(Fig. 1: Two-photon image of the three types of cells in the visual cortex of a rat. Neuronal activity is measured via changes in fluorescence intensity. Green cells are inhibitory neurons, white cells are excitatory neurons, and red cells are astrocytes.)

Waking up the visual system

The ways that neurons in the brain respond to a given stimulus depends on whether an organism is asleep, drowsy, awake, paying careful attention or ignoring the stimulus. However, while the properties of neural circuits in the visual cortex are well known, the mechanisms responsible for the different patterns of activity in the awake and drowsy states remain poorly understood. A team of researchers led by Tadaharu Tsumoto from the RIKEN Brain Science Institute has observed the changes in activity that occur in rodents on waking from anesthesia.

The research team used a technique called two-photon functional calcium imaging to observe the activity of cells in the visual cortex of rats while they are anesthetized and exposed to a visual stimulus of an image moving across a screen. Using rats with inhibitory neurons labeled with a green fluorescent protein, the researchers were able to measure the activity separately in populations of inhibitory and excitatory neurons (Fig. 1). The neuronal activity in response to visual stimulation under anesthesia was recorded, and then the rats were allowed to wake and the change in activity of the two populations of neurons was observed.

Tsumoto’s team found that inhibitory neurons responded more reliably and with stronger activity to visual stimuli in the awake state than in the anesthetized state. The response of the excitatory neurons had a shorter decay time in the awake state, which means that their activity was more tightly linked to the presentation of the visual stimulus than when the animal was under the influence of anesthesia.

These changes that occur during wakefulness allow neurons in the visual cortex to respond more reliably to visual stimuli in their environment. “If animals are awakened from the drowsy state by howls or footsteps of enemies, the sensitivity or resolution of moving visual stimuli will increase so that they can more effectively judge how fast and from which location the enemies are coming,” explains Tsumoto.

The team then found that the basal forebrain region of the brain, which is known to play a role in state-dependent changes in cortical activity through its acetylcholine neurons, is responsible for these shifts in responses of neurons in the visual cortex of mice during wakefulness. They found that stimulating the basal forebrain of anesthetized animals could make visual cortical neurons take on the firing properties of the awake state. These findings highlight the role of the basal forebrain in modulating the responses of visual cortical neurons during wakefulness.

Neuroscientists use snail research to help explain “chemo brain”

It is estimated that as many as half of patients taking cancer drugs experience a decrease in mental sharpness. While there have been many theories, what causes “chemo brain” has eluded scientists.

In an effort to solve this mystery, neuroscientists at The University of Texas Health Science Center at Houston (UTHealth) conducted an experiment in an animal memory model and their results point to a possible explanation. Findings appeared in The Journal of Neuroscience.

In the study involving a sea snail that shares many of the same memory mechanisms as humans and a drug used to treat a variety of cancers, the scientists identified memory mechanisms blocked by the drug. Then, they were able to counteract or unblock the mechanisms by administering another agent.

“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. “Jack” Byrne, Ph.D., senior author, holder of the June and Virgil Waggoner Chair and chairman of the Department of Neurobiology and Anatomy at the UTHealth Medical School. “There is no satisfactory treatment at this time.”

While much work remains, Byrne, who runs the university’s Neuroscience Research Center, said understanding how these drugs impact the brain is an important first step in alleviating this condition characterized by forgetfulness, trouble concentrating and difficulty multitasking.

Byrne’s laboratory is known for its use of a large snail called Aplysia californica to further the understanding of the biochemical signaling among nerve cells (neurons). The snails have large neurons that relay information much like those in humans.

When Byrne’s team compared cell cultures taken from normal snails to those administered a dose of a cancer drug called doxorubicin, the investigators pinpointed a neuronal pathway that was no longer passing along information properly.

With the aid of an experimental drug, the scientists were able to reopen the pathway. Unfortunately, this drug would not be appropriate for humans, Byrne said. “We want to identify other drugs that can rescue these memory mechanisms,” he added.

The scientists confirmed their findings in tests on the nerve cells of rats.

“The big picture is to determine if this cancer drug acts in the same way in humans,” Byrne said.

Researchers Identify New Pathway Linking the Brain to High Blood Pressure

New research by scientists at the University of Maryland School of Medicine (UM SOM) and the Ottawa Heart Institute has uncovered a new pathway by which the brain uses an unusual steroid to control blood pressure. The study, which also suggests new approaches for treating high blood pressure and heart failure, appears today in the journal Public Library of Science (PLOS) One.

