Studies of synaptic plasticity in cerebral cortex and hippocampus
We seek to understand how synapses in the cerebral cortex are modified by experience. Key insight into this process has been gained over the past 40 years by recording the activity of cortical neurons in vivo. These studies show that a cardinal feature of cortical neurons is stimulus-selective receptive fields. For example, neurons in primary visual cortex show selectivity to particular stimulus attributes, such as which eye is stimulated, or the orientation of a contrast border; neurons in the CA1 region of hippocampus show selectivity for positions in space; and so on. Selectivity in many cortical areas can be modified by experience - in fact, experience-dependent shifts in selectivity are the most common correlate of memory formation. Lasting shifts in selectivity are believed to reflect synaptic changes that, distributed over a population of cells, are the neural basis of memory storage. Thus, we frame the question as follows: How do cortical synapses adjust their effectiveness to modify neuronal selectivity and store information?
By combining theoretical analysis with a reductionist experimental approach, we have uncovered properties of synaptic modification that can, in principle, account for observed experience-dependent changes in cellular responses. We established that synapses throughout the cerebral cortex are bidirectionally modifiable, and that the sign or polarity of the modification depends on the type of NMDA receptor (NMDAR) activation at the time of induction. We also showed that the conditions required to induce long-term synaptic potentiation (LTP) or depression (LTD) vary depending on the history of cellular or synaptic activity, a property now called metaplasticity. The major questions that confront us now are the molecular mechanisms of bidirectional synaptic plasticity and metaplasticity, and, of particular importance, the contributions of these mechanisms to naturally occurring synaptic modifications in the brain. We are employing a wide range of techniques - biochemical, anatomical, electrophysiological, and behavioral -to address these key questions in the hippocampus and visual cortex. The lab has made a key discovery on how synapses are weakened, and this promises to shed light on disorders ranging from mental retardation and autism to Alzheimer's disease.
Mark F. Bear received his Ph.D. in neurobiology from Brown University. He took postdoctoral training from Wolf Singer at the Max Planck Institute for Brain Research in Frankfurt, Germany, and from Leon Cooper at Brown. He joined the faculty of the Brown University School of Medicine in 1985 and was named a Howard Hughes Medical Investigator in 1996. At Brown, he was awarded the 2000 Elizabeth H. Leduc Award for teaching excellence in the life sciences, and the Class of 2000 Barrett Hazeltine Citation for teaching excellence. In 2003, he was appointed Picower Professor of Neuroscience at The Picower Institute for Learning and Memory in the Department of Brain and Cognitive Sciences at MIT.
Osterweil, E.K., Chuang, S-C., Chubykin, A.A., Sidorov, M., Bianchi, R., Wong, R.K.S., and Bear, M.F. 2013. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 77(2): 243-250.
Osterweil, E.K., Krueger, D.D., Reinhold, K. and Bear, M.F. 2010. Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J. Neurosci. 30 (46): 15616-15627.
Krueger, D.D. and Bear, M.F. 2010. Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annual Review of Medicine 62:4111-429.
Cooke, S.F. and Bear, M.F. 2010. Visual experience induces long-term potentition (LTP) in the primary visual cortex. J. Neurosci. 30(48): 16304-16313.
Krueger, D.D., Osterweil, E.K., Chen, SP, Tye, LD, and Bear, M.F. 2011. Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome. PNAS USA 108(6): 2587-2592.
Auerbach, B.D., Osterweil, E.K. and Bear, M.F. 2011. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480(7375): 63-68.
Bhakar, A.L., Dölen, G., and Bear, M.F. 2012. The pathophysiology of fragile X (and what it teaches us about synapse). Annual Review of Neuroscience (epub ahead of print 5 April 2012).
Alfred P. Sloan Award
United States Office of Naval Research Young Investigator Award
Society for Neuroscience Young Investigator Award
Brown University Class of 2000 Barrett Hazeltine Citation for Teaching Excellence
William and Enid Rosen Award for Outstanding Contributions to Understanding Fragile X Syndrome, National Fragile X Foundation
Pioneer Award, FRAXA Research Foundation
Award for Outstanding Contributions to the Study of Metabotropic Glutamate Receptors, 7th International mGluR Meeting, Taormina, Italy
Ray Fuller Award, American Society for Pharmacology and Experimental Therapeutics