UCLA neurophysicists determine how environmental stimuli, brain rhythms generate neuronal maps of world.

Place cells in the real world (l) and in virtual reality.

Leaving the house in the morning may seem simple, but with every move we make, our brains are working feverishly to create maps of the outside world that allow us to navigate and to remember where we are.

Take one step out the front door, and an individual brain cell fires. Pass by your rose bush on the way to the car, another specific neuron fires. And so it goes. Ultimately, the brain constructs its own pinpoint geographical chart that is far more precise than anything you’d find on Google Maps.

But just how neurons make these maps of space has fascinated scientists for decades. It is known that several types of stimuli influence the creation of neuronal maps, including visual cues in the physical environment — that rose bush, for instance — the body’s innate knowledge of how fast it is moving, and other inputs, like smell. Yet the mechanisms by which groups of neurons combine these various stimuli to make precise maps are unknown.

To solve this puzzle, UCLA neurophysicists built a virtual-reality environment that allowed them to manipulate these cues while measuring the activity of map-making neurons in rats. Surprisingly, they found that when certain cues were removed, the neurons that typically fire each time a rat passes a fixed point or landmark in the real world instead began to compute the rat’s relative position, firing, for example, each time the rodent walked five paces forward, then five paces back, regardless of landmarks. And many other mapping cells shut down altogether, suggesting that different sensory cues strongly influence these neurons.

Finally, the researchers found that in this virtual world, the rhythmic firing of neurons that normally speeds up or slows down depending on the rate at which an animal moves, was profoundly altered. The rats’ brains maintained a single, steady rhythmic pattern.

The findings, reported in the May 2 online edition of the journal Science, provide further clues to how the brain learns and makes memories.

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Patterns in the brain may relate to impaired information processing.

Jamie Feusner, UCLA

Body dysmorphic disorder is a disabling but often misunderstood psychiatric condition in which people perceive themselves to be disfigured and ugly, even though they look normal to others. New research at UCLA shows that these individuals have abnormalities in the underlying connections in their brains.

Dr. Jamie Feusner, the study’s senior author and a UCLA associate professor of psychiatry, and his colleagues report that individuals with BDD have, in essence, global “bad wiring” in their brains — that is, there are abnormal network-wiring patterns across the brain as a whole.

And in line with earlier UCLA research showing that people with BDD process visual information abnormally, the study discovered abnormal connections between regions of the brain involved in visual and emotional processing.

The findings, published in the May edition of the journal Neuropsychopharmacology, suggest that these patterns in the brain may relate to impaired information processing.

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Rats experience more anxiety and depression when days grow longer.

Rats exposed to less light during the day were more likely to explore the open end of an elevated maze, a behavioral test showing they were less anxious.

Most of us are familiar with the “winter blues,” the depression-like symptoms known as “seasonal affective disorder,” or SAD, that occurs when the shorter days of winter limit our exposure to natural light and make us more lethargic, irritable and anxious. But for rats it’s just the opposite.

Biologists at UC San Diego have found that rats experience more anxiety and depression when the days grow longer. More importantly, they discovered that the rat’s brain cells adopt a new chemical code when subjected to large changes in the day and night cycle, flipping a switch to allow an entirely different neurotransmitter to stimulate the same part of the brain.

Their surprising discovery, detailed in today’s (April 26) issue of Science, demonstrates that the adult mammalian brain is much more malleable than was once thought by neurobiologists. Because rat brains are very similar to human brains, their finding also provides a greater insight into the behavioral changes in our brain linked to light reception. And it opens the door for new ways to treat brain disorders such as Parkinson’s, caused by the death of dopamine-generating cells in the brain.

The neuroscientists discovered that rats exposed for one week to 19 hours of darkness and five hours of light every day had more nerve cells making dopamine, which made them less stressed and anxious when measured using standardized behavioral tests. Meanwhile, rats exposed for a week with the reverse — 19 hours of light and five hours of darkness — had more neurons synthesizing the neurotransmitter somatostatin, making them more stressed and anxious.

“We’re diurnal and rats are nocturnal,” said Nicholas Spitzer, a professor of biology at UC San Diego and director of the Kavli Institute for Brain and Mind. “So for a rat, it’s the longer days that produce stress, while for us it’s the longer nights that create stress.”

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Long suspected, now confirmed: Estrogen, progesterone connected to libido levels in women.

James Roney, UC Santa Barbara

Feeling frisky? If so, chances are greater your estrogen level –– and, perhaps, fertility –– are hitting their monthly peak. If not, you’re more likely experiencing a profusion of desire-deadening progesterone, and the less fertile time in your cycle. Oh, the power of hormones.

