Manipulating memory with light

Just look into the light: not quite, but researchers at the UC Davis Center for Neuroscience and Department of Psychology have used light to erase specific memories in mice, and proved a basic theory of how different parts of the brain work together to retrieve episodic memories.

Optogenetics, pioneered by Karl Diesseroth at Stanford University, is a new technique for manipulating and studying nerve cells using light. The techniques of optogenetics are rapidly becoming the standard method for investigating brain function.

Kazumasa Tanaka, Brian Wiltgen and colleagues at UC Davis applied the technique to test a long-standing idea about memory retrieval. For about 40 years, Wiltgen said, neuroscientists have theorized that retrieving episodic memories — memories about specific places and events — involves coordinated activity between the cerebral cortex and the hippocampus, a small structure deep in the brain.

"The theory is that learning involves processing in the cortex, and the hippocampus reproduces this pattern of activity during retrieval, allowing you to re-experience the event," Wiltgen said. If the hippocampus is damaged, patients can lose decades of memories.

But this model has been difficult to test directly, until the arrival of optogenetics.

Wiltgen and Tanaka used mice genetically modified so that when nerve cells are activated, they both fluoresce green and express a protein that allows the cells to be switched off by light. They were therefore able both to follow exactly which nerve cells in the cortex and hippocampus were activated in learning and memory retrieval, and switch them off with light directed through a fiber-optic cable.

They trained the mice by placing them in a cage where they got a mild electric shock. Normally, mice placed in a new environment will nose around and explore. But when placed in a cage where they have previously received a shock, they freeze in place in a “fear response.”

Tanaka and Wiltgen first showed that they could label the cells involved in learning and demonstrate that they were reactivated during memory recall. Then they were able to switch off the specific nerve cells in the hippocampus, and show that the mice lost their memories of the unpleasant event. They were also able to show that turning off other cells in the hippocampus did not affect retrieval of that memory, and to follow fibers from the hippocampus to specific cells in the cortex.

"The cortex can’t do it alone, it needs input from the hippocampus," Wiltgen said. "This has been a fundamental assumption in our field for a long time and Kazu’s data provides the first direct evidence that it is true."

They could also see how the specific cells in the cortex were connected to the amygdala, a structure in the brain that is involved in emotion and in generating the freezing response.

Multiple neurodevelopmental disorders have a common molecular cause

Neurodevelopmental disorders such as Down syndrome and autism-spectrum disorder can have profound, lifelong effects on learning and memory, but relatively little is known about the molecular pathways affected by these diseases. A study published by Cell Press October 9th in the American Journal of Human Genetics shows that neurodevelopmental disorders caused by distinct genetic mutations produce similar molecular effects in cells, suggesting that a one-size-fits-all therapeutic approach could be effective for conditions ranging from seizures to attention-deficit hyperactivity disorder.

"Neurodevelopmental disorders are rare, meaning trying to treat them is not efficient," says senior study author Carl Ernst of McGill University. "Once we fully define the major common pathways involved, targeting these pathways for treatment becomes a viable option that can affect the largest number of people."

A large fraction of neurodevelopmental disorders are associated with variation in specific genes, but the genetic factors responsible for these diseases are very complex. For example, whereas common variants in the same gene have been associated with two or more different disorders, mutations in many different genes can lead to similar diseases. As a result, it has not been clear whether genetic mutations that cause neurodevelopmental disorders affect distinct molecular pathways or converge on similar cellular functions.

To address this question, Ernst and his team used human fetal brain cells to study the molecular effects of reducing the activity of genes that are mutated in two distinct autism-spectrum disorders. Changes in transcription factor 4 (TCF4) cause 18q21 deletion syndrome, which is characterized by intellectual disability and psychiatric problems, and mutations in euchromatic histone methyltransferase 1 (EHMT1) cause similar symptoms in a disease known as 9q34 deletion syndrome.

Interfering with the activity of TCF4 or EHMT1 produced similar molecular effects in the cells. Strikingly, both of these genetic modifications resulted in molecular patterns that resemble those of cells that are differentiating, or converting from immature cells to more specialized cells. “Our study suggests that one fundamental cause of disease is that neural stem cells choose to become full brain cells too early,” Ernst says. “This could affect how they incorporate into cellular networks, for example, leading to the clinical symptoms that we see in kids with these diseases.”

(Image: Wellcome Images)

Hunger Games: How the brain ‘browns’ fat to aid weight loss

Researchers at Yale School of Medicine have uncovered a molecular process in the brain known to control eating that transforms white fat into brown fat. This process impacts how much energy we burn and how much weight we can lose. The results are published in the Oct. 9 issue of the journal Cell.

