July 23, 2014

Seeing the inner workings of the brain made easier by new technique from Stanford

What do you think about this article?
"Last year Karl Deisseroth, a Stanford professor of bioengineering and of psychiatry and behavioral sciences, announced a new way of peering into a brain – removed from the body – that provided spectacular fly-through views of its inner connections. Since then laboratories around the world have begun using the technique, called CLARITY, with some success, to better understand the brain's wiring. However, Deisseroth said that with two technological fixes CLARITY could be even more broadly adopted. The first problem was that laboratories were not set up to reliably carry out the CLARITY process. Second, the most commonly available microscopy methods were not designed to image the whole transparent brain. "There have been a number of remarkable results described using CLARITY," Deisseroth said, "but we needed to address these two distinct challenges to make the technology easier to use." In a Nature Protocols paper published June 19, Deisseroth presented solutions to both of those bottlenecks. "These transform CLARITY, making the overall process much easier and the data collection much faster," he said. He and his co-authors, including postdoctoral fellows Raju Tomer and Li Ye and graduate student Brian Hsueh, anticipate that even more scientists will now be able to take advantage of the technique to better understand the brain at a fundamental level, and also to probe the origins of brain diseases. This paper may be the first to be published with support of the White House BRAIN Initiative, announced last year with the ambitious goal of mapping the brain's trillions of nerve connections and understanding how signals zip through those interconnected cells to control our thoughts, memories, movement and everything else that makes us us. "This work shares the spirit of the BRAIN Initiative goal of building new technologies to understand the brain – including the human brain," said Deisseroth, who is also a Stanford Bio-X affiliated faculty member. Eliminating fat When you look at the brain, what you see is the fatty outer covering of the nerve cells within, which blocks microscopes from taking images of the intricate connections between deep brain cells. The idea behind CLARITY was to eliminate that fatty covering while keeping the brain intact, complete with all its intricate inner wiring. The way Deisseroth and his team eliminated the fat was to build a gel within the intact brain that held all the structures and proteins in place. They then used an electric field to pull out the fat layer that had been dissolved in an electrically charged detergent, leaving behind all the brain's structures embedded in the firm water-based gel, or hydrogel. This is called electrophoretic CLARITY. The electric field aspect was a challenge for some labs. "About half the people who tried it got it working right away," Deisseroth said, "but others had problems with the voltage damaging tissue." Deisseroth said that this kind of challenge is normal when introducing new technologies. When he first introduced optogenetics, which allows scientists to control individual nerves using light, a similar proportion of labs were not initially set up to easily implement the new technology, and ran into challenges. To help expand the use of CLARITY, the team devised an alternate way of pulling out the fat from the hydrogel-embedded brain – a technique they call passive CLARITY. It takes a little longer, but still removes all the fat, is much easier and does not pose a risk to the tissue. "Electrophoretic CLARITY is important for cases where speed is critical, and for some tissues," said Deisseroth, who is also the D.H. Chen Professor. "But passive CLARITY is a crucial advance for the community, especially for neuroscience." Passive CLARITY requires nothing more than some chemicals, a warm bath and time. Many groups have begun to apply CLARITY to probe brains donated from people who had diseases like