Socially Isolated Rats are More Vulnerable to Addiction

Rats that are socially isolated during a critical period of adolescence are more vulnerable to addiction to amphetamine and alcohol, found researchers at The University of Texas at Austin. Amphetamine addiction is also harder to extinguish in the socially isolated rats.

These effects, which are described this week in the journal Neuron, persist even after the rats are reintroduced into the community of other rats.

“Basically the animals become more manipulatable,” said Hitoshi Morikawa, associate professor of neurobiology in the College of Natural Sciences. “They’re more sensitive to reward, and once conditioned the conditioning takes longer to extinguish. We’ve been able to observe this at both the behavioral and neuronal level.”

Morikawa said the negative effects of social isolation during adolescence have been well documented when it comes to traits such as anxiety, aggression, cognitive rigidity and spatial learning. What wasn’t clear until now is how social isolation affects the specific kind of behavior and brain activity that has to do with addiction.

“Isolated animals have a more aggressive profile,” said Leslie Whitaker, a former doctoral student in Morikawa’s lab and now a researcher at the National Institute on Drug Abuse. “They are more anxious. Put them in an open field and they freeze more. We also know that those areas of the brain that are more involved in conscious memory are impaired. But the kind of memory involved in addiction isn’t conscious memory. It’s an unconscious preference for the place in which you got the reward. You keep coming back to it without even knowing why. That kind of memory is enhanced by the isolation.”

Astrocytes Identified as Target for New Depression Therapy

Neuroscience researchers from Tufts University have found that our star-shaped brain cells, called astrocytes, may be responsible for the rapid improvement in mood in depressed patients after acute sleep deprivation. This in vivo study, published in the current issue of Translational Psychiatry, identified how astrocytes regulate a neurotransmitter involved in sleep. The researchers report that the findings may help lead to the development of effective and fast-acting drugs to treat depression, particularly in psychiatric emergencies.

Drugs are widely used to treat depression, but often take weeks to work effectively. Sleep deprivation, however, has been shown to be effective immediately in approximately 60% of patients with major depressive disorders. Although widely-recognized as helpful, it is not always ideal because it can be uncomfortable for patients, and the effects are not long-lasting.

During the 1970s, research verified the effectiveness of acute sleep deprivation for treating depression, particularly deprivation of rapid eye movement sleep, but the underlying brain mechanisms were not known.

Most of what we understand of the brain has come from research on neurons, but another type of largely-ignored cell, called glia, are their partners. Although historically thought of as a support cell for neurons, the Phil Haydon group at Tufts University School of Medicine has shown in animal models that a type of glia, called astrocytes, affect behavior.  

Haydon’s team had established previously that astrocytes regulate responses to sleep deprivation by releasing neurotransmitters that regulate neurons. This regulation of neuronal activity affects the sleep-wake cycle. Specifically, astrocytes act on adenosine receptors on neurons. Adenosine is a chemical known to have sleep-inducing effects.

During our waking hours, adenosine accumulates and increases the urge to sleep, known as sleep pressure. Chemicals, such as caffeine, are adenosine receptor antagonists and promote wakefulness. In contrast, an adenosine receptor agonist creates sleepiness.

“In this study, we administered three doses of an adenosine receptor agonist to mice over the course of a night that caused the equivalent of sleep deprivation. The mice slept as normal, but the sleep did not reduce adenosine levels sufficiently, mimicking the effects of sleep deprivation. After only 12 hours, we observed that mice had decreased depressive-like symptoms and increased levels of adenosine in the brain, and these results were sustained for 48 hours,” said first author Dustin Hines, Ph.D., a post-doctoral fellow in the department of neuroscience at Tufts University School of Medicine (TUSM).

“By manipulating astrocytes we were able to mimic the effects of sleep deprivation on depressive-like symptoms, causing a rapid and sustained improvement in behavior,” continued Hines.

“Further understanding of astrocytic signaling and the role of adenosine is important for research and development of anti-depressant drugs. Potentially, new drugs that target this mechanism may provide rapid relief for psychiatric emergencies, as well as long-term alleviation of chronic depressive symptoms,” said Naomi Rosenberg, Ph.D., dean of the Sackler School of Graduate Biomedical Sciences and vice dean for research at Tufts University School of Medicine. “The team’s next step is to further understand the other receptors in this system and see if they, too, can be affected.”

(Image: Paul De Koninck)

Study of how eye cells become damaged could help prevent blindness

Light-sensing cells in the eye rely on their outer segment to convert light into neural signals that allow us to see. But because of its unique cylindrical shape, the outer segment is prone to breakage, which can cause blindness in humans. A study published by Cell Press on January 22nd in the Biophysical Journal provides new insight into the mechanical properties that cause the outer segment to snap under pressure. The new experimental and theoretical findings help to explain the origin of severe eye diseases and could lead to new ways of preventing blindness.