Obesity is a rising global epidemic. Excess fatty tissue is a major risk factor for type 2 diabetes, cardiovascular disease, hypertension, neurological disorders, and cancer. People become overweight and obese when energy intake exceeds energy expenditure, and excess calories are stored in the adipose tissues. The adipose organ is made up of both white and brown fat. While white fat primarily stores energy as triglycerides, brown fat dissipates chemical energy as heat. The more brown fat you have, the more weight you can lose.

It has previously been shown that energy-storing white fat has the capacity to transform into energy-burning “brown-like” fat. In this new study, researchers from the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, demonstrate that neurons controlling hunger and appetite in the brain control the “browning” of white fat.

Lead author Xiaoyong Yang, associate professor of comparative medicine and physiology at Yale School of Medicine, conducted the study with Tamas Horvath, professor and chair of comparative medicine, and professor of neurobiology and Obstetrics/gynecology at Yale School of Medicine, and their co-authors.

The team stimulated this browning process from the brain in mice and found that it protected the animals from becoming obese on a high-fat diet. The team then studied the molecular changes in hunger-promoting neurons in the hypothalamus and found that the attachment of a unique sugar called “O-GlcNAc” to potassium ion channels acts as a switch to control brain activity to burn fat.

“Our studies reveal white fat “browning” as a highly dynamic physiological process that the brain controls,” said Yang. “This work indicates that behavioral modifications promoted by the brain could influence how the amount of food we eat and store in fat is burned.”

Yang said hunger and cold exposure are two life-history variables during the development and evolution of mammals. “We observed that food deprivation dominates over cold exposure in neural control of white fat browning. This regulatory system may be evolutionarily important as it can reduce heat production to maintain energy balance when we are hungry. Modulating this brain-to-fat connection represents a potential novel strategy to combat obesity and associated illnesses.”

Legendary Marshmallow Test Yields Lessons for Everyday Challenges in Self-Control

Walter Mischel, the psychologist renowned for the groundbreaking study known as the “marshmallow test,” has finally decided to tell the story of that research for a general audience.

He dedicates the book, aptly titled The Marshmallow Test: Mastering Self-Control, to his now-grown daughters, saying they inspired him when they were young to study self-control in preschoolers.

“I saw dramatic changes in my own children,” says Mischel, the Robert Johnston Niven Professor of Humane Letters in Columbia’s Psychology Department. “I realized I was quite clueless about what was going on in their heads.”

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Mind-controlled prosthetic arms that work in daily life are now a reality

In January 2013 a Swedish arm amputee was the first person in the world to receive a prosthesis with a direct connection to bone, nerves and muscles. An article about this achievement and its long-term stability will now be published in the Science Translational Medicine journal.

“Going beyond the lab to allow the patient to face real-world challenges is the main contribution of this work,” says Max Ortiz Catalan, research scientist at Chalmers University of Technology and leading author of the publication.

“We have used osseointegration to create a long-term stable fusion between man and machine, where we have integrated them at different levels. The artificial arm is directly attached to the skeleton, thus providing mechanical stability. Then the human’s biological control system, that is nerves and muscles, is also interfaced to the machine’s control system via neuromuscular electrodes. This creates an intimate union between the body and the machine; between biology and mechatronics.”

The direct skeletal attachment is created by what is known as osseointegration, a technology in limb prostheses pioneered by associate professor Rickard Brånemark and his colleagues at Sahlgrenska University Hospital. Rickard Brånemark led the surgical implantation and collaborated closely with Max Ortiz Catalan and Professor Bo Håkansson at Chalmers University of Technology on this project.

The patient’s arm was amputated over ten years ago. Before the surgery, his prosthesis was controlled via electrodes placed over the skin. Robotic prostheses can be very advanced, but such a control system makes them unreliable and limits their functionality, and patients commonly reject them as a result.

Now, the patient has been given a control system that is directly connected to his own. He has a physically challenging job as a truck driver in northern Sweden, and since the surgery he has experienced that he can cope with all the situations he faces; everything from clamping his trailer load and operating machinery, to unpacking eggs and tying his children’s skates, regardless of the environmental conditions (read more about the benefits of the new technology below).

The patient is also one of the first in the world to take part in an effort to achieve long-term sensation via the prosthesis. Because the implant is a bidirectional interface, it can also be used to send signals in the opposite direction – from the prosthetic arm to the brain. This is the researchers’ next step, to clinically implement their findings on sensory feedback.

