In Miller Lab Publications, Publications Posted
Siegel M., Buschman T.J., Miller E.K. (2015) Science 348(6241):1352-5
(Thursday) 4:00 pm - 5:00 pm
43 Vassar ST Room 46-3002, Cambridge, MA 02139
In the last 20 years, there have been significant advances in the molecular, cellular, and systems mechanisms underlying the storage of single memories. Real-world memory, however, involves the integration of multiple memories across time, with one memory affecting how others are processed and stored. Recently, memory allocation studies in our lab indicated that one memory can trigger an increase in excitability that then affect the allocation and strength of a subsequent memory, thus possibly linking the two memories across time. Using a number of techniques including in vivo calcium imaging (with head-mounted fluorescent microscopes in freely behaving mice), the TetTag transgenic system, optogenetics, electrophysiology, 2-photon microscopy and novel behavioral designs, we tested key predictions of the memory allocation hypothesis in hippocampal networks. Our results demonstrate that learning-dependent changes in neuronal excitability can serve to link memories across time.
Alcino J. Silva pioneered the field of Molecular and Cellular Cognition, and in 2002 founded and became the first President of the Molecular and Cellular Cognition Society. In 2006/2007 Dr. Silva served as Scientific Director of the Intramural Program of the National Institute of Mental Health. He currently serves as the Director of The UCLA Integrative Center for Learning and Memory and is a Distinguished Professor in the Departments of Neurobiology, Psychiatry & Biobehavioral Sciences and Psychology at UCLA. His laboratory is searching for the molecular, cellular and circuit processes that underlie the allocation, encoding, and storage of information in the brain. Insights into mechanisms of memory are being used to unravel the causes and develop treatments for cognitive deficits associated with aging, intellectual disabilities, and autism. Key discoveries in his laboratory include some of the first mechanisms of mammalian synaptic plasticity involved in learning and memory (e.g., the role of synaptic calmodulin kinase II and the transcription factor CREB), the first molecular and cellular mechanisms of remote memory in neocortical circuits, first description of memory allocation processes in the brain, first report that adult treatments may revert cognitive deficits associated with neurodevelopmental disorders, development of treatments in mice for Neurofibromatosis type I, Tuberous Sclerosis and Noonan Syndrome, two of which were followed up with large scale clinical trials, and the discovery of a set of algorithms to track causal information in biology.
The Picower Institute for Learning and Memory
(Tuesday) 8:00 am - 7:00 pm
43 Vassar ST Room 46-3002, Cambridge, MA 02139
Activity-dependent modification of synaptic transmission is a fundamental mechanism for the central nervous system to encode and store information. In [...]
Activity-dependent modification of synaptic transmission is a fundamental mechanism for the central nervous system to encode and store information. In recent years, great advances have been made in identifying key players and understanding their functional contribution to mediating and regulating synaptic transmission and plasticity. Many of the genes, including neurotransmitter receptors, signaling scaffold proteins, and cell adhesion proteins have been found to be associated with brain disorders, including stroke, schizophrenia, mental retardation and autism spectrum disorders etc. In this symposium, we aim to discuss the recent advances in understanding the underlying mechanisms of synaptic transmission and synaptic plasticity for learning and memory, and the pathophysiology of synapses in brain disorders, to help to understand synapse principles important for learning and memory, and identify pathomechanisms in different disorders.
|8:00 – 8:30 AM||Breakfast|
|8:30 – 8:35 AM||Opening Remarks|
|8:35 – 9:20 AM||Richard Huganir|
|9:20 – 10:00 AM||Gina Turrigiano|
|10:00 – 10:40 AM||Richard Morris|
|10:40 – 11:00 AM||Break|
|11:00 – 11:40 AM||Bernado Sabatini|
|11:40 AM – 12:20 PM||Roger Nicoll|
|12:20 – 1:30 PM||Lunch|
|1:30 – 2:10 PM||Mary Kennedy|
|2:10 – 2:50 PM||Hollis Cline|
|2:50 – 3:30 PM||Troy Littleton|
|2:50 – 3:30 PM||Break|
|3:50 – 4:55 PM||Thomas Südhof|
|4:55 – 5:00 PM||Closing Remark|
|5:00 – 6:00 PM||Reception|
Dr. Richard Huganir is a professor of neuroscience, biological chemistry and pharmacology and molecular science at the Johns Hopkins University School of Medicine. Dr. Huganir’s research focuses on molecular mechanisms that modulate the communication between neurons in the brain. He serves as the director of the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine.
Dr. Huganir and his team focus their efforts on researching the mechanisms that underlie the regulation of the glutamate receptors, the major excitatory neurotransmitter receptors in the brain. These receptors are neurotransmitter-dependent ion channels that allow ions to pass through the neuronal cell membrane, resulting in the excitation of neuronal activity.
