One of the goals of modern neuroscience is to understand the nature and mechanisms underlying complex cognitive phenomena, including learning and memory. This effort is particularly germane to understanding disorders of memory, including Alzheimer's disease. In this regard, considerable effort has been directed at understanding the mechanisms whereby memories are encoded and stored in the brain. We have focused on the analysis of a simple form of associative learning in rats known as Pavlovian fear conditioning. In this type of learning, rats learn to fear a conditional stimulus (CS), such as a tone, that has been paired with an aversive unconditional stimulus (US), such as a foot shock. Fear is expressed by a number of responses, including freezing behavior. Considerable progress has been made in elucidating the neural mechanisms of fear conditioning. For example, it is clear that the amygdala plays an essential role in encoding and storing CS-US associations during conditioning, and the synaptic and cellular mechanisms underlying this process are beginning to be understood. Although the neural mechanisms for CS-US association in fear conditioning are well understood, less is known concerning higher-order memory processes in Pavlovian learning paradigms. For example, memory retrieval is not only related to the strength of the CS-US association, but also to the similarity of the retrieval context to the context of memory encoding. Moreover, stimuli often have ambiguous meanings and context is essential for disambiguating these meanings during memory retrieval. The context specificity of memory relies on two interrelated processes that we term: contextual encoding and contextual retrieval. Contextual encoding indexes memory to the context in which it is encoded, and this enables contextual retrieval to occur in the encoding context. An extensive body of literature indicates an important role for the hippocampus in contextual learning and memory. We hypothesize that the hippocampus plays a critical role in the encoding and retrieval of context-specific fear memories. To this end, the present proposal has three specific aims: 1) to determine the role of the hippocampus in contextual encoding using reversible brain lesions, 2) to investigate the neural circuit by which the hippocampus mediates contextual retrieval using a combination of reversible brain lesions and single-unit electrophysiology, and 3) to determine the nature and scope of the context-specific memories regulated by hippocampal circuitry. These experiments will provide essential information regarding the neural substrates of contextual memory and have broad implications for our understanding of normal and pathological memory more generally.
Showing the most recent 10 out of 71 publications