“This research gives us an entirely new way of understanding how the brain and the cardiovascular system work together,” said Dr. John Hamlyn, professor of physiology at the University of Maryland School of Medicine, one of the principal authors. “It opens a new and exciting way for us to work on innovative treatment approaches that could one day help patients.”

For decades, researchers have known that the brain controls the diameter of the peripheral arteries via the nervous system. Electrical impulses from the brain travel to the arteries via a network of nerves known as the sympathetic nervous system. This system is essential for daily life, but is often chronically overactive in high blood pressure and heart failure. In fact, many drugs that help with hypertension and heart failure work by decreasing both acute and chronic activity in the sympathetic nervous system. However, these drugs often have serious side effects, such as fatigue, dizziness and erectile dysfunction. “These drawbacks have led to the search for novel ways to inhibit the sympathetic nervous system while causing fewer problems for hypertension and heart failure patients,” says Dr. Frans Leenen, director of hypertension at the Ottawa Heart Institute, and a principal author of the study.

Working with an animal model of hypertension, Dr. Hamlyn and Dr. Mordecai Blaustein, professor of physiology and medicine at the UM SOM, and their research partner, Dr. Leenen, found a new link between the brain and increased blood pressure, namely, a little-known steroid called ouabain (pronounced WAH-bane). Ouabain was discovered in human blood more than 20 years ago by Dr. Hamlyn and Dr. Blaustein, along with scientists at the Upjohn Company. The new study is the first to identify the particular pathway that connects the brain to ouabain’s effects on proteins that regulate arterial calcium and contraction. Through this mechanism, ouabain makes arteries more sensitive to sympathetic stimulation, and as a result the enhanced artery constriction promotes chronic hypertension.

“Now that we understand the role of ouabain, we can begin working on how to modify this new pathway to help people with cardiovascular problems,” said Dr. Blaustein. “The potential for this is big.” Dr. Blaustein, who has been doing research on the substance since 1977, said medications that block ouabain’s effects might improve the lives of people with hypertension and heart failure.

The researchers, who include Vera Golovina, Ph.D., an adjunct associate professor of physiology at UM SOM, and Bing Huang, M.D, Ph.D., a research associate at the Ottawa Heart Institute, also found significant new evidence that ouabain is manufactured by mammals, a question that had not been previously answered.

“This discovery underscores the crucial importance of basic research here at the School of Medicine,” said Dean E. Albert Reece, MD, PhD, MBA, as well as vice president of medical affairs, the University of Maryland and the John Z. and Akiko Bowers Distinguished Professor. “These scientists have spent years unraveling the many potential roles of ouabain and how it works, and now we are beginning to see the fruits of their labor.”

Study suggests neurobiological basis of human-pet relationship

It has become common for people who have pets to refer to themselves as  “pet parents,” but how closely does the relationship between people and their non-human companions mirror the parent-child relationship? A small study from a group of Massachusetts General Hospital (MGH) researchers makes a contribution to answering this complex question by investigating differences in how important brain structures are activated when women view images of their children and of their own dogs. Their report is being published in the open-access journal PLOS ONE.

“Pets hold a special place in many people’s hearts and lives, and there is compelling evidence from clinical and laboratory studies that interacting with pets can be beneficial to the physical, social and emotional wellbeing of humans,” says Lori Palley, DVM, of the MGH Center for Comparative Medicine, co-lead author of the report.  “Several previous studies have found that levels of neurohormones like oxytocin – which is involved in pair-bonding and maternal attachment – rise after interaction with pets, and new brain imaging technologies are helping us begin to understand the neurobiological basis of the relationship, which is exciting.”

In order to compare patterns of brain activation involved with the human-pet bond with those elicited by the maternal-child bond, the study enrolled a group of women with at least one child aged 2 to 10 years old and one pet dog that had been in the household for two years or longer. Participation consisted of two sessions, the first being a home visit during which participants completed several questionnaires, including ones regarding their relationships with both their child and pet dog. The participants’ dog and child were also photographed in each participants’ home.

The second session took place at the Athinoula A. Martinos Center for Biomedical Imaging at MGH, where functional magnetic resonance imaging (fMRI) – which indicates levels of activation in specific brain structures by detecting changes in blood flow and oxygen levels – was performed as participants lay in a scanner and viewed a series of photographs. The photos included images of each participant’s own child and own dog alternating with those of an unfamiliar child and dog belonging to another study participant. After the scanning session, each participant completed additional assessments, including an image recognition test to confirm she had paid close attention to photos presented during scanning, and rated several images from each category shown during the session on factors relating to pleasantness and excitement.