Researchers have long suspected a correlation between hormone levels and libido, but now scientists at UC Santa Barbara, led by James Roney, a professor in the Department of Psychological and Brain Sciences, have actually demonstrated hormonal predictors for sexual desire. Their findings appear in the current issue of the journal Hormones and Behavior.

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UCLA researchers will lead network of U.S. academic centers to explore experimental drugs.

James McCracken, UCLA

UCLA has been awarded a $9 million contract by the National Institute of Mental Health for an ambitious effort to rapidly study promising new drugs that may help restore normal development and brain function in children with autism spectrum disorders.

UCLA researchers will create and lead a network of U.S. academic centers that will carry out early “high risk/high reward” studies of experimental medications over a three-year period. The goal of the project, New Experimental Medicine Studies: Fast–Fail Trials in Autism Spectrum Disorders, is to determine within weeks rather than years (“fast”) if a particular pharmacological compound is working or not (“fail”).

Recent progress in identifying the genes and biological components involved in autism spectrum disorders (ASD) holds great promise for the identification of life-changing treatments for individuals of all ages, said the project’s principal investigator, Dr. James McCracken, a professor of psychiatry and director of the division of child and adolescent psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA.

“Current medical treatments are commonly prescribed by physicians for ASD but only to manage difficult behaviors, like aggressiveness, hyperactivity and self-injury,” McCracken said. “Such treatments can be important and helpful, but they do not impact the core problems of the disorders.

“This is definitely the most exciting time yet to be involved in treatment research for ASD,” he added. “Our basic science colleagues are generating enormous information on the likely underlying causes of this common and often disabling condition. We are well positioned to apply the basic science and find drugs that make a difference.”

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UC San Diego scientists recall EP, perhaps the world’s second-most famous amnesiac.

These photomicrographs depict comparative stained sections of a healthy brain (top) and of patient EP, in which significant structures in the medial temporal lobe are heavily damaged or missing. The letters identify specific brain structures, such as EC and PRC for entorhinal cortex and perirhinal cortex, respectively, both important to memory formation and function.

An international team of neuroscientists has described for the first time in exhaustive detail the underlying neurobiology of an amnesiac who suffered from profound memory loss after damage to key portions of his brain.

Writing in this week’s online early edition of PNAS, principal investigator Larry R. Squire, Ph.D., professor in the departments of neurosciences, psychiatry and psychology at the UC San Diego School of Medicine and Veteran Affairs San Diego Healthcare System – with colleagues at UC Davis and the University of Castilla-La Mancha in Spain – recount the case of EP, a man who suffered radical memory loss and dysfunction following a bout of viral encephalitis.

EP’s story is strikingly similar to the more famous case of HM, who also suffered permanent, dramatic memory loss after small portions of his medial temporal lobes were removed by doctors in 1953 to relieve severe epileptic seizures. The surgery was successful, but left HM unable to form new memories or recall people, places or events post-operation.

HM (later identified as Henry Gustav Molaison) was the subject of intense scientific scrutiny and study for the remainder of his life. When he died in 2008 at the age of 82, he was popularized as “the world’s most famous amnesiac.” His brain was removed and digitally preserved at The Brain Observatory, a UC San Diego-based lab headed by Jacopo Annese, Ph.D., an assistant adjunct professor in the Department of Radiology and a co-author of the PNAS paper.

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UCLA study finds scientific basis for cognitive complaints of breast cancer patients.

Patricia Ganz, UCLA

For many years, breast cancer patients have reported experiencing difficulties with memory, concentration and other cognitive functions following cancer treatment. Whether this mental “fogginess” is psychosomatic or reflects underlying changes in brain function has been a bone of contention among scientists and physicians.

Now, a new study led by Dr. Patricia Ganz, director of cancer prevention and control research at UCLA’s Jonsson Comprehensive Cancer Center, demonstrates a significant correlation between poorer performance on neuropsychological tests and memory complaints in post-treatment, early-stage breast cancer patients — particularly those who have undergone combined chemotherapy and radiation.

“The study is one of the first to show that such patient-reported cognitive difficulties — often referred to as ‘chemo brain’ in those who have had chemotherapy — can be associated with neuropsychological test performance,” said Ganz, who is also a professor of health policy and management at UCLA’s Fielding School of Public Health and a professor of medicine at the David Geffen School of Medicine at UCLA.

The study was published today (April 18) in the online edition of the Journal of the National Cancer Institute and will appear in an upcoming print edition of the journal.