epilepsy or autism, which might have left clues in the brain to help scientists understand and eventually treat the disease. But scientists, including Deisseroth, had been wary of trying electrophoretic CLARTY on these valuable clinical samples with even a very low risk of damage. "It's a rare and precious donated sample, you don't want to have a chance of damage or error," Deisseroth said. "Now the risk issue is addressed, and on top of that you can get the data very rapidly." Fast CLARITY imaging in color The second advance had to do this rapidity of data collection. In studying any cells, scientists often make use of probes that will go into the cell or tissue, latch onto a particular molecule, then glow green, blue, yellow or other colors in response to particular wavelengths of light. This is what produces the colorful cellular images that are so common in biology research. Using CLARITY, these colorful structures become visible throughout the entire brain, since no fat remains to block the light. But here's the hitch. Those probes stop working, or get bleached, after they've been exposed to too much light. That's fine if a scientist is just taking a picture of a small cellular structure, which takes little time. But to get a high-resolution image of an entire brain, the whole tissue is bathed in light throughout the time it takes to image it point by point. This approach bleaches out the probes before the entire brain can be imaged at high resolution. The second advance of the new paper addresses this issue, making it easier to image the entire brain without bleaching the probes. "We can now scan an entire plane at one time instead of a point," Deisseroth said. "That buys you a couple orders of magnitude of time, and also efficiently delivers light only to where the imaging is happening." The technique is called light sheet microscopy and has been around for a while, but previously didn't have high enough resolution to see the fine details of cellular structures. "We advanced traditional light sheet microscopy for CLARITY, and can now see fine wiring structures deep within an intact adult brain," Deisseroth said. His lab built their own microscope, but the procedures are described in the paper, and the key components are commercially available. Additionally, Deisseroth's lab provides free training courses in CLARITY, modeled after his optogenetics courses, to help disseminate the techniques. Brain imaging to help soldiers The BRAIN Initiative is being funded through several government agencies including the Defense Advanced Research Projects Agency (DARPA), which funded Deisseroth's work through its new Neuro-FAST program. Deisseroth said that like the National Institute of Mental Health (NIMH, another major funder of the new paper), DARPA "is interested in deepening our understanding of brain circuits in intact and injured brains to inform the development of better therapies." The new methods Deisseroth and his team developed will accelerate both human- and animal-model CLARITY; as CLARITY becomes more widely used, it will continue to help reveal how those inner circuits are structured in normal and diseased brains, and perhaps point to possible therapies. ### Other arms of the BRAIN Initiative are funded through the National Science Foundation (NSF) and the National Institutes of Health (NIH). A working group for the NIH arm was co-led by William Newsome, professor of neurobiology and director of the Stanford Neurosciences Institute, and also included Deisseroth and Mark Schnitzer, associate professor of biology and of applied physics. That group recently recommended a $4.5 billion investment in the BRAIN Initiative over the next 12 years, which NIH Director Francis Collins approved earlier this month." In addition to funding by DARPA and NIMH, the work was funded by the NSF, the National Institute on Drug Abuse, the Simons Foundation and the Wiegers Family Fund. For more information on the brain, mental health, and social work topics please visit Professional Counselor Continuing Education

