other work, will translate into a clinical trial and a treatment,” said the stem cell biologist. “But of course that’s just a wager.”

Motor cortex shown to play active role in learning movement patterns

Skilled motor movements of the sort tennis players employ while serving a tennis ball or pianists use in playing a concerto, require precise interactions between the motor cortex and the rest of the brain. Neuroscientists had long assumed that the motor cortex functioned something like a piano keyboard.

"Every time you wanted to hear a specific note, there was a specific key to press," says Andrew Peters, a neurobiologist at UC San Diego’s Center for Neural Circuits and Behavior. "In other words, every specific movement of a muscle required the activation of specific cells in the motor cortex because the main job of the motor cortex was thought to be to listen to the rest of the cortex and press the keys it’s directed to press."

But in a study published in this week’s advance online publication of the journal Nature, Peters, the first author of the paper, and his colleagues found that the motor cortex itself plays an active role in learning new motor movements. In a series of experiments using mice, the researchers showed in detail how those movements are learned over time.

"Our finding that the relationship between body movements and the activity of the part of the cortex closest to the muscles is profoundly plastic and shaped by learning provides a better picture of this process," says Takaki Komiyama, an assistant professor of biology at UC San Diego who headed the research team. "That’s important, because elucidating brain plasticity during learning could lead to new avenues for treating learning and movement disorders, including Parkinson’s disease."

With Simon Chen, another UC San Diego neurobiologist, the researchers monitored the activity of neurons in the motor cortex over a period of two weeks while mice learned to press a lever in a specific way with their front limbs to receive a reward.

"What we saw was that during learning, different patterns of activity—which cells are active, when they’re active—were evident in the motor cortex," says Peters. "This ends up translating to different patterns of activity even for similar movements. Once the animal has learned the movement, similar movements are then accompanied by consistent activity. This consistent activity moreover is totally new to the animal: it wasn’t used early in learning even with movements that were similar to the later movement."

"Early on," Peters says, "the animals will occasionally make movements that look like the expert movements they make after learning. The patterns of brain activity that accompany those similar early and late movements are actually completely different though. Over the course of learning, the animal generates a whole new set of activity in the motor cortex to make that movement. In the piano keyboard analogy, that’s like using one key to make a note early on, but a different key to make the same note later."

By Restoring Sense of Touch to Amputees, HAPTIX Seeks to Overcome Physical and Psychological Effects of Upper Limb Loss

To understand the meaning of “proprioception,” try a simple experiment. Close your eyes and lift your right arm above your head. Then, move it down so that it’s parallel to the ground. Make a fist and release it. Move it forward, and then swing it around behind you like you’re stretching. Finally, freeze in place, open your eyes, and look. Is your arm positioned where you thought it would be?

For most people, the answer will be, “Yes.” That’s because your brain and nervous system worked together to move your body according to your intent and processed the sensory feedback to know where your arm was in space despite not being able to visually track it.

For many upper-limb amputees using prosthetic devices, the answer would be, “No.” They wouldn’t have confidence that their device would be where they think it is because current prostheses lack provisions for providing complex tactile and proprioceptive feedback to the user. Without this feedback, even the most advanced prosthetic limbs will remain numb to the user and manipulation functions will be impaired.

DARPA’s new Hand Proprioception and Touch Interfaces (HAPTIX) program seeks to deliver those kinds of naturalistic sensations to amputees, and in the process, enable intuitive, dexterous control of advanced prosthetic devices that substitute for amputated limbs, provide the psychological benefit of improving prosthesis “embodiment,” and reduce phantom limb pain. The program builds on neural-interface technologies advanced during DARPA’s Revolutionizing Prosthetics and Reliable Neural-Interface Technology (RE-NET) programs that made major steps forward in providing a direct and powerful link between user intent and prosthesis control.

HAPTIX aims to achieve its goals by developing interface systems that measure and decode motor signals recorded in peripheral nerves and/or muscles. The program will adapt one of the advanced prosthetic limb systems developed under Revolutionizing Prosthetics to incorporate sensors that provide tactile and proprioceptive feedback to the user, delivered through patterned stimulation of sensory pathways in the peripheral nerve. One of the key challenges will be to identify stimulation patterning strategies that elicit naturalistic sensations of touch and movement. The ultimate goal is to create a fully-implantable device that is safe, reliable, effective, and approved for human use.

“Peripheral nerves are information-rich and readily accessible targets for interfacing with the human nervous system. Research performed under DARPA’s RE-NET program and elsewhere showed that these nerves maintain motor and sensory fibers that previously innervated the amputated limb, and that these fibers remain functional for decades after limb loss,” said Doug Weber, the DARPA program manager. “HAPTIX will try to tap in to these biological communication pathways so that users can control and sense the prosthesis via the same neural signaling pathways used for intact hands and arms.”