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Study uncovers how acute stress primes the brain for improved performance.

Brain cells called astrocytes (pink) appear to be key players in the response to acute stress. Stress hormones stimulate astrocytes to release fibroblast growth factor 2 (green), which in turn lead to new neurons (blue).

Overworked and stressed out? Look on the bright side. Some stress is good for you.

“You always think about stress as a really bad thing, but it’s not,” said Daniela Kaufer, associate professor of integrative biology at the University of California, Berkeley. “Some amounts of stress are good to push you just to the level of optimal alertness, behavioral and cognitive performance.”

New research by Kaufer and UC Berkeley postdoctoral fellow Elizabeth Kirby has uncovered exactly how acute stress – short-lived, not chronic – primes the brain for improved performance.

In studies on rats, they found that significant, but brief stressful events caused stem cells in their brains to proliferate into new nerve cells that, when mature two weeks later, improved the rats’ mental performance.

“I think intermittent stressful events are probably what keeps the brain more alert, and you perform better when you are alert,” she said.

Kaufer, Kirby and their colleagues in UC Berkeley’s Helen Wills Neuroscience Institute describe their results in a paper published today (April 16) in the new open access online journal eLife.

The UC Berkeley researchers’ findings, “in general, reinforce the notion that stress hormones help an animal adapt – after all, remembering the place where something stressful happened is beneficial to deal with future situations in the same place,” said Bruce McEwen, head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at The Rockefeller University, who was not involved in the study.

Kaufer is especially interested in how both acute and chronic stress affect memory, and since the brain’s hippocampus is critical to memory, she and her colleagues focused on the effects of stress on neural stem cells in the hippocampus of the adult rat brain. Neural stem cells are a sort of generic or progenitor brain cell that, depending on chemical triggers, can mature into neurons, astrocytes or other cells in the brain. The dentate gyrus of the hippocampus is one of only two areas in the brain that generate new brain cells in adults, and is highly sensitive to glucocorticoid stress hormones, Kaufer said.

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Lin Tian seeks to better understand the complex mechanisms of living organisms.

Lin Tian, UC Davis

Lin Tian, assistant professor of biochemistry and molecular medicine at UC Davis School of Medicine, is one of 28 scientists worldwide awarded a 2013 Young Investigator Grant from the Human Frontier Science Program to better understand the complex mechanisms of living organisms.

The 2013 competition involved a yearlong selection process that began with more than 715 letters of intent and nearly 100 full applications. Tian and her collaborator will receive support of $250,000 per year for the three-year project.

Tian will use optical imaging and behavioral analysis to understand the function of the outermost neocortical layer of the brain, known as Layer 1, which is involved in higher brain function and a wide range of daily activities. She will conduct her studies in mice.

“Whether you are trying to tie your shoe laces, texting a message, learning to use an iPad, running, drinking or talking, you are using the neocortex,” Tian said. “This region allows us to perceive sensations, generate voluntary motor control, mentally visualize and manipulate two- and three-dimensional objects in time and space and use language.

“It works like a hub to integrate distant and local activity to orchestrate a brain function, but we do not yet understand how integration between the distant brain and local cortical computation occurs and don’t have a way to measure activity at individual synapses.”

Tian’s research will focus on creating novel and specialized optical sensors to track communication that occurs at Layer 1 when mice are performing tasks. She is working in collaboration with Leopoldo Petreanu at the Champalimaud Neuroscience Programme in Portugal. These new tools will potentially allow neuroscientists to use synaptic resolution to establish the relationship between connectivity and function in circuits of any length across the nervous system. These developments are critical to understanding brain function, Tian said.

The Human Frontier Science Program is an international program of research support that funds leading-edge research at all levels of biological complexity, from biomolecules to the interactions between organisms.

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Results of UCSF clinical trial may change standard of care for primary CNS lymphoma.

James Rubenstein, UC San Francisco

A phase two clinical trial testing a new protocol for treating a relatively rare form of brain cancer, primary CNS lymphoma, may change the standard of care for this disease, according to doctors at UC San Francisco who led the research.

Described this week in the Journal of Clinical Oncology, the trial involved 44 patients who were given a combination of high-dose chemotherapy with immune therapy, rather than the standard combination of chemotherapy with a technique known as whole-brain radiotherapy.

The new treatment approach was significantly less toxic because it avoided whole-brain radiotherapy, which at high doses can kill brain cells and lead to a progressive deterioration of the function of the nervous system in patients. Many patients die from the toxicity of the radiation as opposed to the cancer itself.

