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The neurobiology of Learning and Memory and the incredible plastic brain When you learn something new, the connections between your brain cell change in dynamic ways. Because new experiences can cause nerve cells, or neurons, and their connections, called synapses, to be molded into a different shape with better properties, we say the brain is plastic, or has plasticity. This plasticity of the brain enables us to learn and form new memories. We use many different techniques to help us study brain plasticity during learning and memory. We use rats and mice to study behavior. We use compound light microscopes to study changes in neurons. We use an electron microscope to study changes in synapses. We use many molecular and biochemical techniques to study proteins, RNA, and other molecules in neurons and synapses. These tools help us study the links between behavior and changes in the brain and how different types of changes in the brain interact with each other. We have discovered several important things in the field of the cellular and molecular basis of learning memory. We have observed that when rats live in a complex environment with many opportunities for new experiences, their neurons form more synapses than neurons of rats who live in simple cages with little opportunity for new experience. Also, rats who have learned how to navigate a complex acrobatic obstacle course have more synapses per neuron compared to rats who engage in simple exercise such as running in a running wheel. Many of our investigations of learning and memory are focused at the molecular level. We have discovered that proteins are manufactured at synapses in response to specific types of synaptic activity. Every day we learn more about how the special proteins and other molecules found at synapses are involved in learning and memory. Each project described in this brochure relates to the molecular and cellular understanding of how the brain accomplishes the complex tasks of information processing and storage we call learning and memory. The neurobiology of Fragile X mental retardation syndrome When the brain lacks the tools to learn, mental retardation develops. People affected with Fragile X Syndrome lack the ability to manufacture one protein. The absence of this protein, called FMRP (Fragile X Mental Retardation Protein), affects their ability to learn. We have discovered that FMRP is made at synapses. Genetic engineering technology allows us to study a mouse model of Fragile X syndrome. We have shown that the mouse model has abnormal neuronal spines which look very much like those of human Fragile X brains. Now we are investigating deeper into the Fragile X mouse brain. We are studying the biochemical processes in which FMRP plays a role. One recent discovery is that FMRP at synapses is required for the manufacture of other proteins that manufacture proteins. This is an important discovery that may one day provide a way to bypass the absence of FMRP. Autopsies of brains from human Fragile X patients show that their neurons look very different from those of unaffected people. A neuron has arm-like projections with many branches. The smallest branches are called spines and they make synapses with other neurons. The spines of neurons in a Fragile X brain have shapes that resemble immature, developing spines instead of the mature spines we see in a normal brain. We are studying how the lack of FMRP might disrupt the normal shape of neurons. Fetal Alcohol Syndrome a possibility for therapeutic intervention Alcohol consumption during pregnancy can lead to serious brain damage in the developing fetus. The most severe form, fetal alcohol syndrome, exhibits distinct physical abnormalities (e.g., very particular facial features), growth and development delay, mental retardation (with a wide spectrum from total withdrawal from reality to slight but significant deficits in learning and memory). For the developing fetal brain the effect of alcohol is disastrous: brain size may decrease by 20-30% (depending on the dose of alcohol that mother (and baby) consumed) because of the resulting death of neurons. A less severe but still debilitating syndrome, alcohol-related neurodevelopmental disorder, exhibits no facial abnormalities but involves loss of neurons, growth retardation, mild to severe mental retardation, and psychosocial dysfunction. We are studying rehabilitative intervention in this disorder, using an animal model. It is well known that all neurons in most areas of the nervous system are born early in development and can never be replaced once they die, unlike other cells in the body. What can be done, using our knowledge of brain plasticity, is to try to modify the remaining neurons (the survivors) so that they compensate, at least to some extent, for the loss of some of their neighbors. In our animal model of drinking during the third trimester of pregnancy, rats that receive alcohol are initially very clumsy on the