"To our knowledge, this is the first theory that explains how the structural rigidity of the outer segment can make it prone to damage," says senior study author Aphrodite Ahmadi of the State University of New York Cortland. "Our theory represents a significant advance in our understanding of retinal degenerative diseases."

The outer segment of photoreceptors consists of discs packed with a light-sensitive protein called rhodopsin. Discs made at nighttime are different from those produced during the day, generating a banding pattern that was first observed in frogs but is common across species. Mutations that affect photoreceptors often destabilize the outer segment and may damage its discs, leading to cell death, retinal degeneration, and blindness in humans. But until now, it was unclear which structural properties of the outer segment determine its susceptibility to damage.

To address this question, Ahmadi and her team examined tadpole photoreceptors under the microscope while subjecting them to fluid forces. They found that high-density bands packed with a high concentration of rhodopsin were very rigid, which made them more susceptible to breakage than low-density bands consisting of less rhodopsin. Their model confirmed their experimental results and revealed factors that determine the critical force needed to break the outer segment.

The findings support the idea that mutations causing rhodopsin to aggregate can destabilize the outer segment, eventually causing blindness. “Further refinement of the model could lead to novel ways to stabilize the outer segment and could delay the onset of blindness,” says Ahmadi.

Uncovering the secrets of 3D vision: How glossy objects can fool the human brain

It’s a familiar sight at the fairground: rows of people gaping at curvy mirrors as they watch their faces and bodies distort. But while mirrored surfaces may be fun to look at, new findings by researchers from the Universities of Birmingham, Cambridge and Giessen, suggest they pose a particular challenge for the human brain in processing images for 3D vision.

The researchers have taken advantage of the unusual visual behaviour of curved mirrors to study stereopsis: the process by which the brain combines images from the two eyes to see in 3D.

The work, published online in the Proceedings of the National Academy of Sciences (PNAS), used mathematical analysis and perceptual measurements to show that people often see the ‘wrong’ shape for glossy objects (like chrome bumpers or brass door knobs) because of the way the brain employs ‘quality control’ mechanisms when it views the world with two eyes. This reveals how the brain checks the ‘usefulness’ of the signals it receives from the senses, explaining why we sometimes misperceive shapes and distances. It also has some connections with the design of robotic systems.

‘We often think that the 3D information we get from having two eyes provides the gold standard for seeing in depth; but glossy objects pose a difficult challenge to the brain because the stereoscopic information often indicates depths that don’t match the physical shape of the object’ explains Dr Andrew Welchman, a Wellcome Trust Senior Research Fellow at the University of Birmingham. ‘We found that the brain is sometimes ‘fooled’ into seeing the wrong 3D shape, but this depends on statistical properties of the stereo images that indicate how ‘useful’ the information is,’ he adds.

To carry out the project, the team developed mathematical models that calculate the pattern of reflections seen when viewing glossy objects, and measured the perceived 3D appearance of these shapes.

‘When a curved mirrored object reflects its surroundings, the reflections appear at a different depth than the glossy surface itself. This makes it difficult for the brain to work out the true 3D distance to the surface’ explains Dr Alex Muryy, a research fellow at Birmingham who conducted the analyses. ‘We found that even simple objects can produce very complex depth profiles, and reflections can behave very differently from normal stereoscopic information.’ Understanding these differences provided the key to reveal the generalised way in which the brain analyses incoming information to judge the circumstances in which information should be trusted.

‘Stereoscopic information is often highly informative, but in certain circumstances it can tell us the wrong thing or be unreliable. The challenge is therefore to understand how the brain knows when it should or should not trust this 3D information,’ says Professor Roland Fleming, Giessen University in Germany. ‘We have uncovered signals that are likely to be important in guiding the brain’s use of the information by studying glossy objects. In particular, we can understand people’s misperceptions because in these circumstances 3D reflections fall within the normal range of values, meaning that the brain takes the depth signals at face value.’

Researchers map emotional intelligence in the brain

A new study of 152 Vietnam veterans with combat-related brain injuries offers the first detailed map of the brain regions that contribute to emotional intelligence – the ability to process emotional information and navigate the social world.

The study found significant overlap between general intelligence and emotional intelligence, both in terms of behavior and in the brain. Higher scores on general intelligence tests corresponded significantly with higher performance on measures of emotional intelligence, and many of the same brain regions were found to be important to both. (Watch a video about the research.)

The study appears in the journal Social Cognitive & Affective Neuroscience.

“This was a remarkable group of patients to study, mainly because it allowed us to determine the degree to which damage to specific brain areas was related to impairment in specific aspects of general and emotional intelligence,” said study leader Aron K. Barbey, a professor of neuroscience, of psychology and of speech and hearing science at the Beckman Institute for Advanced Science and Technology at the University of Illinois.