Of 16 women originally enrolled, complete information and MR data was available for 14 participants. The imaging studies revealed both similarities and differences in the way important brain regions reacted to images of a woman’s own child and own dog. Areas previously reported as important for functions such as emotion, reward, affiliation, visual processing and social interaction all showed increased activity when participants viewed either their own child or their own dog. A region known to be important to bond formation – the substantia nigra/ventral tegmental area (SNi/VTA) – was activated only in response to images of a participant’s own child. The fusiform gyrus, which is involved in facial recognition and other visual processing functions, actually showed greater response to own-dog images than own-child images.

“Although this is a small study that may not apply to other individuals, the results suggest there is a common brain network important for pair-bond formation and maintenance that is activated when mothers viewed images of either their child or their dog,” says Luke Stoeckel, PhD, MGH Department of Psychiatry, co-lead author of the PLOS One report. “We also observed differences in activation of some regions that may reflect variance in the evolutionary course and function of these relationships. For example, like the SNi/VTA, the nucleus accumbens has been reported to have an important role in pair-bonding in both human and animal studies. But that region showed greater deactivation when mothers viewed their own-dog images instead of greater activation in response to own-child images, as one might expect. We think the greater response of the fusiform gyrus to images of participants’ dogs may reflect the increased reliance on visual than verbal cues in human-animal communications.”

Co-author Randy Gollub, MD, PhD, of MGH Psychiatry adds, “Since fMRI is an indirect measure of neural activity and can only correlate brain activity with an individual’s experience, it will be interesting to see if future studies can directly test whether these patterns of brain activity are explained by the specific cognitive and emotional functions involved in human-animal relationships. Further, the similarities and differences in brain activity revealed by functional neuroimaging may help to generate hypotheses that eventually provide an explanation for the complexities underlying human-animal relationships.”

The investigators note that further research is needed to replicate these findings in a larger sample and to see if they are seen in other populations – such as women without children, fathers and parents of adopted children – and in relationships with other animal species. Combining fMRI studies with additional behavioral and physiological measures could obtain evidence to support a direct relationship between the observed brain activity and the purported functions.

(Image: Fotolia)

Strong working memory put brakes on problematic drug use

Adolescents with strong working memory are better equipped to escape early drug experimentation without progressing into substance abuse issues, says a University of Oregon researcher.

Most important in the picture is executive attention, a component of working memory that involves a person’s ability to focus on a task and ignore distractions while processing relevant goal-oriented information, says Atika Khurana, a professor in the Department of Counseling Psychology and Human Services.

Khurana, also a member of the UO’s Prevention Science Institute, is lead author of a study online ahead of print in the quarterly journal Development and Psychopathology. The findings, drawn from a long-term study of 382 adolescents in a mostly at-risk urban population, provide a rare, early view of adolescents’ entry into the use of alcohol, tobacco and marijuana.

Khurana collaborated with researchers at the University of Pennsylvania and Children’s Hospital of Philadelphia. They focused on 11- to 13-year-old children as they began to explore risky and sensation-seeking experiences that often mark the road to independence and adulthood. Previous studies generally have relied on adult recall of when individuals began experimenting, with early drug use thought to be a marker of later substance abuse problems.

"Not all forms of early drug use are problematic," Khurana said. "There could be some individuals who start early, experiment and then stop. And there are some who could start early and go on into a progressive trajectory of continued drug use. We wanted to know what separates the two?"

During four assessments, participants provided self-reports of drug use in the previous 30 days. Four working memory tests also were conducted: Corsi block tapping, in which subjects viewed identical blocks that lit up randomly on a screen and tapped each box in reverse order of the lighting sequence; a digit-span test where numbers shown are to be repeated in reverse order; a letter two-back test, in which subjects identify specific letters in time-sensitive sequences; and a spatial working-memory task where hidden tokens must be found quickly within sets of four to eight randomly positioned boxes on a computer screen.

The pattern that emerged was that early drug experimentation more likely to lead into progressive drug use among young people whose impulsive tendencies aren’t kept in check by strong working memory ability. Later assessments of the participants, who have now reached late adolescence, are being analyzed, but it appears that the compulsive progression, not just the experimentation, of drug use is likely to lead to disorder, Khurana said.

"Prefrontal regions of the brain can apply the brakes or exert top-down control over impulsive, or reward seeking urges," Khurana said. "By its nature, greater executive attention enables one to be less impulsive in one’s decisions and actions because you are focused and able to control impulses generated by events around you. What we found is that if teens are performing poorly on working memory tasks that tap into executive attention, they are more likely to engage in impulsive drug-use behaviors."