May 21, 2014

Having a Sense of Purpose May Add Years to Your Life

What do you think about this article originally published by The Assoc for Psychological Science? "Feeling that you have a sense of purpose in life may help you live longer, no matter what your age, according to research published in Psychological Science, a journal of the Association for Psychological Science. The research has clear implications for promoting positive aging and adult development, says lead researcher Patrick Hill of Carleton University in Canada: “Our findings point to the fact that finding a direction for life, and setting overarching goals for what you want to achieve can help you actually live longer, regardless of when you find your purpose,” says Hill. “So the earlier someone comes to a direction for life, the earlier these protective effects may be able to occur.” This is an image of a sunrise over a road in the countryside.Previous studies have suggested that finding a purpose in life lowers risk of mortality above and beyond other factors that are known to predict longevity. But, Hill points out, almost no research examined whether the benefits of purpose vary over time, such as across different developmental periods or after important life transitions. Hill and colleague Nicholas Turiano of the University of Rochester Medical Center decided to explore this question, taking advantage of the nationally representative data available from the Midlife in the United States (MIDUS) study. The researchers looked at data from over 6000 participants, focusing on their self-reported purpose in life (e.g., “Some people wander aimlessly through life, but I am not one of them”) and other psychosocial variables that gauged their positive relations with others and their experience of positive and negative emotions. Over the 14-year follow-up period represented in the MIDUS data, 569 of the participants had died (about 9% of the sample). Those who had died had reported lower purpose in life and fewer positive relations than did survivors. Greater purpose in life consistently predicted lower mortality risk across the lifespan, showing the same benefit for younger, middle-aged, and older participants across the follow-up period. This consistency came as a surprise to the researchers: “There are a lot of reasons to believe that being purposeful might help protect older adults more so than younger ones,” says Hill. “For instance, adults might need a sense of direction more, after they have left the workplace and lost that source for organizing their daily events. In addition, older adults are more likely to face mortality risks than younger adults.” “To show that purpose predicts longer lives for younger and older adults alike is pretty interesting, and underscores the power of the construct,” he explains. Purpose had similar benefits for adults regardless of retirement status, a known mortality risk factor. And the longevity benefits of purpose in life held even after other indicators of psychological well-being, such as positive relations and positive emotions, were taken into account. “These findings suggest that there’s something unique about finding a purpose that seems to be leading to greater longevity,” says Hill. The researchers are currently investigating whether having a purpose might lead people to adopt healthier lifestyles, thereby boosting longevity. Hill and Turiano are also interested in examining whether their findings hold for outcomes other than mortality. “In so doing, we can better understand the value of finding a purpose throughout the lifespan, and whether it provides different benefits for different people,” Hill concludes. Preparation of the manuscript was supported through funding from the National Institute of Mental Health (Grant T32-MH018911-23), and the data collection was supported by Grant P01-AG020166 from the National Institute on Aging. ### All data and materials have been made publicly available via the Interuniversity Consortium for Political and Social Research and can be accessed at the following URLs: http://doi.org/10.3886/ICPSR04652.v6 and http://midus.colectica.org/. The complete Open Practices Disclosure for this article can be found at http://pss.sagepub.com/content/by/supplemental-data. This article has received badges for Open Data and Open Materials. More information about the Open Practices badges can be found at https://osf.io/tvyxz/wiki/view/ and http://pss.sagepub.com/content/25/1/3.full." For more information and resources on mental health and social work, please visit Marriage and Family Therapist Continuing Education

May 06, 2014

Study finds family-based exposure therapy effective treatment for young children with OCD

