Synapase Modification /Memory Retention /Life Span Model

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This proposal focuses on two research objectives: animal models of aging and functional senescence. The long term goal of this research project is to understand the neurological properties of a novel animal model of extended life span that contribute to its capacity to retain learned memories during aging. In general, studies indicate that the ability to learn and remember declines, on average, in the latter part of the life span (e.g., decreased retention of spatial memory). Recently, an animal model of extended life span has been described by investigators in our research group, the growth hormone receptor knockout (GH-R-KO) mouse, that shows enhanced retention of memories during aging (28 days post training) relative to controls. Furthermore, these mice do not show any deficit in memory retention when compared with young control animals. The acquisition and storage of memory is believed to be associated with an underlying modification of synapses. Two forms of synaptic modification that have been proposed to be putative biological substrates for cognitive function (learning and memory) are long term potentiation (LTP) and long term depression (LTD). While only limited evidence directly links LTP or LTD with the mechanisms used by the brain in vivo, several studies have noted a correlation between the inability of aged animals to retain spatial memory and a quicker decay of LTP. Furthermore, recent data suggest that the ability to elicit LTD, and reverse LTP may also be enhanced during aging. In this study, behaviorally haracterized (Le., inhibitory ,avoidance task, water maze) adult and aged GH-R-KO mice and controls will be used to test two hypotheses concerning mechanisms that may contribute to a preservation of memory retention during aging. Hippocampal region CA1 will be examined. Hypothesis 1: Aged GH-R-KO mice showing retention of learned memory do not display an accelerated decay of LTP. If LTP is indeed a cellular correlate for learning and memory, then one would predict that its accelerate decay could account for an impairment in memory retention during aging. Adult and aged GH-R-KO mice and controls will be behaviorally characterized. Subsequently, hippocampal slices will be prepared from these animals and extracellular recordings will be made in CA1 (stratum radiatum) to characterize the time course of LTP decay. LTP will be induced using 4 trains of 100 Hz stimulation (1s duration) every 5 min. Hypothesis 2: Aged GH-R-KO mice showing little or no impairment in memory retention do not show an enhanced capacity to evoke LTD or reverse LTP in vitro. Since altering these properties could also contribute to a decrease in retention performance during aging (Le., increase in forgetting) extracellular recordings will be made in hippocampal region CA1 of brain slices prepared from behaviorally characterized animals to assess: 1) the capacity to evoke LTD using prolonged low frequency stimulation (LFS; 900 lpulses/l Hz) and 2) the capacity to reverse LTP using multiple short-duration LFS bursts (30pulses/lHz; 10 min between bursts).