He received his undergraduate degree in biochemistry from Vassar College and earned his Ph.D. in biochemistry, molecular and cell biology from Cornell University. He was a postdoctoral fellow with the Nobel Laureate, Dr. Paul Greengard, at Yale University School of Medicine. Dr. Huganir joined the Johns Hopkins faculty in 1988. Dr. Huganir received the Young Investigator Award from the Society for Neuroscience and the Santiago Grisolia Award, among others. He is a member of the American Academy of Arts and Sciences and the National Academy of Sciences and a fellow of the American Association for the Advancement of Science.
Gina Turrigiano is a full professor in the Dept. of Biology, the Volen Center for Complex Systems, and the Center for Behavioral Genomics at Brandeis.She has received numerous awards for her research including a Sloan Foundation fellowship, a MacArthur foundation “genius” award, McKnight Foundation Technological Innovation and Neurobiology of Disease awards, an NIH director’s pioneer award, and the HFSP Nakasone Award. she is a fellow of the American Academy of Arts and Sciences and a member of the National Academy of Sciences. Her scientific interests include mechanisms of synaptic and intrinsic plasticity and the experience-dependent rewiring of neocortical microcircuitry.
Gina Turrigiano studies mechanisms of homeostatic synaptic plasticity and the role of these stabilizing mechanisms in the development and function of the cortex. Her work has been instrumental in demonstrating the existing of “self-tuning” mechanisms that allow neurons and circuits to adjust their excitability to prevent states of hyper- or hypoexcitability that underlie brain disorders such as epilepsy and autism spectrum disorders.
Richard Morris is Professor of Neuroscience at the University of Edinburgh and an Adjunct Professor of the Norwegian Technical University in Trondheim (NTNU). He graduated in Natural Sciences at the University of Cambridge in 1969 and completed a D.Phil at the University of Sussex.
His principal research interest is the neurobiology of learning and memory. In 1986, he made the key observation that activation of NMDA receptors in the hippocampus is critical for memory encoding. Other contributions include the development of the open-field ‘watermaze’, now used worldwide, joint development (with Julie Frey) of the ‘synaptic tagging and capture’ hypothesis and, more recently, new paradigms to study paired-associate recall in animals and gene-activation associated with the encoding and assimilation of new information into mental schemas.
He was elected to Fellowship of the Royal Society in 1997. He is also a Fellow of a number of other institutions, including the American Academy of Arts and Sciences. He has won several awards, notably the Zotterman Medal of the Swedish Physiological Society in Stockholm (1999), the Feldberg Prize (2006) and the Fondation Ipsen Neuronal Plasticity Prize (2013), and has served as President of the Federation of European Neuroscience Societies (2006-2008). He was awarded a CBE in 2007.
In the first few years of life, humans tremendously expand their behavior repertoire and gain the ability to engage in complex, learned, and reward-driven actions. Similarly, in the few weeks after birth, mice gain the ability to perform sophisticated spatial navigation, forage independently for food, and to engage in reward reinforcement learning. Our laboratory seeks to uncover the mechanisms of synapse and circuit plasticity that permit new behaviors to be learned and refined. We are interested both in the developmental changes that occur after birth that make learning possible as well in the circuit changes that are triggered by the process of learning. We examine these processes in the cerebral cortex, the hippocampus, and the basal ganglia, crucial structures for the processing of sensory information, for associative learning and spatial navigation, and for goal-direct locomotion. In order to accomplish these studies, we rely heavily on optical approaches to examine and manipulate synapses and circuits in relatively intact brain tissue and we design and build microscopes as necessary for our research. Studies are typically performed in brain slices or awake-behaving mice and utilize a variety of genetic, biochemical, and electrophysiological approaches. Lastly, we use these same approaches and the knowledge gained from the study of normal circuit development to uncover perturbations of cell and synapse function that may contribute to human neuro-psychiatric disorders, including autism, Parkinson’s disease, and Alzheimer’s disease.
My lab is interested in elucidating the cellular and molecular mechanisms underlying learning and memory in the mammalian brain. Long-term potentiation (LTP), a phenomenon in which brief repetitive activity causes a long lasting (many weeks) enhancement in the strength of synaptic transmission, is generally accepted to be a key cellular substrate for learning and memory. My lab uses a combination of electrophysiological and molecular techniques to elucidate the molecular basis of LTP. We have found that LTP involves the rapid activity-dependent trafficking of glutamate receptors to the synapse. This trafficking requires the interaction of two families of synaptic proteins. One family is a novel group of proteins that, we discovered which bind to glutamate receptors and act as auxiliary subunits. These proteins are not only essential for the trafficking of the glutamate receptors, but also control the gating of the receptor channel. The other family is comprised of a family of scaffolding proteins that bind to the auxiliary subunits and thereby anchor the receptors at the synapse. Much of the current work in the lab is focused on how activity controls this receptor trafficking and how the increase in synaptic strength during LTP is stabilized and maintained.