What do you think of this article on kids and OCD? "Bradley Hasbro Children’s Research Center study finds family-based exposure therapy effective treatment for young children with OCD 5/5/2014 • Children five to eight years old with emerging OCD can benefit from therapies used for older children A new study from the Bradley Hasbro Children’s Research Center has found that family-based cognitive behavioral therapy (CBT) is beneficial to young children between the ages of five and eight with Obsessive-Compulsive Disorder (OCD). The study, now published online in JAMA Psychiatry, found developmentally sensitive family-based CBT that included exposure/response prevention (EX/RP) was more effective in reducing OCD symptoms and functional impairment in this age group than a similarly structured relaxation program. Jennifer Freeman, PhD, a staff psychologist at the Bradley Hasbro Children’s Research Center and clinical co-director of the Intensive Program for OCD at Bradley Hospital, led the study. “CBT has been established as an effective form of OCD treatment in older children and adolescents, but its effect on young children has not been thoroughly examined,” said Freeman. “These findings have significant public health implications, as they support the idea that very young children with emerging OCD can benefit from behavioral treatment.” During the 14-week randomized, controlled trial, which was conducted at three academic medical centers over a five-year period, the team studied 127 children between the ages of five and eight with a primary diagnosis of OCD. Each child received either family-based CBT with EX/RP or family-based relaxation therapy. The family-based CBT focused on providing the child and parent “tools” to understand, manage and reduce OCD symptoms. This includes psychoeducation, parenting strategies, and family-based exposure treatment, so children can gradually practice facing feared situations while learning to tolerate anxious feelings. The family-based relaxation therapy focused on learning about feelings and implementing muscle relaxation strategies aimed at lowering the child’s anxiety. At the end of the trial period, 72 percent of children receiving CBT with EX/RP were rated as “much improved” or “very much improved” on the Clinical Global Impression-Improvement scale, versus 41 percent of children receiving the family-based relaxation therapy. According to Freeman, the traditional approach for children this young presenting with OCD symptoms has been to watch and wait. “This study has shown that children with early onset OCD are very much able to benefit from a treatment approach that is uniquely tailored to their developmental needs and family context,” said Freeman. “Family-based EX/RP treatment is effective, tolerable and acceptable to young children and their families.” Freeman hopes that the family-based CBT model will become the first-line choice for young children with OCD in community mental health clinics where they first present for treatment. Earlier intervention may better address the chronic issues many children have with OCD, as well as the impact the debilitating illness can have on their overall development. “We use this family-based CBT model for treating children in this age range in both our Pediatric Anxiety Research Clinic and our Intensive Outpatient Program with much success,” said Freeman. “My hope is that others will utilize this treatment model to the benefit of young children at the onset of their illness.” “The findings from this study support extending downward the age range that can benefit from CBT with EX/RP for pediatric OCD treatment,” said Freeman. “With appropriate parental support, young children with OCD can make significant gains beyond what can be expected from having parents attempt to teach relaxation strategies to their children with OCD.” This study was funded by the National Institute of Mental Health (NIMH) under grant number 1R01MH079217. Freeman’s principal affiliation is the Bradley Hasbro Children’s Research Center, a division of the Lifespan health system in Rhode Island. She is also co-director of the Pediatric Anxiety Research Clinic at the Bradley Hasbro Children’s Research Center and clinical co-director of the Intensive Program for OCD at Bradley Hospital. She is an associate professor (research) at The Warren Alpert Medical School of Brown University, Department of Psychiatry and Human Behavior." For more information on PTSD and other mental health resources, please visit, Aspira Continuing Education Online Courses or our Anxiety Disorders CE Course

April 16, 2014

