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 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.


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