Working memory, which is essential for abilities such as abstract thinking, problem solving, and cognitive flexibility, is significantly impaired with normal aging in a large proportion of humans and non-human primates. While it is known that these abilities are mediated in large part by pyramidal cells of the prefrontal cortex (PFC), the specific neural substrates of age-related decline in PFC function are not known. Given our aging population, this is a highly relevant question that will be directly addressed in an innovative manner by the proposed studies, which employ a unique experimental model- the behaviorally characterized rhesus monkey. Information during working memory tasks is encoded in a temporally dynamic and specific manner by the action potential (AP) firing rates of layer 3 pyramidal cells in the PFC. Preliminary studies demonstrate that there is a significant age-related increase in the firing rates of these cells in vitro, and their firing rates are significantly associated with cognitive performance. The overall goal of this proposal is to comprehensively and simultaneously examine, within individual layer 3 pyramidal cells, age-related alterations in interrelated cellular properties (ionic currents, synaptic responses, morphology), which likely contribute to functionally significant alterations in firing rate. Aged and young rhesus monkeys will be assessed on a battery of cognitive tasks, enabling determination of degree of cognitive impairment. Whole-cell patch-clamp recordings and Lucifer Yellow (LY) filling of layer 3 pyramidal cells in PFC slices prepared from these monkeys will then be employed in three highly integrated Specific Aims.
In Aim 1, intrinsic membrane and AP firing properties will be assessed with current-clamp recordings; subsequently, voltage-clamp analyses of currents that influence the temporal pattern of AP firing, (lc, IAHP, sIAHP and lh), will be used to test the specific hypothesis that age-related changes in the properties of these currents lead to increased firing rates.
In Aim 2, voltage-clamp recordings will assess age-related changes in glutamatergic and GABAergic postsynaptic currents in these cells, testing the specific hypothesis that changes in synaptic transmission are related to altered signaling.
Aim 3 experiments will explore age-related changes in the detailed dendritic architecture and dendritic spines of LY-filled layer 3 pyramidal cells, testing the specific hypothesis that alterations in morphological structure underlie changes in the signaling properties of these cells. Data from each of these aims will be cross correlated and also correlated with cognitive performance scores within the aged group of monkeys. This multi-faceted approach will provide unique information on the effects of normal aging on diverse but interrelated cellular properties within individual neurons that play a critical role in the execution of working memory tasks. Such information is vital to the development of a detailed understanding of the cellular mechanisms of cognitive decline, and a prerequisite for the future development of therapeutic interventions.
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