Neurobiologists find chronic stress in early life causes anxiety, aggression in adulthood

Cold Spring Harbor, NY -- In recent years, behavioral neuroscientists have debated the meaning and significance of a plethora of independently conducted experiments seeking to establish the impact of chronic, early-life stress upon behavior – both at the time that stress is experienced, and upon the same individuals later in life, during adulthood. These experiments, typically conducted in rodents, have on the one hand clearly indicated a link between certain kinds of early stress and dysfunction in the neuroendocrine system, particularly in the so-called HPA axis (hypothalamic-pituitary-adrenal), which regulates the endocrine glands and stress hormones including corticotropin and glucocorticoid. Yet the evidence is by no means unequivocal. Stress studies in rodents have also clearly identified a native capacity, stronger in some individuals than others, and seemingly weak or absent in still others, to bounce back from chronic early-life stress. Some rodents subjected to early life stress have no apparent behavioral consequences in adulthood – they are disposed neither to anxiety nor depression, the classic pathologies understood to be induced by stress in certain individuals. Today, a research team led by Associate Professor Grigori Enikolopov of Cold Spring Harbor Laboratory (CSHL) reports online in the journal PlOS One the results of experiments designed to assess the impacts of social stress upon adolescent mice, both at the time they are experienced and during adulthood. Involving many different kinds of stress tests and means of measuring their impacts, the research indicates that a "hostile environment in adolescence disturbs psychoemotional state and social behaviors of animals in adult life," the team says. The tests began with 1-month-old male mice – the equivalent, in human terms of adolescents -- each placed for 2 weeks in a cage shared with an aggressive adult male. The animals were separated by a transparent perforated partition, but the young males were exposed daily to short attacks by the adult males. This kind of chronic activity produces what neurobiologists call social-defeat stress in the young mice. These mice were then studied in a range of behavioral tests. "The tests assessed levels of anxiety, depression, and capacity to socialize and communicate with an unfamiliar partner," explains Enikolopov. These experiments showed that in young mice chronic social defeat induced high levels of anxiety helplessness, diminished social interaction, and diminished ability to communicate with other young animals. Stressed mice also had less new nerve-cell growth (neurogenesis) in a portion of the hippocampus known to be affected in depression: the subgranular zone of the dentate gyrus. Another group of young mice was also exposed to social stress, but was then placed for several weeks in an unstressful environment. Following this "rest" period, these mice, now old enough to be considered adults, were tested in the same manner as the other cohort. In this second, now-adult group, most of the behaviors impacted by social defeat returned to normal, as did neurogenesis, which retuned to a level seen in healthy controls. "This shows that young mice, exposed to adult aggressors, were largely resilient biologically and behaviorally," says Dr. Enikolopov. However, in these resilient mice, the team measured two latent impacts on behavior. As adults they were abnormally anxious, and were observed to be more aggressive in their social interactions. "The exposure to a hostile environment during their adolescence had profound consequences in terms of emotional state and the ability to interact with peers," Dr. Enikolopov observes. ### The research described in this release was supported by the Russian Foundation for Basic Research and by the National Institute of Mental Health. "Extended Effect of Chronic Social Defeat Stress in Childhood on Behaviors in Adulthood" appears online in PlOS One Tuesday, March 25, 2014. The authors are: Irina L. Kovalenko, Anna G. Galyamina, Dmitry A. Smagin, Tatyana V. Michurina, Natalia N. Kudryavtseva and Grigori Enikolopov. About Cold Spring Harbor Laboratory Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for the impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL's multidisciplinary scientific community is more than 600 researchers and technicians strong and its Meetings & Courses program hosts more than 12,000 scientists from around the world each year to its Long Island campus and its China center LCSW Continuing Education

