We are analyzing the neurobiology of associative learning in the mammalian brain at cellular and systems levels using both in vivo and in vitro techniques. Eyeblink conditioning is used as a model Pavlovian behavioral paradigm, as it offers excellent stimulus control, ease of precise behavioral measurement, and robust associative learning. Our program focuses on characterizing the ways in which neurons store new information during associative learning at the cellular and subcellular levels.

Experiments focus on the hippocampus, a paleocortical region involved in transferring information during learning from the short- to long-term memory store. Single neuron recording in the conscious rabbit is used to localize and functionally characterize the cell types involved in laying down the "memory trace" in the hippocampus. In parallel experiments, we make biophysical measurements from hippocampal brain slices taken from eyeblink-trained animals to define what ionic mechanisms underlie the changes in neuronal excitability recorded in the intact animal. We have observed conditioning-specific alterations in postsynaptic intrinsic currents likely to enhance cellular excitability and are performing current and whole-cell patch clamp recordings to characterize them and their relation to acquisition and consolidation of the eyeblink-conditioned response.

An important focus of our research is on cellular mechanisms for altered learning in aging. We are using a combination of behavioral and biophysical approaches to address this question. We have evaluated several pharmacological agents designed to compensate for cellular changes that we have identified in the aging brain. These behavioral pharmacological experiments arecombined with neurophysiological and biophysical analyses to explore the cellular mechanisms by which the drugs may be operating to enhance learning rate in aging animals.

Other ongoing and developing experimental lines include functional magnetic resonance imaging in rabbits and humans; eyeblink conditioning combined with other cognitive evaluations in young, aging, and neurologically impaired humans; development of eyeblink conditioning and other behavioral tasks in the mouse so that we may examine aged, transgenic, and knockout strains of mice behaviorally, biophysically, and with pharmacological agents.