A previous study led by Barbey mapped the neural basis of general intelligence by analyzing how specific brain injuries (in a larger sample of Vietnam veterans) impaired performance on tests of fundamental cognitive processes.

In both studies, researchers pooled data from CT scans of participants’ brains to produce a collective, three-dimensional map of the cerebral cortex. They divided this composite brain into 3-D units called voxels. They compared the cognitive abilities of patients with damage to a particular voxel or cluster of voxels with those of patients without injuries in those brain regions. This allowed the researchers to identify brain areas essential to specific cognitive abilities, and those that contribute significantly to general intelligence, emotional intelligence, or both.

They found that specific regions in the frontal cortex (behind the forehead) and parietal cortex (top of the brain near the back of the skull) were important to both general and emotional intelligence. The frontal cortex is known to be involved in regulating behavior. It also processes feelings of reward and plays a role in attention, planning and memory. The parietal cortex helps integrate sensory information, and contributes to bodily coordination and language processing.

“Historically, general intelligence has been thought to be distinct from social and emotional intelligence,” Barbey said. The most widely used measures of human intelligence focus on tasks such as verbal reasoning or the ability to remember and efficiently manipulate information, he said.

“Intelligence, to a large extent, does depend on basic cognitive abilities, like attention and perception and memory and language,” Barbey said. “But it also depends on interacting with other people. We’re fundamentally social beings and our understanding not only involves basic cognitive abilities but also involves productively applying those abilities to social situations so that we can navigate the social world and understand others.”

The new findings will help scientists and clinicians understand and respond to brain injuries in their patients, Barbey said, but the results also are of broader interest because they illustrate the interdependence of general and emotional intelligence in the healthy mind.

Less tau reduces seizures and sudden death in severe epilepsy

Deleting or reducing expression of a gene that carries the code for tau, a protein associated with Alzheimer’s disease, can prevent seizures in a severe type of epilepsy linked to sudden death, said researchers at Baylor College of Medicine and the Mayo Clinic in Jacksonville, Fla., in a report in the current issue of the Journal of Neuroscience.

A growing understanding of the link between epilepsy and some forms of inherited Alzheimer’s disease led to the finding that could point the way toward new drugs for seizure disorders said Dr. Jeffrey Noebels, professor of neurology at BCM, and director of the Blue Bird Circle Developmental Neurogenetics Laboratory.

In her research, Jerrah Holth, a graduate student in molecular and human genetics at BCM who was working with mice with the severe form of epilepsy in Noebel’s laboratory, deleted the gene for tau. She found that reducing or eliminating tau also prevented the seizures in a severe form of epilepsy that has been associated with sudden death and reduced deaths in the animals.

In an earlier experiment, Noebels, in collaboration with Dr. Lennart Mucke at the Gladstone Research Laboratory at the University of California San Francisco, found that mice who carried a human gene that leads to accumulation of the beta amyloid protein and the amyloid plaques that accumulate in the brains of people with Alzheimer’s disease, also had epileptic seizures arising in the hippocampus, the region of the brain associated with memory storage and retrieval.

"This led to the paradigm-shifting hypothesis that excessive neuronal network activity, rather than too little, may contribute to lower cognitive performance and dementia in some forms of Alzheimer’s disease. When this happens, the progression of memory loss may accelerate," said Noebels.

The finding also demonstrated the two disorders may share defects in signaling within brain memory circuits.

The two labs went on to show that deleting the second gene for tau ameliorated both cognitive losses and seizures in the mice whose inherited disorder mimicked Alzheimer’s disease found in humans.

Holth’s finding demonstrates that tau is involved in a far broader range of epilepsy than previously suspected, said Noebels. The type of epilepsy she studied resulted from an inherited potassium ion channel defect that affects the flow of the potassium in and out of nerve cells. She found that removing the gene encoding Tau not only dramatically reduced seizures, but prevented the mice from dying early, which typically happens in these animals.

"Even a partial reduction of the amount of tau protein by 50 percent was highly effective," said Holth. Her finding suggests developing new drugs that lower the normal interactions of the tau protein may reduce seizures and sudden unexpected death for persons with intractable epilepsies, a problem in nearly one-third of the 5 million Americans with this disorder.

Currently, Noebels and his colleagues in the Blue Bird Laboratory are studying whether the loss of tau can correct a seizure disorder once it is already established. If these studies prove fruitful, “the pharmacological discovery programs under development for treatment of Alzheimer’s disease may one day find their way to the epilepsy clinic,” said Noebels.

