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

Focusing on faces

Researchers find neurons in amygdala of autistic individuals have reduced sensitivity to eye region of others' faces Difficulties in social interaction are considered to be one of the behavioral hallmarks of autism spectrum disorders (ASDs). Previous studies have shown these difficulties to be related to differences in how the brains of autistic individuals process sensory information about faces. Now, a group of researchers led by California Institute of Technology (Caltech) neuroscientist Ralph Adolphs has made the first recordings of the firings of single neurons in the brains of autistic individuals, and has found specific neurons in a region called the amygdala that show reduced processing of the eye region of faces. Furthermore, the study found that these same neurons responded more to mouths than did the neurons seen in the control-group individuals. "We found that single brain cells in the amygdala of people with autism respond differently to faces in a way that explains many prior behavioral observations," says Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and coauthor of a study in the November 20 issue of Neuron that outlines the team's findings. "We believe this shows that abnormal functioning in the amygdala is a reason that people with autism process faces abnormally." The amygdala has long been known to be important for the processing of emotional reactions. To make recordings from this part of the brain, Adolphs and lead author Ueli Rutishauser, assistant professor in the departments of neurosurgery and neurology at Cedars-Sinai Medical Center and visiting associate in biology at Caltech, teamed up with Adam Mamelak, professor of neurosurgery and director of functional neurosurgery at Cedars-Sinai, and neurosurgeon Ian Ross at Huntington Memorial Hospital in Pasadena, California, to recruit patients with epilepsy who had electrodes implanted in their medial temporal lobes—the area of the brain where the amygdala is located—to help identify the origin of their seizures. Epileptic seizures are caused by a burst of abnormal electric activity in the brain, which the electrodes are designed to detect. It turns out that epilepsy and ASD sometimes go together, and so the researchers were able to identify two of the epilepsy patients who also had a diagnosis of ASD. By using the implanted electrodes to record the firings of individual neurons, the researchers were able to observe activity as participants looked at images of different facial regions, and then correlate the neuronal responses with the pictures. In the control group of epilepsy patients without autism, the neurons responded most strongly to the eye region of the face, whereas in the two ASD patients, the neurons responded most strongly to the mouth region. Moreover, the effect was present in only a specific subset of the neurons. In contrast, a different set of neurons showed the same response in both groups when whole faces were shown. "It was surprising to find such clear abnormalities at the level of single cells," explains Rutishauser. "We, like many others, had thought that the neurological abnormalities that contribute to autism were spread throughout the brain, and that it would be difficult to find highly specific correlates. Not only did we find highly specific abnormalities in single-cell responses, but only a certain subset of cells responded that way, while another set showed typical responses to faces. This specificity of these cell populations was surprising and is, in a way, very good news, because it suggests the existence of specific mechanisms for autism that we can potentially trace back to their genetic and environmental causes, and that one could imagine manipulating for targeted treatment." "We can now ask how these cells change their responses with treatments, how they correspond to similar cell populations in animal models of autism, and what genes this particular population of cells expresses," adds Adolphs. To validate their results, the researchers hope to identify and test additional subjects, which is a challenge because it is very hard to find people with autism who also have epilepsy and who have been implanted with electrodes in the amygdala for single-cell recordings, says Adolphs. "At the same time, we should think about how to change the responses of these neurons, and see if those modifications correlate with behavioral changes," he says MHC Continuing Education ### Funding for the research outlined in the Neuron paper, titled "Single-neuron correlates of abnormal face processing in autism," was provided by the Simons Foundation, the Gordon and Betty Moore Foundation, the Cedars-Sinai Medical Center, Autism Speaks, and the National Institute of Mental Health. Additional coauthors were Caltech postdoctoral scholar Oana Tudusciuc and graduate student Shuo Wang.