complex acrobatic obstacle course that we use as a rehabilitative procedure, including parallel bars and a rope ladder. After a period of such training their performance improves so dramatically that they are no longer different from normal rats. We have discovered that this improvement in performance involves plastic changes in brain cells, in which they add extra synaptic connections. Investigators at other institutions have begun human intervention trials, based in part on our work. The neurobiology of Major Depression a brain disorder Depression is a common psychiatric illness that is frequently debilitating and often life-threatening. It is the number one cause of disability and death worldwide. Medical research has indicated that humans become vulnerable to depression through a complex interaction of genetics, early experience, and the present environment. We are studying how different kinds of experience can affect the emergence of depressive and anxious behaviors in rodents. We are also looking for brain changes that are associated with animal models of depression and how these changes can be influenced by experience. The neuroanatomy of Schizophrenia a brain disorder Schizophrenia affects about 1% of the population worldwide, and although sometimes devastating, it is generally treatable. These people often have psychotic symptoms (e.g., hallucinations, delusions), as well as difficulties with concentration and memory. Research suggests that the psychotic symptoms and cognitive deficits may involve anatomical brain changes at the cellular level. In order to learn more about this brain disorder, we are working with colleagues in Russia to compare the microscopic anatomy of brains from schizophrenic and normal people. We will summarize research in the causes of schizophrenia, how it affects the brain and its treatment. Autism a neurodevelopmental disorder Autism is a rare brain disorder that can have a devastating impact on patients and their families. In the severe form of autism, children lose their language ability and social skills, and they often do repetitive, odd behaviors. Research has indicated that genetics and possibly prenatal brain damage may cause these symptoms. Autism was widely believed to be untreatable until the 1990’s, when research showed that early intense therapy could substantially help many autistic children. We are working with some other scientists to study the neuropathology of autistic individuals who generously donated their brains to research. In parallel, we are studying an animal model of autism, using subtle prenatal brain damage and then seeing how that affects behavior and neural plasticity later. Animal Research and Welfare without lab animals, where would we be? There is not a person alive today who has not somehow benefited from the advances in health care that were made possible by medical research using laboratory animals. However, most of us take for granted the availability of antibiotics, drugs for treatment of a wide variety of diseases such as hypertension, high cholesterol, diabetes, AIDS, mental illness, vaccines against diseases that no longer threaten our health, and cancer therapies that have cured or lengthened lives. Today, open-heart surgery, neurosurgery, thoracic surgery, and organ transplantation are routinely done. All of these lifesaving surgical procedures were made possible from knowledge gained from using animal models in scientific research. Yet in spite of this remarkable progress in medical science, there is still much work to be done. There is a long list of diseases for which there is still no prevention, treatment, or cure. These include Alzheimer’s disease, Parkinson’s disease, Fragile X Mental Retardation, cystic fibrosis, muscular dystrophy, cancer, and AIDS. The use of animals as models in scientific research along with non-animal technologies will continue to be essential to our quality of life. Adapted from ”Understanding the Use of Animals in Biomedical Research,” Foundation for Biomedical Research 1992. Contact Information: About projects 1-3: Kathy Bates Beckman Institute University of Illinois at Urbana-Champaign 405 N. Mathews Ave. Urbana, IL 61801 (217) 333-4472 [email protected] http://soma.npa.uiuc.edu/labs/greenough/home.html About projects 4-6: James E. Black, Ph.D., M.D.. Beckman Institute University of Illinois at Urbana-Champaign Psychiatry Department 405 N. Mathews Ave. Urbana, IL 61801 (217) 244-9018 [email protected] Research funding: - FRAXA Research Foundation - Kiwanis Nervous System Research Foundation - McDonnell Foundation - National Institutes of Health (NIH) - National Association for Research on Schizophrenia and Depression (NARSAD) - Cure Autism Now Foundation Your Brain! What’s going on in there? Here is a quick look at some of the brain research going on at the University of Illinois’ Beckman Institute... Research conducted by William T. Greenough, Ph.D. James E. Black, M.D., Ph.D. Ivan Jeanne Weiler, Ph.D. Anna Y. Klintsova, Ph.D. Take a Look