Long-term memory formation

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NYU scientists find that growth factors that build brains also build memories New York University "A team of New York University neuroscientists has determined how a pair of growth factor molecules contributes to long-term memory formation, a finding that appears in the journal Neuron. "These results give us a better understanding of memory's architecture and, specifically, how molecules act as a network in creating long-term memories," explains the paper's senior author, Thomas Carew, a professor in NYU's Center for Neural Science and dean of NYU's Faculty of Arts and Science. "More importantly, this marks another step toward elucidating the intricacies of memory function, which is vital in the development of cognitive therapies to address related afflictions." The importance of growth factor molecules (GFs) has long been known. They are critical in building brains beginning in utero and until adulthood. Moreover, over time, it's been established that GFs are "recycled" from brain builders to engineers of long-term memories. Less clear, however, is how the wide range of GF families, as well as different members within each family, act to help us create these memories. In working to address this question, the NYU research team, which also included graduate student Ashley Kopec, the study's lead author, and research scientist Gary Philips, focused on two GF families: TrkB and TGFβr-II, which represent two distinct classes of GFs that utilize different types of receptors to exert their actions in the brain. In their study, the researchers examined GFs in Aplysia californica, the California sea slug. Aplysia is a model organism that is quite powerful for this type of research because its neurons are 10 to 50 times larger than those of higher organisms, such as vertebrates, and it possesses a relatively small network of neurons--characteristics that readily allow for the examination of molecular signaling during memory formation. Specifically, to produce a form of "threat memory" called sensitization in a simple reflex system of Aplysia, the researchers presented the sea slugs with a pair of mild tail shocks delivered 45 minutes apart--the first to instill a "molecular context" in the neurons of the reflex and the second to use that context to drive molecular mechanisms that are required to form a long-term memory -- and then examined GF activity at both periods, Time 1 and Time 2. Their results showed differences in the role of these two GF families across two dimensions: time and space. At Time 1, when the context for the memory is first created, TrkB plays a critical role while TGFβr-II is irrelevant. However, at Time 2, when a long-term memory is actually formed, the roles are reversed: TGFβr-II is active, but TrkB is insignificant. In addition, the results showed spatial differences. In Aplysia, the simple neural circuit that mediates the reflex modified by learning is made up of unique sensory neurons and motor neurons. The sensory neurons' cell bodies live in one compartment of the brain while their companion synapses, which pass along signals to other cells, reside in another. In the Neuron study, the researchers found that the TrkB effects are exerted only at synapses while TGFβr-II functions only at the cell body. Overall the study provides new insights into how different GF families play unique roles both in time and in space, thus helping to elucidate the "when," "where," and "how" of memory formation." ### The research was supported by grants from the National Institute of Mental Health (RO1 MH 041083, F31 MH 100889). For more information on memory, please visit Aging and Long Term Care CE Course