Researchers identify dozens of new de novo genetic mutations in schizophrenia

Many newly discovered genes most active during fetal development New York, NY (October 3, 2012) — Columbia University Medical Center (CUMC) researchers have identified dozens of new spontaneous genetic mutations that play a significant role in the development of schizophrenia, adding to the growing list of genetic variants that can contribute to the disease. The study, the largest and most comprehensive of its kind, was published today in the online edition of the journal Nature Genetics. Although schizophrenia typically onsets during adolescence and early adulthood, many of the mutations were found to affect genes with higher expression during early-to-mid fetal development. Together, the findings show that both the function of the mutated gene and when the gene is expressed are critically important in determining the risk for schizophrenia. The findings inform epidemiologic studies showing that environmental factors, such as malnutrition or infections during pregnancy, can contribute to the development of schizophrenia. "Our findings provide a mechanism that could explain how prenatal environmental insults during the first and second trimester of pregnancy increase one's risk for schizophrenia," said study leader Maria Karayiorgou, MD, professor of psychiatry at CUMC, and acting chief, division of Psychiatric and Medical Genetics, New York State Psychiatric Institute. "Patients with these mutations were much more likely to have had behavioral abnormalities, such as phobias and anxiety in childhood, as well as worse disease outcome." In an earlier study of 53 families, the team of investigators found that spontaneous, or de novo, mutations — genetic errors that are present in patients but not in their parents — play a role in a substantial portion of sporadic cases of schizophrenia. The mutations were found in the part of the genome that codes for proteins, known as the exome. In the larger, current study, the researchers performed whole-exome sequencing on 231 patient "trios" from the United States and South Africa. Each trio consisted of a patient and both of his or her parents, who were unaffected by the disease. By comparing the exomes of the patients with those of their parents, the researchers were able to identify de novo rather than heritable, mutations that may contribute to schizophrenia. This is the first study of this scale to search for single nucleotide variations in the exomes of schizophrenia patients. Previous studies from the Columbia group and others searched for much larger genetic variations, such as gene deletions or duplications. The researchers identified many mutated genes with diverse functions. They also identified four new genes (LAMA2, DPYD, TRRAP, and VPS39) affected by recurrent de novo events within or across the two populations, a finding unlikely to have occurred by chance. The researchers estimate that several hundred loci (genetic locations) can contribute to the development of schizophrenia. "The chance that two patients have exactly the same mutation or combination of mutations is rather small" said Dr. Karayiorgou. "What is intriguing is that despite this variability, people with schizophrenia tend to have, more or less, the same phenotype—that is, the same clinical presentation. Our hypothesis is that many neural circuits are extremely important in schizophrenia and that these circuits are vulnerable to a number of influences. So, when any of the genes involved in these circuits are mutated, the end result is the same." According to the researchers, the challenge remains to identify the affected biological processes and neural circuits, and to determine how they are affected. "Although the genetics of schizophrenia are extremely complex, a coherent picture of the disease is beginning to emerge," said co-director of the study Dr. Joseph Gogos, MD, PhD, and associate professor of physiology and neuroscience at Columbia University Medical Center. "Our studies show that dozens, and perhaps hundreds, of different spontaneous mutations can raise one's risk for schizophrenia. On the surface, this is daunting, but using these new findings to understand how these mutations affect the same neural circuits, including during early fetal development, raises hopes that it may be possible to develop effective prevention and treatment strategies for the disease." Social Worker CEUs The paper is titled, "De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia." The other contributors are Bin Xu (CUMC), Iuliana Ionita-Laza (CUMC), J. Louw Roos (University of Pretoria, Pretoria, South Africa), Braden Boone (Hudson Alpha Institute for Biotechnology, Huntsville, Ala.), Scarlet Woodrick (CUMC), Yan Sun (CUMC) and Shawn Levy (Hudson Alpha Institute for Biotechnology). The research was partially supported by National Institute of Mental Health grants MH061399 and MH077235 and the Lieber Center for Schizophrenia Research at Columbia University. The authors declare no financial conflict of interest. About Schizophrenia Contrary to popular belief, schizophrenia is not a split personality; it is a chronic, severe, and disabling brain disorder that affects just over one percent of the adult population and is characterized by loss of contact with reality (psychosis), hallucinations (usually, hearing voices), firmly held false beliefs (delusions), abnormal thinking, a restricted range of emotions (flattened affect) or inappropriate and disorganized behavior, social withdrawal, and diminished motivation. The disease often strikes in the early adult years, and although many individuals experience some recovery, many others experience substantial and lifelong disability. People with schizophrenia often have problems functioning in society and in relationships and are over-represented on disability rolls and among the homeless and imprisoned. The precise causes of schizophrenia are not known, but current research suggests a combination of hereditary and environmental factors. Fundamentally, however, it is a biologic problem (involving changes in the brain), not one caused by poor parenting or a mentally unhealthy environment. Since the causes of schizophrenia are not clear, treatments focus on eliminating disease symptoms. Treatments include antipsychotic medications and various psychosocial treatments. ### Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in 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. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest in the United States. www.cumc.columbia.edu Columbia Psychiatry is ranked among the best departments and psychiatric research facilities in the Nation and has contributed greatly to the understanding of and current treatment for psychiatric disorders. Located at the New York State Psychiatric Institute on the NewYork-Presbyterian Hospital/Columbia University Medical Center campus in the Washington Heights community of Upper Manhattan, the department enjoys a rich and productive collaborative relationship with physicians in various disciplines at Columbia University's College of Physicians and Surgeons. Columbia Psychiatry is home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders, and childhood psychiatric disorders. http://columbiapsychiatry.org/

