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

New evidence that chronic stress predisposes brain to mental illness

By Robert Sanders, Media Relations | February 11, 2014 BERKELEY — University of California, Berkeley, researchers have shown that chronic stress generates long-term changes in the brain that may explain why people suffering chronic stress are prone to mental problems such as anxiety and mood disorders later in life. myelin stained blue Myelin is stained blue in this cross section of a rat hippocampus. Myelin, which speeds electrical signals flowing through axons, is produced by oligodendrocytes, which increase in number as a result of chronic stress. New oligodendrocytes are shown in yellow. Image by Aaron Friedman and Daniela Kaufer. Their findings could lead to new therapies to reduce the risk of developing mental illness after stressful events. Doctors know that people with stress-related illnesses, such as post-traumatic stress disorder (PTSD), have abnormalities in the brain, including differences in the amount of gray matter versus white matter. Gray matter consists mostly of cells – neurons, which store and process information, and support cells called glia – while white matter is comprised of axons, which create a network of fibers that interconnect neurons. White matter gets its name from the white, fatty myelin sheath that surrounds the axons and speeds the flow of electrical signals from cell to cell. How chronic stress creates these long-lasting changes in brain structure is a mystery that researchers are only now beginning to unravel. In a series of experiments, Daniela Kaufer, UC Berkeley associate professor of integrative biology, and her colleagues, including graduate students Sundari Chetty and Aaron Freidman, discovered that chronic stress generates more myelin-producing cells and fewer neurons than normal. This results in an excess of myelin – and thus, white matter – in some areas of the brain, which disrupts the delicate balance and timing of communication within the brain. “We studied only one part of the brain, the hippocampus, but our findings could provide insight into how white matter is changing in conditions such as schizophrenia, autism, depression, suicide, ADHD and PTSD,” she said. The hippocampus regulates memory and emotions, and plays a role in various emotional disorders. Kaufer and her colleagues published their findings in the Feb. 11 issue of the journal Molecular Psychiatry. Does stress affect brain connectivity? Kaufer’s findings suggest a mechanism that may explain some changes in brain connectivity in people with PTSD, for example. One can imagine, she said, that PTSD patients could develop a stronger connectivity between the hippocampus and the amygdala – the seat of the brain’s fight or flight response – and lower than normal connectivity between the hippocampus and prefrontal cortex, which moderates our responses. “You can imagine that if your amygdala and hippocampus are better connected, that could mean that your fear responses are much quicker, which is something you see in stress survivors,” she said. “On the other hand, if your connections are not so good to the prefrontal cortex, your ability to shut down responses is impaired. So, when you are in a stressful situation, the inhibitory pathways from the prefrontal cortex telling you not to get stressed don’t work as well as the amygdala shouting to the hippocampus, ‘This is terrible!’ You have a much bigger response than you should.” white matter fibers in human brain White matter fiber architecture of the brain. Human Connectome Project. She is involved in a study to test this hypothesis in PTSD patients, and continues to study brain changes in rodents subjected to chronic stress or to adverse environments in early life. Stress tweaks stem cells Kaufer’s lab, which conducts research on the molecular and cellular effects of acute and chronic stress, focused in this study on neural stem cells in the hippocampus of the brains of adult rats. These stem cells were previously thought to mature only into neurons or a type of glial cell called an astrocyte. The researchers found, however, that chronic stress also made stem cells in the hippocampus mature into another type of glial cell called an oligodendrocyte, which produces the myelin that sheaths nerve cells. The finding, which they demonstrated in rats and cultured rat brain cells, suggests a key role for oligodendrocytes in long-term and perhaps permanent changes in the brain that could set the stage for later mental problems. Oligodendrocytes also help form synapses – sites where one cell talks to another – and help control the growth pathway of axons, which make those synapse connections. The fact that chronic stress also decreases the number of stem cells that mature into neurons could provide an explanation for how chronic stress also affects learning and memory, she said. Kaufer is now conducting experiments to determine how stress in infancy affects the brain’s white matter, and whether chronic early-life stress decreases resilience later in life. She also is looking at the effects of therapies, ranging from exercise to antidepressant drugs, that reduce the impact of stress and stress hormones. Kaufer’s coauthors include Chetty, formerly from UC Berkeley’s Helen Wills Neuroscience Institute and now at Harvard University; Friedman and K. Taravosh-Lahn at UC Berkeley’s Department of Integrative Biology; additional colleagues from UC Berkeley and others from Stanford University and UC Davis. The work was supported by a BRAINS (Biobehavioral Research Awards for Innovative New Scientists) award from the National Institute of Mental Health of the National Institutes of Health (R01 MH087495), a Berkeley Stem Cell Center Seed Grant, the Hellman Family Foundation and the National Alliance for Research on Schizophrenia and Depression. RELATED INFORMATION •Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus (2/11/14 Molecular Psychiatry) •Daniela Kaufer’s web site •Researchers find out why some stress is good for you (4/16/13 press release) For more information on this and other mental health topics, please visit Counselor CEUs