April 02, 2014

Autism Spectrum Disorder: Uncovering Clues to a Complicated Condition

Autism Spectrum Disorder Uncovering Clues to a Complicated Condition Autism is a complex brain disorder that first appears during early childhood. It affects how a person behaves and interacts with others. People with autism might not look you in the eye when talking. They may spend a lot of time lining up toys or other objects. Or they may say the same sentence over and over. The disorder is so variable—affecting each person in very different ways—that it can be difficult to diagnose and treat. This variability is why autism is called a “spectrum” disorder. It spans the spectrum from mild to severe and includes a wide range of symptoms. NIH-funded scientists have been working to uncover the secrets of autism. They’ve identified genes that may boost the risk for autism. They’ve developed therapies that can help many of those affected. And they’ve found that starting treatment as early as possible can lead to better outcomes. Still, there’s much more we need to learn about this complicated condition. About 1 in 88 children may have autism spectrum disorder, according to the U.S. Centers for Disease Control and Prevention. The number of affected children has been growing in recent years. Many researchers believe this increase is due to better diagnosis and awareness. Others suspect that yet-unknown factors may be partly to blame. Although the exact causes of autism are unclear, research suggests that both genes and the environment play important roles. Autism affects a child’s development in different ways, and so it’s known as a developmental disorder. Parents are often the first to suspect that something may not be quite right with their child’s development. They may notice their baby doesn’t make eye contact, becomes overly focused on certain objects or isn’t “babbling” like other children the same age. “A parent may first have concerns when a child is under 2 years of age,” says Dr. Connie Kasari, a child development expert at the University of California, Los Angeles. “A more certain diagnosis can usually be made by age 2, but some cases might not be clear until much later.” There are no direct tests, like blood tests or brain scans, that can identify autism. Instead, the condition is diagnosed by looking at a child’s behaviors and development. “All affected children have some sort of social impairment, but symptoms vary along a continuum,” Kasari says. “Impairment can range from kids who are in their ‘own world’ and seemingly unaware of others to high-functioning individuals who are just awkward and seem to miss the point of social interactions.” In May 2013, the American Psychiatric Association updated an important book that’s used to diagnose and classify mental disorders. The DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) includes an updated definition for autism spectrum disorder. The condition is now identified by looking for 2 broad categories of symptoms: problems with social communication and the presence of “stereotyped” behaviors, such as walking in certain patterns or insisting on specific or unusual routines. To be diagnosed with autism, these symptoms must arise during early childhood, even if they’re not noticed until later, when social demands increase. “The new DSM-5 definition moves all the disorders into a single spectrum, rather than the 4 separate autistic disorders described in the past,” says NIH pediatrician and neuroscientist Dr. Susan Swedo. She chaired the expert panel that updated the DSM-5 definition of autism spectrum disorders. “The new criteria are also more inclusive of minorities, adolescents and young adults with autism than the previous edition, which focused more on boys ages 4 to 9.” Getting diagnosed as early as possible is crucial. “Autism is treatable even though it’s not curable,” says Dr. David Mandell, an expert in autism and health services at the University of Pennsylvania. “If we intervene early enough with appropriate and intensive care, we can reduce a lot of impairments for many kids who have autism.” Research has shown that therapies focusing on behavior and communication can be helpful. Some drugs can also reduce certain related symptoms, but no medications have been approved by the U.S. Food and Drug Administration specifically for treating the main symptoms of autism. “Because autism is such a complicated disorder, no one therapy fits everyone,” Kasari explains. Kasari and her colleagues developed and tested several treatments that focus on improving social skills and communication. In one study, preschoolers with autism received intense training in basic skills such as playing and sharing attention. Five years later, these children tended to have stronger vocabularies and better communication skills than children who received standard therapy. “We’ve found that if we can improve these basic skills, we can also improve language learning for these kids,” Kasari says. “We’re now studying 2 potential therapies in at-risk babies, ages 12- to 21-months old, to see if we can push language development along faster for the children.” Scientists are also looking for ways to predict likely outcomes for children with autism. One NIH-funded team found that the brain waves of some 2-year-olds with autism can have a distinctive pattern when they listen to familiar words. The children with more severe social symptoms didn’t have a typical focused response in the brain region that processes language. Follow-up studies showed that these brain responses predicted the children’s developmental abilities 2 and 4 years later. “In the future, we’d like to be able to assess a child based on brain function or their genetic profile and then identify the intervention that might be best for that particular kid,” Mandell says. A growing number of studies are looking at autism in older age groups. “While we think about autism as a disorder of childhood, it actually continues through adolescence and into adulthood,” Mandell says. “Some adults with autism have been misdiagnosed, and they can find themselves being treated for other conditions. We’d like to develop better screening tools and ultimately provide these adults with skills and supports to help them become happy and productive citizens.” While research is ongoing, it’s clear that early diagnosis and treatment can improve outcomes for those with autism. If you’re concerned about your child’s social communication and behaviors, don’t wait. Talk with your child’s doctor. You may be referred to a specialist who can do a thorough evaluation. The earlier autism is diagnosed, the sooner specific therapy can begin Social Worker Continuing Education

March 24, 2014

Brain Region Singled Out for Social Memory, Possible Therapeutic Target for Select Brain Disorders

