It is our goal to understand the activity patterns that alter synaptic strength in the intact brain. Because alterations of synaptic strength are fundamental to learning and memory, understanding these changes in synaptic strength is fundamental to understanding diseases which destroy the fundamental cognitive abilities of learning and memory (e.g., Alzheimer's disease and traumatically-induced memory loss). It is also important to understand synaptic modification because, when taken too far, the same events that lead to synaptic modification also lead to cell death (e.g. calcium influx). Finally, it is our hope that the development of neural transplantation techniques can benefit from an understanding of how the brain normally controls its connectivity so that a rational therapy of transplantation may be invented that makes use of the normal mechanisms of synaptic modification to incorporate transplanted tissue into an injured cortex. Just as the whole organism learns and remembers based on associations, so too do microscopic associations occur at neurons. Based on these microscopic associations, synapses are altered to encode the macroscopic associations experienced by the organism. That is, individual neurons, as postsynaptic integrators, ultimately mediate associations between active synapses. We are particularly trying to understand the spatial and temporal definition of associativity at the neuronal level. Based on both experiments and models, it seems likely that such spatial and temporal restrictions can be dynamically regulated. The focus of the proposed studies is the development of biophysical models that quantitatively represent our understanding of associative synaptic modification including the spatial and temporal restrictions that, in essence, define a neuronal association or, more generally, neuronal integration. Yet to be incorporated into these models, but crucial to our understanding of synaptic modification, is long-term depression of synaptic strength. Such processes oppose long-term potentiation and are part of the proposed research. Finally, our biophysical models also require new quantitative anatomical data. All of our animal studies will use the rat hippocampus. Because we are interested in applying our own and others' results to the intact animal, many of the physiology experiments will use extracellular recording in acute anesthetized animals. Other experiments will use dissected hippocampal tissue slices and both extracellular and intracellular neurophysiological methods. We will also quantify the anatomy of normal neurons from the intact animal and the anatomy of intracellularly labeled and physiologically characterized neurons from tissue slice experiments. Our biophysical models are computer simulations that use such quantitative anatomical and physiological data in order to predict the experimental data from associative modification experiments. If successful in these predictions, a relatively simple, consistent biophysical model is the true expression and test of our understanding of neuronal integration as it affects associative synaptic modification.
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