Dramatic advances have been made in recent years in the theory of how information may be represented, stored and retrieved in neural networks and in the methodology for studying interactions among groups of neurons. Animal models of aging in rodents suggest that altered connectivity and plasticity mechanisms within the hippocampus contribute to altered network function associated with changes in spatial cognition. In addition to changes in temporal lobe circuits and episodic memory during aging, some of the earliest alterations detected in memory across the lifespan occur in frontal lobe-dependent tasks, including working memory and attention. Each of these cognitive functions, of course, is essential for effective interaction with our environment. Only humans spontaneously develop Alzheimer's disease. Thus other animals provide a good model of normative age changes. Even in humans, the proportion of people across the USA over 71 who are demented, from all causes, is 14%. This suggests that it is critical to understand normal cognitive aging processes in their own right, as this reflects 86% of aged individuals. The two Aims of this proposal are to better understand the underlying causes of two hallmarks of cognitive aging - behavioral slowing and multi-tasking deficits. Both of these cognitive operations are sensitive to prefrontal cortical function and different aspects of working memory. The systematic studies proposed in each Aim address each of these questions utilizing the animal model best suited to gaining insight into the origins of these two phenomena of cognitive aging in humans.
Aim 1 examines working memory and the effect of age on speed of network dynamics in young and aged rats while performing the W-track continuous alternation task and recording simultaneously from the prefrontal cortex (PFC) and the hippocampus. The questions addressed in this Aim include how the aging brain adapts to the changed dynamics intrinsic to both hippocampus and PFC, and how these structures interact or compete during aging to find solutions to this spatial working memory problem. While rodent models have the advantage of the use of unrestrained behavior conditions and more complex recording configurations, there are cases in which there is significant evolutionary advantage to using nonhuman primates, particularly with respect to the prefrontal cortex and tasks that do not require free movement.
Aim 2, therefore, examines working memory in young and aged bonnet macaques in an interference task that evaluates multi-tasking ability in the awake, behaving state while monitoring activity across populations of neurons recorded in PFC. In this Aim, the cellular correlates of multi-tasking are examined for the first time in an aging primate model, to assess how aging weakens the resilience of working memory circuits in the face of interference. For these different questions, each model has unique strengths and will allow us to begin to bridge the gap between principles learned from studying animal models, to those that underlie the neural basis of human cognitive aging.
This research will enable a better understanding of how networks critical for cognition are altered during the aging process. Experiments are designed to determine why cognitive slowing occurs during aging, why older individuals have more difficulty holding information in working memory and are more susceptible to interference when multi-tasking. This knowledge will be used to test possible treatments that target points of known circuit dysfunction in order to optimize cognitive healthspan in the elderly.
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