Researchers have found in mice that a formerly obscure region of the hippocampus called CA2 is important for social memory, the ability of an animal to recognize another of the same species. Identifying the role of this region could be useful in understanding and treating disorders characterized by altered social behaviors such as schizophrenia, bipolar disorder, and autism. Funded in part by the National Institute of Mental Health (NIMH), the study was published last month online in Nature. Background The hippocampus is essential for learning and memory—specifically the storage of knowledge of who, what, where, and when. Clues about the hippocampus’s roles emerged from the famous case of patient HM (Henry Molaison), who had most of his hippocampus removed by surgeons in 1953 to cure his epilepsy. HM became unable to form new memories of people he subsequently worked with for years. Most previous studies of how memory is harnessed have focused on the trisynaptic pathway. In this neural circuit, information that is obtained from the entorhinal cortex—the main interface between the hippocampus and the neocortex or the outermostpart of the brain involved in higher functions such as thought or action—proceeds to the dentate gyrus, the front gate of the hippocampus. Granule neurons from the dentate gyrus then shuttle the information to interneurons and pyramidal cells of the CA3 region of the hippocampus, which then sends the information to the CA1 region, the main source of hippocampal output. Absent from this circuit is the CA2 subfield. “Although the CA2 subregion was discovered over 75 years ago, it has received very little attention,” said Steven A. Siegelbaum, Ph.D., lead author of the study. He ascribes two reasons for the inattention: size and location. CA2 has 10 percent the number of neurons of CA1 or CA3, raising questions about its importance. The region is also squeezed between CA1 and CA3, making it difficult to study with traditional approaches of physical or chemical lesions, which lack the precision to selectively target CA2. To circumvent these problems, Siegelbaum, a neuroscience professor at Columbia University and a Howard Hughes Medical Institute Investigator, and Frederick L. Hitti, an M.D.-Ph.D. student, generated a special transgenic mouse in which the CA2 neurons could be selectively inhibited in adult animals. Once these neurons were inactivated, the mice underwent a series of behavioral tests. Results of the Study Normally when a mouse encounters another mouse it does not know, it gives it a “sniff test” and is more interested in this new mouse versus a familiar acquaintance. The CA2-inactive mouse, however, shows no recognition of mice it has seen before and ends up sniffing indiscriminately familiar and novel mice. The mice showed no loss in the ability to discriminate social or non-social odors, such as food buried deeply in its litterbox. Although a pronounced loss of social memory is seen in the CA2-inactive mice, the mice did not experience changes in other hippocampal-specific behaviors such as spatial and contextual memory, and could still distinguish between novel and familiar inanimate objects. Significance “Because several neuropsychiatric disorders are associated with altered social behaviors, our findings raise the possibility that CA2 dysfunction may contribute to these behavioral changes,” said Siegelbaum. Individuals with schizophrenia and bipolar disorder have lowered numbers of CA2 inhibitory neurons. Similarly, individuals with autism have altered signaling of vasopressin, a social behavior hormone that interacts with a specific class of receptors found predominantly in this region. However, the CA2-inactive mice did not display classic symptoms of autism as they had normal levels of sociability, providing evidence that sociability and social memory involve different brain functions. Techniques such as the one detailed here are examples of research tools that the NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN ) Initiative hopes to build upon to further our understanding of the human brain. What’s Next Siegelbaum’s group hopes to use the same genetic technology to examine whether there are changes in CA2 function in mouse models of psychiatric disorders such as autism and schizophrenia. If so, they plan to screen for drugs that restore normal CA2 function and ask whether this drug treatment helps reverse any behavioral changes seen in the mice. Such research offers the possibility of finding new drug targets and approaches for treating the behavioral changes associated with these disorders Alcoholism and Drug Abuse Counselors Continuing Education Reference Hitti FL, Siegelbaum SA. The Hippocampal CA2 Region is Essential for Social Memory. Nature , published online February 23, 2014. Grant 5F30MH098633-02