“Reliable communication between the prosthesis and the body has been the missing link for the clinical implementation of neural control and sensory feedback, and this is now in place,” says Max Ortiz Catalan. “So far we have shown that the patient has a long-term stable ability to perceive touch in different locations in the missing hand. Intuitive sensory feedback and control are crucial for interacting with the environment, for example to reliably hold an object despite disturbances or uncertainty. Today, no patient walks around with a prosthesis that provides such information, but we are working towards changing that in the very short term.”

The researchers plan to treat more patients with the novel technology later this year.

“We see this technology as an important step towards more natural control of artificial limbs,” says Max Ortiz Catalan. “It is the missing link for allowing sophisticated neural interfaces to control sophisticated prostheses. So far, this has only been possible in short experiments within controlled environments.”

Amputees discern familiar sensations across prosthetic hand

Even before he lost his right hand to an industrial accident 4 years ago, Igor Spetic had family open his medicine bottles. Cotton balls give him goose bumps.

Now, blindfolded during an experiment, he feels his arm hairs rise when a researcher brushes the back of his prosthetic hand with a cotton ball.

Spetic, of course, can’t feel the ball. But patterns of electric signals are sent by a computer into nerves in his arm and to his brain, which tells him different. “I knew immediately it was cotton,” he said.

That’s one of several types of sensation Spetic, of Madison, Ohio, can feel with the prosthetic system being developed by Case Western Reserve University and the Louis Stokes Cleveland Veterans Affairs Medical Center.

Spetic was excited just to “feel” again, and quickly received an unexpected benefit. The phantom pain he’d suffered, which he’s described as a vice crushing his closed fist, subsided almost completely. A second patient, who had less phantom pain after losing his right hand and much of his forearm in an accident, said his, too, is nearly gone.

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Neurons in human muscles emphasize stimulation from the outside world

Stretch sensors in our muscles participate in reflexes that serve the subconscious control of posture and movement. According to a new study published in the Journal of Neuroscience, these sensors respond weakly to muscle stretch caused by one’s voluntary action, and most strongly to stretch that is imposed by external forces. The ability to reflect causality in this manner can facilitate appropriate reflex control and accurate self-perception.  

“The results of the study show that stretch receptors in our muscles indicate more than which limb is moving or how fast; these sensors also adjust their signals according to who caused the movement,” says Michael Dimitriou, who conducted this study and is currently a post doc at the Department of Integrative Medical Biology, Umeå University, Sweden.

Normally, we can easily distinguish between movements we make ourselves and movements that are imposed on our body by external forces. The ability to discriminate between self-generated and externally generated sensory events is crucial for accurate perception and the control of posture and movement. This ability is also believed to form the foundation on which conscious self-awareness is built.

Such discrimination between self and other has previously been thought to arise as a result of complex computations performed in the brain, that use prior knowledge or memories of the consequences of own actions. But the study by Michael Dimitriou shows that information on the cause of a sensory effect can be provided in real-time by so-called ‘muscle spindles’, a class of stretch receptors found in most of our skeletal muscles.

Muscle spindles differ from other sensory receptors, such as stretch receptors in the skin, because their sensitivity can be controlled by the nervous system via specialized motor neurons. The purpose of this control has been unclear. The neural data presented by Michael Dimitriou indicates that these specialized motor neurons increase the sensitivity of stretch receptors when the body is exposed to an externally imposed stretch stimulus, such as when a falling ball is caught in the hand. Because amplified spindle responses mean stronger stretch reflexes, the resulting muscle activity instantly counteracts movement of the hand. When making a voluntary movement, however, the nervous system ‘automatically’ reduces the sensitivity of spindles in the stretching muscles, thereby making it possible for us to move without setting off strong stretch reflexes that would otherwise counteract movement. Uncontrollably strong stretch reflexes are commonly referred to as ‘spasticity’.

“These results provide an explanation of how reflexes can be functionally adjusted to help us achieve our everyday tasks, without requiring conscious control of reflex sensitivity or complex computations in the brain for predicting the sensory consequences of our actions,” says Michael Dimitriou.

He believes that these new findings are important both for understanding the neural mechanisms that underlie movement control and self-perception, but also for understanding pathological states where these mechanisms are disturbed.

“With these findings, we also get new insights into mechanisms whose malfunction may contribute to neuromuscular problems such as spasticity or alien hand syndrome (also known as ‘Dr. Strangelove syndrome’), and help identify potential treatment targets for these conditions,” says Michael Dimitriou.