The new treatment also seemed to work better, with the majority of patients on the trial still alive with a follow-up of nearly five years, researchers found.

The lymphoma-free survival of patients with this form of brain cancer was doubled compared to the lymphoma-free survival in previous multicenter U.S. cooperative-group-sponsored clinical trials involving brain radiotherapy, said UCSF oncologist James Rubenstein, M.D., Ph.D., associate professor of medicine, who led the study.

In addition, unlike previous treatments for primary CNS lymphoma, the new approach was equally effective in older patients – those over 60 – as it was in younger patients. This is particularly significant given that the incidence of this type of brain tumor appears to be increasing in patients 65 and older.

Rubenstein is a member of the UCSF Helen Diller Family Comprehensive Cancer Center, which is one of the country’s leading research and clinical care centers, and is the only comprehensive cancer center in the San Francisco Bay Area.

The work raises the possibility of taking a “personalized medicine” approach to guiding treatment for this form of cancer because the researchers identified a biomarker – a gene called BCL6 – which could predict the outcome of treatment depending on how much of the gene was present in the tumor.

A randomized clinical trial, which will test the effectiveness of the new therapeutic approach in a larger patient population, is now enrolling at UCSF and at other medical centers in the United States.

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Project to provide insight on diseases, how we think, learn and remember.

University of California scientists are among the brains behind President Obama’s national initiative to map the human brain.

On April 2, Obama proposed an initial $100 million investment this year in the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative. The goal is to help researchers find new ways to treat, cure and prevent brain disorders such as Alzheimer’s disease, epilepsy and traumatic brain injury, according to a White House press release.

The idea to map the brain was proposed last year by a group of leading scientists that included Lawrence Berkeley National Lab Director Paul Alivisatos and Ralph Greenspan, associate director of UC San Diego’s Kavli Institute.

“The Brain Activity Map is a very promising project for developing revolutionary new tools to advance neuroscience and to enable improved understanding of neurological diseases,” Alivisatos said. “It is exciting that the nation will lean forward to make progress in this important area.”

Cornelia “Cori” Bargmann, a former UCSF professor now at Rockefeller University, and William Newsome of Stanford University, will co-chair BRAIN.

BRAIN will combine the efforts of universities, private organizations and federal research agencies, such as the National Institutes of Health, in a massive project to decipher how the brain works.

UC neuroscientists, chemists, computer scientists, physicists and engineers will take part in the effort.

“There is this enormous mystery waiting to be unlocked, and the BRAIN Initiative will change that by giving scientists the tools they need to get a dynamic picture of the brain in action and better understand how we think and how we learn and how we remember,” Obama said. “And that knowledge could be — will be — transformative.”

For more coverage of UC’s role in the BRAIN initiative, view these links:

• UC Berkeley: Campus poised to join Obama’s BRAIN initiative
• Chancellor leads UCLA contingent to White House for announcement of BRAIN initiative
• UC San Diego: Mapping the mind
• Brain research at UC San Diego brings excitement to celebration of former engineering dean
• UCSF: President Obama unveils brain mapping project
• UCTV: UC and the BRAIN initiative

Schwann cell protein plays major role in neuropathic pain.

Schwann cell myelinating axons. Credit: David Furness

An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, says a key protein in Schwann cells performs a critical, perhaps overarching, role in regulating the recovery of peripheral nerves after injury. The discovery has implications for improving the treatment of neuropathic pain, a complex and largely mysterious form of chronic pain that afflicts over 100 million Americans.

The findings are published in the March 27, 2013 issue of the Journal of Neuroscience.

Neuropathic pain occurs when peripheral nerve fibers (those outside of the brain and spinal cord) are damaged or dysfunctional, resulting in incorrect signals sent to the brain. Perceived pain sensations are frequently likened to ongoing burning, coldness or “pins and needles.” The phenomenon also involves changes to nerve function at both the injury site and surrounding tissues.

Not surprisingly, much of the effort to explain the causes and mechanisms of neuropathic pain has focused upon peripheral nerve cells themselves. The new study by principal investigator Wendy Campana, PhD, associate professor in UC San Diego’s Department of Anesthesiology, with colleagues at UC San Diego and in Japan, Italy and New York, points to a surprisingly critical role for Schwann cells – a type of glial support cell.

Schwann cells promote the growth and survival of neurons by releasing molecules called trophic factors, and by supplying the myelin used to sheathe neuronal axons. Myelination of axons helps increase the speed and efficacy of neural impulses, much as plastic insulation does with electrical wiring.

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