March 12, 2014

Researchers pinpoint brain region essential for social memory

Potential target for treating autism, schizophrenia, and other brain disorders NEW YORK, NY (February 23, 2014) — Columbia University Medical Center (CUMC) researchers have determined that a small region of the hippocampus known as CA2 is essential for social memory, the ability of an animal to recognize another of the same species. A better grasp of the function of CA2 could prove useful in understanding and treating disorders characterized by altered social behaviors, such as autism, schizophrenia, and bipolar disorder. The findings, made in mice, were published today in the online edition of Nature. Scientists have long understood that the hippocampus—a pair of seahorse-shaped structures in the brain's temporal lobes—plays a critical role in our ability to remember the who, what, where, and when of our daily lives. Recent studies have shown that different subregions of the hippocampus have different functions. For instance, the dentate gyrus is critical for distinguishing between similar environments, while CA3 enables us to recall a memory from partial cues (e.g., Proust's famous madeleine). The CA1 region is critical for all forms of memory. "However, the role of CA2, a relatively small region of the hippocampus sandwiched between CA3 and CA1, has remained largely unknown," said senior author Steven A. Siegelbaum, PhD, professor of neuroscience and pharmacology, chair of the Department of Neuroscience, a member of the Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, and a Howard Hughes Medical Institute Investigator. A few studies have suggested that CA2 might be involved in social memory, as this region has a high level of expression of a receptor for vasopressin, a hormone linked to sexual motivation, bonding, and other social behaviors. To learn more about this part of the hippocampus, the researchers created a transgenic mouse in which CA2 neurons could be selectively inhibited in adult animals. Once the neurons were inhibited, the mice were given a series of behavioral tests. "The mice looked quite normal until we looked at social memory," said first author Frederick L. Hitti, an MD-PhD student in Dr. Siegelbaum's laboratory, who developed the transgenic mouse. "Normally, mice are naturally curious about a mouse they've never met; they spend more time investigating an unfamiliar mouse than a familiar one. In our experiment, however, mice with an inactivated CA2 region showed no preference for a novel mouse versus a previously encountered mouse, indicating a lack of social memory." In two separate novel-object recognition tests, the CA2-deficient mice showed a normal preference for an object they had not previously encountered, showing that the mice did not have a global lack of interest in novelty. In another experiment, the researchers tested whether the animals' inability to form social memories might have to do with deficits in olfaction (sense of smell), which is crucial for normal social interaction. However, the mice showed no loss in ability to discriminate social or non-social odors. In humans, the importance of the hippocampus for social memory was famously illustrated by the case of Henry Molaison, who had much of his hippocampus removed by surgeons in 1953 in an attempt to cure severe epilepsy. Molaison (often referred to as HM in the scientific literature) was subsequently unable to form new memories of people. Scientists have observed that lesions limited to the hippocampus also impair social memory in both rodents and humans. "Because several neuropsychiatric disorders are associated with altered social behaviors, our findings raise the possibility that CA2 dysfunction may contribute to these behavioral changes," said Dr. Siegelbaum. This possibility is supported by findings of a decreased number of CA2 inhibitory neurons in individuals with schizophrenia and bipolar disorder and altered vasopressin signaling in autism. Thus, CA2 may provide a new target for therapeutic approaches to the treatment of social disorders. The paper is titled, "The hippocampal CA2 region is essential for social memory." ### The study was supported by a Ruth L. Kirschstein F30 National Research Service Award from the National Institute of Mental Health and the Howard Hughes Medical Institute. The authors declare no financial or other conflicts of interests. The Mortimer B. Zuckerman Mind Brain Behavior Institute Columbia University's Mortimer B. Zuckerman Mind Brain Behavior Institute is an interdisciplinary hub for scholars across the university, created on a scope and scale to explore the human brain and behavior at levels of inquiry from cells to society. The institute's leadership, which includes two Nobel Prize-winning neuroscientists, and many of its principal investigators will be based at the 450,000-square-foot Jerome L. Greene Science Center, now rising on the university's new Manhattanville campus. In combining Columbia's preeminence in neuroscience with its strengths in the biological and physical sciences, social sciences, arts, and humanities, the institute provides a common intellectual forum for research communities from Columbia University Medical Center, the Faculty of Arts and Sciences, the School of Engineering and Applied Science, and professional schools on both the Morningside Heights and Washington Heights campuses. Their collective mission is to further our understanding of the human condition and to find cures for disease. Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org. For more information on related mental health, nursing and social work topics, visit Continuing Education for Social Workers