In addition to the improved motor performance that restored touch and proprioception would convey to the user, mounting evidence suggests that sensory stimulation in amputees may provide important psychological benefits such as improving prosthesis “embodiment” and reducing the phantom limb pain that is suffered by approximately 80 percent of amputees. For this reason, DARPA seeks the inclusion of psychologists in the multi-disciplinary teams of scientists, engineers, and clinicians proposing to develop the electrodes, algorithms, and electronics technology components for the HAPTIX system. Teams will need to consider how the use of HAPTIX system may impact the user in several important domains including motor and sensory function, psychology, pain, and quality of life.

“We have the opportunity to not only significantly improve an amputee’s ability to control a prosthetic limb, but to make a profound, positive psychological impact,” Weber said. “Amputees view existing prostheses as if they were tools, like a wrench, used only to perform a specific job, so many people abandon their prostheses unless absolutely needed. We believe that HAPTIX will create a sensory experience so rich and vibrant that the user will want to wear his or her prosthesis full-time and accept it as a natural extension of the body. If we can achieve that, DARPA is even closer to fulfilling its commitment to help restore full and natural functionality to wounded service members.”

The program plan culminates with a 12-month, take-home trial of the complete HAPTIX prosthesis system. To aid performers in the completion of the steps necessary to achieve regulatory approvals for human trials, DARPA consulted with the U.S Food and Drug Administration to incorporate regulatory timelines into the program process.

“Once development of the HAPTIX system is complete, we want people to benefit immediately and be able to use their limb all day, every day, and in every aspect of their lives,” Weber said. “The experience needs to be comfortable and easy. Take-home trials are the first step in making that vision a reality.”

If it is successful, the HAPTIX program will create fully-implantable, modular, and reconfigurable neural-interface microsystems that communicate wirelessly with external modules, such as the prosthesis interface link. Because such technology would have broad application and could fuel future medical devices, HAPTIX also plans to fund teams to pursue the science and technology that would support next-generation HAPTIX capabilities.

Full details of the HAPTIX opportunity are available on the Federal Business Opportunities website at: http://go.usa.gov/kyjJ.

The Ways to Control Dreaming

In 2008, Isaac Katz, a civil service officer, passed away just before reaching his 78th birthday. He had been struggling with cardiovascular problems for some time. His son, Arnon Katz, now a 47-year-old tech entrepreneur, was beside himself with grief, and frustrated by the fact that he would never speak to his father again.

At the time, the younger Katz had been training himself to lucid dream—a phenomenon in which the dreamer becomes aware they are dreaming and can potentially control their actions as well as the content and context of the dream. But despite keeping a dream journal and diligently practicing other techniques, hadn’t had any success. All that changed, though, a year after his father’s death.

Katz recalled in a recent phone interview that he was mid-dream when his mother suddenly warned him in a voiceover, “Hey, you’re dreaming right now, so don’t take what your father is saying too seriously.”

Katz told me, “Suddenly everything slowed down and became incredibly vivid and real. I knew I was dreaming, but I felt I was with my father and could choose what to say as if I was awake. When I woke up, I realized that our brains are capable of creating an entire reality apart from waking life.” Many other lucid dreamers have said something similar.

Katz said the experience allowed him to finally “close the circle.” The frustration he felt in the year following his father’s death was gone.

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Beyond the Damaged Brain

Until the past few decades, neuroscientists really had only one way to study the human brain: Wait for strokes or some other disaster to strike people, and if the victims pulled through, determine how their minds worked differently afterward. Depending on what part of the brain suffered, strange things might happen. Parents couldn’t recognize their children. Normal people became pathological liars. Some people lost the ability to speak — but could sing just fine.

These incidents have become classic case studies, fodder for innumerable textbooks and bull sessions around the lab. The names of these patients — H. M., Tan, Phineas Gage — are deeply woven into the lore of neuroscience.

When recounting these cases today, neuroscientists naturally focus on these patients’ deficits, emphasizing the changes that took place in their thinking and behavior. After all, there’s no better way to learn what some structure in the brain does than to see what happens when it shorts out or otherwise gets destroyed.

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Girls called ‘too fat’ are more likely to become obese

Calling a girl “too fat” may increase her chances of being obese in the future, new research suggests.

In a letter published Monday in JAMA Pediatrics, researchers at UCLA report that 10-year-old girls who are told they are too fat by people that are close to them are more likely to be obese at 19 than girls who were never told they were too fat.

And that’s regardless of what they weighed at the beginning of the study. 

"Making people feel bad about their weight can backfire," said Janet Tomiyama, an assistant professor of psychology at UCLA and the study’s senior author. "It can be demoralizing. And we know that when people feel bad, they often reach out to food for comfort."

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New tests in UK Biobank trial