The findings suggest new approaches for early intervention since weaknesses in executive functioning often underlie self-control issues in children as young as 3 years old, she said. A family environment strong in structured routines and cognitive-stimulation could strengthen working memory skills, she said.

For older children, interventions could be built around activities that encourage social competence and problem solving skills in combination with cognition-building efforts to increase self-control and working memory. The latter allows people to temporarily store, organize and manipulate mental information and is vital for evaluating consequences of decisions.

"We need to compensate for the weakness that exists, before drug experimentation starts to help prevent the negative spiral of drug abuse," Khurana said.

BRAIN initiative is underway, funding new ways to map cells, circuits

Scientists will aim to capture the workings of the human brain in comprehensive recordings, to watch the brain while in motion and to reimagine the world’s most complex biological organism as a buzzing network of interlocking circuits with the award of $46 million in study grants announced Tuesday.

The announcement marks the first concrete steps taken under the Obama administration’s BRAIN Initiative, short for Brain Research Through Advancing Innovative Neurotechnologies. Unveiled in April 2013, the initiative is a planned 12-year effort to spur new understanding of the brain in sickness and in health by improving technologies used to map, record, probe and stimulate its workings.

President Obama has sought $110 million for the BRAIN initiative in 2014 and $200 million for the 2015 fiscal year, which begins on Wednesday, with future years’ funding to be worked out. He has likened the initiative to the Human Genome Project, which has dramatically deepened understanding of the roles played by nearly 25,000 genes that make up human DNA, and has advanced medicine along a wide front.

On Tuesday, Obama administration officials revealed which researchers and universities will carry out the first federally funded projects under the initiative’s banner, naming more than 100 investigators in 15 states and several countries.

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Orchestral manoeuvres: multiple sclerosis faces the music

The conductor walks to the stand and takes his place in front of the orchestra. He raises his baton and, with a dramatic flourish, one hundred individuals come to life. From nowhere, the stillness becomes a beautiful harmony as each member takes their part in a complex symphony.

Consider the workings and structure of the human brain – our most complicated organ – in terms of this orchestra. When it works, it is capable of something more remarkable than the greatest musical compositions in human history, but when it is affected by a condition such as multiple sclerosis (MS), “the brain’s tightly orchestrated biological functions become discordant – the conductor begins to fail at their job and several instruments go out of tune,” said Professor Robin Franklin, Head of Translational Science at the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute and Director of the MS Society Cambridge Centre for Myelin Repair.

His research team and those led by other Stem Cell Institute researchers Drs Thóra Káradóttir, Mark Kotter and Stefano Pluchino are each looking at a different aspect of this errant orchestra. They hope that their collective knowledge will one day help ‘re-tune’ the brains of MS patients to self-repair.

In its simplest terms, MS is a disease in which the immune system turns on itself, destroying the oligodendrocytes that make a protective sheath called myelin, which encases nerve fibres. This halts the transmission of neural messages, and eventually leads to nerve fibre damage, resulting in a progressive loss of movement, speech and vision for the 100,000 people in the UK who have MS.

However, the complexities of treating the disease go beyond simply stopping the destruction of myelin, said Franklin: “The myelin damage causes a build-up of debris, which needs removing, and the environment surrounding the cells needs to be conducive to regenerating the sheath. When we think about repairing the damage, we need to be considering several different biological phenomena at the same time.”

Although there are drugs available for modifying the early stages of MS – including alemtuzumab (Lemtrada), developed in Cambridge – there are no treatments that regenerate the damaged tissue. Moreover, although the disease evolves over decades, with periods of remission followed by relapses, there is no treatment once patients have reached the progressive stage (estimated to be about 50% of current patients).

Oligodendrocytes – the master manufacturers of myelin – are formed by a type of stem cell in the brain called oligodendrocyte progenitor cells (OPCs), and are responsible for re-wrapping, or remyelinating, the bare axons with myelin in response to injuries or diseases. But this regenerative ability decreases with age and MS. “As the disease progresses, the need for intervention that galvanises the natural healing process becomes ever more important,” explained Franklin. “Working with colleagues at the Harvard Stem Cell Institute, we’ve shown that the effects of age on remyelination are reversible, which gives us some confidence that we can use the brain’s own OPCs for myelin regeneration.”

However, to understand how to stimulate the brain’s own repair mechanisms first requires an understanding of how the brain detects injury and initiates repair.

Thóra Káradóttir believes that one way the brain ‘senses’ problems are afoot is through the drop in how fast neural messages are passed across the brain. “The difference in speed between an intact neuron and a damaged one can be like comparing the speed of a cheetah to a tortoise,” she said. “I’m eavesdropping on the information superhighway by attaching electrodes to neurons and OPCs.”

