A prominent feature of human memory dysfunction is retrograde amnesia, which refers to a loss of memories that were acquired before the onset of amnesia. In humans retrograde memory loss is often temporally graded. That is, remote memory (information learned long before the onset of memory impairment) is often spared, or much less impaired, relative to information learned recently. It is recognized that the study of retrograde amnesia can reveal an enormous amount about the organization of normal long-term memory. The proposal requests support for three, conceptually related projects concerning the organization of remote memory. All three projects will examine the relationship of hippocampal function to the retrieval of recent memory and remote memory using rats as the model system and sophisticated, modern experimental methods. These projects represent a rigorous evaluation of remote memory and the results will be important for theories concerning the organization of memory. The first project 1) Reevaluating Remote Context Fear Memory and the Hippocampus will systematically and rigorously test the hypothesis that recent context fear memory is vulnerable to hippocampal damage, but remote context fear memory is spared following hippocampal damage. All rats will undergo context fear conditioning. The lesions will be made 1 day or 100 days after conditioning. The location and extent of the lesions will be manipulated (full hippocampal lesions, dorsal hippocampal lesions, or ventral hippocampal). Two different lesions methods will be used (excitotoxic or thermocoagulation). The second project 2) The Organization of Remote Spatial Memory will evaluate the possibility that spatial memory reorganizes over time, like other forms of nonspatial memory, but that the hippocampus is always required for the behavioral expression of spatial memory. A disruptive, LTP reversing drug infusion procedure will be applied 1 day or 2 months after learning. This procedure leaves the hippocampus intact during the retention test so memory can be studied independent of performance. The third project 3) The Hippocampus, Perirhinal Cortex, and Remote Recognition memory will evaluate the independent contributions the hippocampus and perirhinal cortex make to both recent and remote recognition memory-a form of memory that is frequently studied in humans, non-human primates, and rodents. A disruptive, LTP reversing drug infusion procedure will be applied 1 day or 2 months after learning. The dorsal and ventral regions of the hippocampus, or the perirhinal cortex will be targeted. PUBLIC HEALTH RELEVANCE: By the age of 70 years, 60% of the population will experience significant memory related problems including Alzheimer's (30%) and Benign Senescent Forgetfulness (30%). If current trends continue, by the year 2050, 14 million older Americans are expected to have AD. Given that close to 40% of the population served by the VA is elderly and age is the greatest risk factor for AD and other memory problems, the increasing incidence of memory related problems in veteran's healthcare systems will significantly impact the VA's mission. One of the most fundamental questions in brain science is how the brain stores and reorganizes memory over time. Basic research on memory processes and identifying the neural structures involved in memory storage are critical steps for developing treatments to ameliorate or prevent memory problems and to combat the personal and financial cost of memory loss.