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

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

Suicidal ideation among US soldiers begins before enlistment

The following article was published March 2014 by NIMH. What are your thoughts?

Early interventions might hold the key to reducing the high Army suicide rate Nearly 60% of soldier suicide attempts can be traced to pre-enlistment mental disorders, which are much more common among nondeployed U.S. Army soldiers than demographically similar populations of civilians (25.1% vs. 11.6%), according to a major new study. The vast majority (76.6%) of soldiers with mental disorders say their conditions started before enlistment, researchers found. These are among the initial results published online today in JAMA Psychiatry based on a survey carried out as part of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS), the largest study of mental health risk and resilience ever conducted among U.S. Army personnel. Althoughthe suicide death rate in the U.S. Army has historically been below the civilian rate, the Army rate began climbing at the beginning of the Iraq and Afghanistan conflicts, and by 2008, it exceeded the demographically matched civilian rate (20.2 suicide deaths per 100,000 vs. 19.2). Concerns about this increase led to Army STARRS, a partnership between the Army and the NIMH designed to help understand and address this issue. The initial findings published today include three papers that use different strategies to evaluate suicide risk and protective factors among service people, including an analysis comparing the prevalence of mental disorders among Army and civilian populations. "Some of the differences in disorder rates are truly remarkable," said Ronald Kessler, McNeil Family Professor of Health Care Policy at Harvard Medical School and senior author of the paper on mental disorder prevalence. "The rate of major depression is 5 times as high among soldiers as civilians, intermittent explosive disorder 6 times as high, and PTSD nearly 15 times as high." The most common disorders in the Army STARRS survey were attention deficit hyperactivity disorder (ADHD) and intermittent explosive disorder (IED), or recurrent and uncontrollable anger attacks, Kessler said. The findings suggest that soldiers did not have higher rates of most "internalizing disorders" (anxiety disorders and depression) than civilians before enlistment, but rather developed high rates of these disorders only after they enlisted in the Army. The situation was different, though, for "behavioral disorders" (ADHD, IED and substance abuse), which were much more common among young people who subsequently enlisted in the Army than those who did not. Rates for these disorders increased even more after enlistment. Nearly half of current soldier internalizing disorders and 80% of behavioral disorders started before enlistment "These results are a wake-up call highlighting the importance of outreach and intervention for new soldiers who enter the Army with pre-existing mental disorders," said Robert Ursano, Chair of the Department of Psychiatry at the Uniformed Services University of the Health Sciences and co-principal investigator of Army STARRS. A second Army STARRS paper appearing today in JAMA Psychiatry revealed that 13.9% of soldiers considered suicide at some point in their lifetime, 5.3% had made a suicide plan, and 2.4% had attempted suicide, with between 47% to 60% of these outcomes first occurring prior to enlistment. Pre-existing mental disorders were found to be by far the strongest predictors of these suicidal behaviors. "It is striking that nearly 50% of the soldiers who attempted suicide made their first attempt before joining the Army, as applicants are asked about any history of suicide attempts in recruitment interviews and those who report such a history typically are excluded from service," said Matthew Nock, professor of psychology at Harvard University and lead author of this report on soldier suicidality. Nock noted that the most practical implication of this finding might be that the Army should develop outreach and intervention programs for new soldiers based on the realization that a nontrivial proportion of new soldiers come into the Army with a history of mental disorder and suicidality, and that applicants are not always forthcoming about these concerns during the recruitment process. The researchers added that intermittent explosive disorder is of special importance because it was the only disorder found to predict suicide attempts after developing suicidal thoughts, which has important implications for screening and prevention. This important finding shows that it is not only depression and PTSD that predict suicide attempts. A third JAMA Psychiatry article by lead author Michael Schoenbaum of NIMH examined the suicide and accident death rates in relation to basic sociodemographic and Army experience factors in the 975,057 regular Army soldiers who served between Jan. 1, 2004, and Dec. 31, 2009, charting variations in the rates based on a variety of factors including sex, race, education level and rank. ### Written by Jake Miller The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is funded by the U.S. Army and the National Institute of Mental Health. The study is led by co-principal investigators Robert J. Ursano (Uniformed Services University of the HealthSciences) and Murray B. Stein (University of California, San Diego), with site investigators Steven G. Heeringa (University of Michigan) and Ronald C. Kessler (Harvard Medical School), and with collaborating scientists Lisa J. Colpe (NIMH), and Michael Schoenbaum (NIMH). More information at: http://www.armystarrs.org/media_room ADDITIONAL CONTACT INFORMATION Army STARRS Co-Principal Investigator Robert J. Ursano, MD, Uniformed Services University of the Health Sciences: Contact: Sharon Willis, 301-295-3578, sharon.willis@usuhs.edu Army STARRS Co-Principal Investigator Murray B. Stein. MD, MPH, University of California, San Diego: Contact: Debra Kain, 619-543-6202, DDKain@ucsd.edu Lead author and Army STARRS Site Principal Investigator Ronald C. Kessler, PhD, Harvard Medical School: Contact: David Cameron, (617) 432-0441, david_cameron@hms.harvard.edu Lead author and Army STARRS Site Co-Principal Investigator Matthew Nock, PhD, Harvard University: Contact: Peter Reuell, (617) 495-1585, preuell@harvard.edu For commentary on the significance of the Army STARRS reports: Lieutenant General (Retired) Eric Schoomaker, MD, former Surgeon General of the United States Army and Commanding General, United States Army Medical Command Contact: Sharon Holland (301) 295-3578, sharon.holland@usuhs.edu REFERENCES Thirty-day prevalence of DSM-IV mental disorders among non-deployed soldiers in the U.S. Army: Results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Kessler RC, Heeringa SG, Stein MB, Colpe LJ, Fullerton CS, Hwang I, Naifeh JA, Nock MK, Petukhova M, Sampson NA, Schoenbaum M, Zaslavsky AM, Ursano RJ. JAMA Psychiatry. Prevalence and correlates of suicidal behavior among soldiers: Results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Nock MK, Stein MB, Heeringa SG, Ursano RJ, Colpe LJ, Fullerton CS, Hwang I, Naifeh JA, Sampson NA, Schoenbaum M, Zaslavsky AM, Kessler RC. JAMA Psychiatry. Predictors of suicide and accident death in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Schoenbaum M, Kessler RC, Gilman SE, Colpe LJ, Heeringa SG, Stein MB, Ursano RJ, Cox KL. JAMA Psychiatry. For more information on combat PTSD and other mental health information, please visit Continuing Education for Counselors