Her findings show that damaged fibres release a molecule called glutamate. “It’s their ‘cry for help’ to OPCs. If it doesn’t happen, or if the OPCs don’t ‘hear’, then repair is reduced.” She is working with Numedicus, a company that specialises in developing secondary uses for existing drugs, to test drugs that she hopes will be able to amplify this signal and increase the repair process.

Meanwhile, Robin Franklin’s team has shown that it’s possible to kick-start OPCs, driving the formation of oligodendrocytes and sheath formation, using a drug that targets retinoid X receptor-gamma, a molecule found within OPCs. The results are positive and clinical trials will shortly commence in collaboration with Dr Alasdair Coles from the Department of Clinical Neurosciences and the MRC Centre for Regenerative Medicine at the University of Edinburgh.

What’s interesting about the rejuvenation of remyelination is that the treatment primarily affected inflammation in demyelinating lesions, and specifically the recruitment of cells called macrophages. These are the body’s ‘big eaters’ – their role is to search out and gobble up rubbish. “We have identified myelin debris as a potent inhibitor of stem cells. Learning how it is being sensed by stem cells enabled us to overcome this inhibition by using drugs such as ibudilast.  A clinical trial to test these effects is currently undergoing preparation,” explained Mark Kotter.

Franklin and Kotter’s work is representative of an interesting turn in MS research within the field. Increasingly, investigators are looking at how the environment around the damage can be improved to help natural remyelination. “It’s a curious paradox,” said Franklin. “MS is caused by the immune system but components of the immune system are also key to its recovery.”

Stefano Pluchino’s team, for instance, has shown that injecting brain stem cells into mice with MS works in a surprising way. Instead of making new oligodendrocytes (or other brain cells), the cells seem to work by re-setting the damaging immune response, creating better conditions for the brain’s own stem cells to replace or restore what has been damaged. He is now developing more-efficient stem cells and new drugs, including nanomedicines, to foster the healing of the damaged brain.

Given the complex landscape of abnormal activities happening in the MS brain, will combination therapies be the way forward? “Certainly,” said Franklin. “Over the next ten years we will see an increased understanding of the fundamental biology in MS, we will identify more targets which may yield effective drugs and we’ll have more-refined strategies for running clinical trials. What makes Cambridge rare is the spectrum of skills here – from understanding the fundamental biology of myelin repair through to clinical trials.”

A discovery could prevent the development of brain tumours in children

Scientists at the IRCM discovered a mechanism that promotes the progression of medulloblastoma, the most common brain tumour found in children. The team, led by Frédéric Charron, PhD, found that a protein known as Sonic Hedgehog induces DNA damage, which causes the cancer to develop. This important breakthrough will be published in the October 13 issue of the prestigious scientific journal Developmental Cell. The editors also selected the article to be featured on the journal’s cover.

Sonic Hedgehog belongs to a family of proteins that gives cells the information needed for the embryo to develop properly. It also plays a significant role in tumorigenesis, the process that transforms normal cells into cancer cells.

“Our team studied a protein called Boc, which is a receptor located on the cell surface that detects Sonic Hedgehog,” explains Lukas Tamayo-Orrego, PhD student in Dr. Charron’s laboratory and co-first author of the study. “We had previously shown that Boc is important for the development of the cerebellum, the part of the brain where medulloblastoma arises, so we decided to further investigate its role.”

“With this study, we found that the presence of Boc is required for Sonic Hedgehog to induce DNA damage,” adds Dr. Charron, Director of the Molecular Biology of Neural Development research unit at the IRCM. “In fact, Boc causes DNA mutations in tumour cells, which promotes the progression of precancerous lesions into advanced medulloblastoma.”

“Our study shows that when Boc is inactivated, the number of tumours is reduced by 66 per cent,” says Frederic Mille, PhD, co-first author of the article and former postdoctoral fellow in Dr. Charron’s research unit. “The inactivation of Boc therefore reduces the development of early medulloblastoma into advanced tumours.”

Medulloblastoma ranks among the leading causes of cancer-related mortality in children. Current treatments include surgery, as well as radiation therapy and chemotherapy. Although the majority of children survive the treatment, radiation therapy damages normal brain cells in infants and toddlers and causes long-term harm.

“As a result, many children who undergo these treatments suffer serious side effects including cognitive impairment and disorders,” states Dr. Charron. “Our results indicate that Boc could potentially be targeted to develop a new therapeutic approach that would stop the growth and progression of medulloblastoma and could reduce the adverse side effects of current treatments.”