Research Project
6436121
The overall aim of this component project is to define the nature and distribution of changes in critical circuitry and morphological plasticity that contribute to age-related cognitive decline. Three Specific Aims are targeted for investigation. Our previous research indicates that the integrity for projects from the entorhinal cortex to the hippocampus predict individual differences in the cognitive outcome of aging. It is not known, however, whether this coupling reflects the selective vulnerability of cells in the entorhinal cortex, or whether cognitive aging is associated with a widespread pattern of connectional disruption among multiple cortical components of the hippocampal system. Specific Aim 1 addresses this using established confocal microscopy methods to quantify the number and intensity of synaptophysin immunoreactive boutons in the entorhinal perirhinal and postrhinal cortices of behaviorally characterized young and aged rats. Results will be collected separately for superficial and deep cortical layers to determine if the disrupted organization of major inputs to the hippocampus is coupled to changes in the output the parahippocampal region receives from the hippocampus. Specific Aim 2 moves beyond a static, snapshot of connectional integrity to test the proposal that cognitive aging is coupled to deficits in the dynamic regulation of morphological plasticity in the hippocampus. Specific Aim 2 moves beyond a static, snapshot of connectional integrity to test the proposal that cognitive aging is coupled to deficits in the dynamic regulation of morphological plasticity in the hippocampus. Studies examining this hypothesis will utilize a cAMP- induced motel of enhanced synaptic efficacy in the hippocampal slice that is known to engage substantial, functionally relevant morphological remodeling of hippocampal slice that is known to engage substantial, functionally relevant morphological remodeling of hippocampal connectivity. Taking advantage of selective immunohistochemical investigations will yield novel data on the capacity of the aged hippocampus for activity-dependent structural plasticity, specifically in relation to the cognitive outcome of aging. Specific Aim 3 targets a broader network level of analysis of understanding how changes in connectivity might influence information processing in the aged brain. Using a recently validated method in which neurons activated during a prior behavioral guide are visualized by in situ hybridization for the immediate early gene Arc, subjects will be tested in a redundant place/cue version of the task that aged and aged rats learn at equivalent rates, but use different strategies to solve. The specific hypothesis under consideration is that this age-dependent differences in task strategy selection results from a shift in the relative balance of hippocampal and dorsal striatal circuitry engaged during learning. Taken together, these experiments are anticipated to realize significant progress toward defining the nature and distribution of changes in the circuit results will also inform other program initiatives, identifying vulnerable classes of cells and projection systems for molecular, biochemical and physiological analysis.