(Image: ALAMY)

UCLA study first to image concussion-related abnormal brain proteins in retired NFL players

Now, for the first time, UCLA researchers have used a brain-imaging tool to identify the abnormal tau proteins associated with this type of repetitive injury in five retired National Football League players who are still living. Previously, confirmation of the presence of this protein, which is also associated with Alzheimer’s disease, could only be established by an autopsy.

The preliminary findings of the small study are reported Jan. 22 in the online issue of the American Journal of Geriatric Psychiatry, the official journal of the American Association for Geriatric Psychiatry.

Previous reports and studies have shown that professional athletes in contact sports who are exposed to repetitive mild traumatic brain injuries may develop ongoing impairment such as chronic traumatic encephalopathy (CTE), a degenerative condition caused by a build up of tau protein. CTE has been associated with memory loss, confusion, progressive dementia, depression, suicidal behavior, personality changes, abnormal gait and tremors.

"Early detection of tau proteins may help us to understand what is happening sooner in the brains of these injured athletes," said lead study author Dr. Gary Small, UCLA’s Parlow–Solomon Professor on Aging and a professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA. "Our findings may also guide us in developing strategies and interventions to protect those with early symptoms, rather than try to repair damage once it becomes extensive."

Small notes that larger follow-up studies are needed to determine the impact and usefulness of detecting these tau proteins early, but given the large number of people at risk for mild traumatic brain injury — not only athletes but military personnel, auto accident victims and others — a means of testing what is happening in the brain during the early stages could potentially have a considerable impact on public health.

Alzheimer’s researchers trying brain zaps

It has the makings of a science fiction movie: zap someone’s brain with mild jolts of electricity to try to stave off the creeping memory loss of Alzheimer’s disease.

And it’s not easy. Holes are drilled into the patient’s skull so tiny wires can be implanted into just the right spot.

A dramatic shift is beginning in the frustrating struggle to find something to slow the damage of this epidemic: The first U.S. experiments with “brain pacemakers” for Alzheimer’s are getting under way. Scientists are looking beyond drugs to implants in the hunt for much-needed new treatments.

The research is in its infancy. Only a few dozen people with early-stage Alzheimer’s will be implanted in a handful of hospitals. No one knows if it might work, and if it does, how long the effects might last.

Kathy Sanford was among the first to sign up. The Ohio woman’s early-stage Alzheimer’s was gradually getting worse. She still lived independently, posting reminders to herself, but no longer could work. Medications weren’t helping.

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Robot Allows ‘Remote Presence’ in Programming Brain and Spine Stimulators

With the rapidly expanding use of brain and spinal cord stimulation therapy (neuromodulation), new “remote presence” technologies may help to meet the demand for experts to perform stimulator programming, reports a study in the January issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

The preliminary study by Dr. Ivar Mendez of Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, Canada, supports the feasibility and safety of using a remote presence robot—called the “RP-7”—to increase access to specialists qualified to program the brain and spine stimulators used in neuromodulation.

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(Image: NEUROSURGERY® Editorial Office)

Light Switch Inside Brain: Laser Controls Individual Nerve Cells in Mouse

Activating and deactivating individual nerve cells in the brain is something many neuroscientists wish they could do, as it would help them to better understand how the brain works.

Scientists in Freiburg and Basel, Switzerland, have developed an implant that is able to genetically modify specific nerve cells, control them with light stimuli, and measure their electrical activity all at the same time. This novel 3-in-1 tool paves the way for completely new experiments in neurobiology, also at Freiburg’s new Cluster of Excellence BrainLinks-BrainTools.

Birthe Rubehn and her colleagues from the Department of Microsystems Engineering (IMTEK) and the Bernstein Center of the University of Freiburg as well as the Friedrich Miescher Institute for Biomedical Research in Basel describe the prototype of their implant in the journal Lab on a Chip. They report that initial experiments in which they implanted prototypes into mice were successful: The team was able to influence the activity of nerve cells in the brain in a controlled manner by means of laser light pulses.

The team used an innovative genetic technique that makes nerve cells change their activity by shining different colored lights on them. In optogenetics, genes from certain species of algae are inserted into the genome of another organism, for instance a mouse. The genes lead to the inclusion of light-sensitive pores for electrically charged particles into a nerve cell’s membrane. These additional openings allow neuroscientists to control the cells’ electrical activity.

However, only the new implant from Freiburg and Basel makes this principle actually practicable. The device, at its tip only a quarter of a millimeter wide and a tenth of a millimeter thick, was constructed on the basis of polymers, special plastics whose safety for implantation into the nervous system has been proven.

Unlike probes developed so far, it is capable of injecting substances necessary for genetic modification, emitting light for the stimulation of the nerve cells, and measuring the effect through various electrical contacts all at once. Besides optimizing the technique for production, the scientists want to develop a second version whose injection channel dissolves over time, reducing the implant’s size even further.