Johns Hopkins research may improve early detection of dementia

Using scores obtained from cognitive tests, Johns Hopkins researchers think they have developed a model that could help determine whether memory loss in older adults is benign or a stop on the way to Alzheimer's disease. The risk of developing dementia increases markedly when a person is diagnosed with mild cognitive impairment, a noticeable and measurable decline in intellectual abilities that does not seriously interfere with daily life. But physicians have no reliable way to predict which people with mild cognitive impairment are likely to be in the 5 to 10 percent a year who progress to dementia. In a proof-of-concept study, the Johns Hopkins investigators analyzed records of 528 people age 60 and over, who were referred to the Johns Hopkins Medical Psychology Clinic for cognitive testing as part of a dementia work-up between 1996 and 2004. The results were compared to those of 135 healthy older adults who participated in a study of normal aging. Both groups completed tests of memory, language, attention, processing speed and drawing abilities from which 13 scores were recorded Nursing CEUs Since each person is naturally more skillful in some areas than in others, the scores of healthy adults showed a symmetrical, bell-shaped range: Most of their scores were high, a few were a bit lower, and a few were even lower. By grouping the patients into cohorts based on the severity of their dementia, the researchers found a trend in the test scores that is likely to mimic the deterioration of an individual's scores over time. At the outset, he says, Alzheimer's disease subtly disrupts some mental abilities, while leaving others intact. Thus, well before a person develops clear cognitive impairment, his or her performance declines slightly on a few measures. When shown on a graph, these changes cause the healthy symmetric, bell-shaped curve to shift and become asymmetrical. Regardless of how low a person's test scores were, the researchers determined that lopsidedness in their score distribution correlated with dementia. They predicted that people with low scores that were evenly distributed were not likely to develop dementia. But those with clearly lopsided test score distributions on the 13 measures administered were already experiencing varying levels of dementia. "Departures from the normal bell-shaped pattern of variability on cognitive tests might determine which people with low scores develop dementia," says David J. Schretlen, Ph.D., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and leader of a study published online Nov. 12 in the journal Neuropsychology. Since these declines can be subtle, the researchers also increased the precision of cognitive testing by accounting for the effects of age, sex, race and education on test performance. The challenge for doctors, Schretlen explains, is that most normal, healthy people will produce a few low scores on cognitive testing. That makes it nearly impossible to know at the outset whether a patient who reports forgetfulness and produces one or two low scores has a benign form of mild cognitive impairment, or is in the earliest stage of dementia. As a result, doctors often tell such patients to return for follow-up testing in a year or two. But if future research confirms it, this new statistical model could help doctors get the prognosis right earlier in the disease, at the first visit, and start treating patients accordingly. Mostly, Schretlen says, doctors could use the new model to reassure patients who are not at risk of dementia, while fast-tracking interventions for those who are. Because there currently are no effective treatments for Alzheimer's disease, those likely headed that way could be counseled to take the good time they have to organize their affairs, and do things they have always wanted to do. They also could be fast-tracked into clinical trials of medications to slow the progression of dementia. "If we are going to have any hope of helping patients with Alzheimer's disease, we need to do it as early as possible," Schretlen says. "Once the brain deteriorates, there's no coming back." Recent failures of drugs in late-stage clinical trials for Alzheimer's disease have been a real blow, he adds, but new treatments are being developed. The new way of reading existing test scores follows a 2008 study by the same researchers showing that one of every six healthy adults scored poorly on two or more of 10 tests in a brief cognitive battery — even though there was nothing wrong with them. The main reason it is difficult to tell whether older people have benign mild cognitive impairment or not is because they are not routinely screened for cognitive impairment, he says. A visit to a specialist comes only after someone has noticed symptoms, and then cognitive testing is interpreted without the benefit of a baseline assessment. What would solve this problem, he says, would be for everyone over the age of 55 to get routine neurocognitive testing every five years. ### The study was supported by the Therapeutic Cognitive Neuroscience Fund; the Benjamin and Adith Miller Family Endowment on Aging, Alzheimer's and Autism; the William and Mary Ann Wockenfuss Research Fund Endowment; and the National Institutes of Health's National Institute of Mental Health (MH60504). Under an agreement with Psychological Assessment Resources, Inc., Schretlen is entitled to a share of royalties on sales of a test and software used in the study. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies. Other Johns Hopkins researchers involved in the study include Gila Z. Reckess, Ph.D.; Mark Varvaris, B.A.; and Barry Gordon, M.D., Ph.D. For more information about Schretlen, click here. Johns Hopkins Medicine (JHM), headquartered in Baltimore, Maryland, is a $6.7 billion integrated global health enterprise and one of the leading health care systems in the United States. JHM unites physicians and scientists of the Johns Hopkins University School of Medicine with the organizations, health professionals and facilities of The Johns Hopkins Hospital and Health System. JHM's vision, "Together, we will deliver the promise of medicine," is supported by its mission to improve the health of the community and the world by setting the standard of excellence in medical education, research and clinical care. Diverse and inclusive, JHM educates medical students, scientists, health care professionals and the public; conducts biomedical research; and provides patient-centered medicine to prevent, diagnose and treat human illness. JHM operates six academic and community hospitals, four suburban health care and surgery centers, and more than 30 primary health care outpatient sites. The Johns Hopkins Hospital, opened in 1889, was ranked number one in the nation for 21 years in a row by U.S. News & World Report. For more information about Johns Hopkins Medicine, its research, education and clinical programs, and for the latest health, science and research news, visit http://www.hopkinsmedicine.org Aging and Long Term Care CE Course Johns Hopkins Medicine Media Relations and Public Affairs