Dr. Mary Kennedy is the Allen and Lenabelle Davis Professor of Biology in the Division of Biology and Biological Engineering at Caltech. Her lab studies the molecular organization of signal transduction systems in synapses of the central nervous system. Employing a combination of biochemical, cell biological, and recombinant DNA techniques, they have discovered the structures and functional roles of proteins in the postsynaptic density, a highly organized scaffold of signaling proteins that controls synaptic plasticity. Mutations in many of these proteins confer risk for mental and cognitive disorders. Her lab is beginning to use methods associated with Systems Biology to understand how postsynaptic signaling proteins function together to regulate synaptic strength and influence the formation and reorganization of neuronal circuits. Professor Kennedy was elected to the American Academy of Arts and Sciences in 2002, is presently Vice-Chair of the Faculty at Caltech, has been a councilor of the Society for Neuroscience, and was awarded the Fondation Ipsen Neural Plasticity Prize in 2006, recognizing her work on the roles of protein complexes in synaptic plasticity.
Hollis Cline, PhD, is the Hahn Professor of Neuroscience in the departments of Molecular and Cellular Neuroscience, and Chemical Physiology at The Scripps Research Institute in La Jolla, CA. She is a Councilor for the National Eye Institute, and has served on the Board of Scientific Councilors for the National Institute of Neurological Disorders and Stroke (NINDS) and on the Blue Ribbon Review Panel for the 10-year review of the National Institute of Child Health and Development (NICHD). Dr. Cline is a Fellow of the American Association for the Advancement of Science and has received the prestigious NIH Director’s Pioneer Award. Dr. Cline is currently President of the Society for Neuroscience. She received her BA from Bryn Mawr College and her PhD from the University of California at Berkeley, followed by postdoctoral training at Yale University and Stanford University.
Dr. Cline’s research has demonstrated the roles of a variety of activity-dependent mechanisms in controlling structural plasticity of neuronal dendrites and axons, synaptic maturation and topographic map formation. This body of work has helped to generate a comprehensive understanding of the role of experience in shaping brain development. Two key points to emerge from her research is that circuit formation in vivo is a dynamic process throughout development that is continuously guided by experience, and that the basic mechanisms governing brain development, plasticity, information processing and organizational principles of brain circuits are highly conserved across vertebrates.
The computational power of the brain depends on synaptic connections that link together billions of neurons. The focus of my laboratory’s work is to understand the mechanisms by which neurons form synaptic connections, how synapses transmit information, and how synapses change during learning and memory. To complement this basic research in neuroscience, we also study how alterations in neuronal signaling underlie several neurological diseases, including epilepsy, autism and Huntington’s Disease. We combine molecular biology, protein biochemistry, electrophysiology, and imaging approaches with Drosophila genetics to address these questions. Moving beyond genomic data to determine how proteins specify the distinctive signaling properties of neurons and enable them to interconnect into computational circuits that dictate behavior are major goals for the next decade of neuroscience research. Despite the dramatic differences in complexity between Drosophila and humans, genomic analysis has confirmed that key neuronal proteins and the functional mechanisms they govern are remarkably similar. As such, we are attempting to elucidate the mechanisms underlying synapse formation, function and plasticity using Drosophila as a model system. By characterizing how neurons integrate synaptic signals and modulate synaptic growth and strength, we hope to bridge the gap between molecular components of the synapse and the physiological responses they mediate.
Thomas Südhof’s laboratory studies how synapses form in the brain, how their properties are specified, and how they accomplish the rapid and precise signaling that forms the basis for all information processing by the brain. Moreover, as increasing evidence links impairments in synaptic transmission to diseases such as Alzheimer’s and autism, Südhof’s interests have include understanding possible molecular mechanisms contributing to these and related disorders.
The projects in the Südhof laboratory are guided by two overall directions that are closely related to each other, and linked to different psychiatric diseases. First, the Südhof laboratory is interested in understanding how synapses are formed. Synapses exhibit a high degree of specificity in terms of which neurons they connect, and an astounding diversity in terms of physiological properties. Here, Südhof’s laboratory is focusing on synaptic cell-adhesion molecules, in particular neurexins and neuroligins that are essential components of synapses. Second, the Südhof laboratory would like to understand how information transfer is triggered at a synapse rapidly and precisely. Work in the laboratory over the last two decades demonstrated that the neurotransmitter signal is released when calcium in the presynaptic neuron binds to a protein called synaptotagmin, which serves as the switch for release. Release then occurs by fusion of neurotransmitter-containing vesicles at the active zone of the presynaptic neuron. The Südhof laboratory now focuses on understanding how this fusion process works, how calcium regulates fusion beyond binding to synaptotagmin, and how fusion becomes impaired in neurodegenerative diseases that appear to involve, at least in part, dysfunction of some of the fusion proteins.
The Picower Institute for Learning and Memory