Genetic Switch Involved in Depression

The activity of a single gene sets in motion some of the brain changes seen in depression, according to a new study. The finding suggests a promising target for potential therapies. People with major depressive disorder, or major depression, have feelings of sadness, loss, anger or frustration that interfere with daily life for weeks or longer. The symptoms of depression also include memory loss and trouble thinking. Past studies have found that people with major depression have brains that are physically different from those of non-depressed people. The depressed brain has a smaller prefrontal cortex, a region at the front of the brain that handles emotion and complicated thought. The area also has fewer and smaller neurons (nerve cells) in the depressed brain. To gain insight into the neural mechanisms at work, a group led by Dr. Ronald Duman of Yale University began with data collected in a previous study. They had done a comparison of postmortem brains from 15 depressed people and 15 non-depressed people who were matched in age, ethnicity and gender. Using DNA microarray chips to analyze the activity of 20,000 genes, the researchers had found numerous genes that were expressed (turned on and off) differently in the brains of depressed people. For the new study, the team focused specifically on genes related to synapses, the place where signals pass from one neuron to another. The work was funded in part by NIH’s National Institute of Mental Health (NIMH) and National Center for Research Resources (NCRR). The findings were published in the September 2012 issue of Nature Medicine. Analysis revealed that about 30% of the genes with significantly lower expression in the depressed brains related to some aspect of synapse function. Further experiments found significantly reduced expression for 5 particular genes in the prefrontal cortex of depressed people. The scientists searched for transcription factors—proteins that bind to the DNA of other genes to turn them on or off—that were capable of regulating the 5 genes. They found one called GATA1 that is expressed significantly more in the brains of people with major depressive disorder. Expression of the Gata1 gene in the prefrontal cortex was also higher in a rat model of depression. Raising expression of Gata1 in cultured rat neurons decreased the expression of synapse-related genes. It also decreased the number of connections between neurons, supporting the idea that higher Gata1 expression can lead to the changes seen in depressed brains. The researchers next tested the gene in rats and found that putting extra copies of Gata1 into their brains made them behave as if they were depressed MHC Ceus “We show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated,” Duman explains. These findings may point toward a new target for treatment. “We hope that by enhancing synaptic connections, either with novel medications or behavioral interventions, we can develop more effective antidepressant therapies,” says Duman. — by Helen Fields Related Links: Depression: http://www.nimh.nih.gov/health/topics/depression/index.shtml More Young Neurons Equals Better Brain Function: http://www.nih.gov/researchmatters/april2011/ 04112011brainfunction.htm Brain Basics: Know Your Brain: http://www.ninds.nih.gov/disorders/brain_basics/know_your_brain.htm Reference: Nat Med. 2012 Aug 12. [Epub ahead of print] PMID: 22885997.