The objective of this research program is to understand the basis of memory impairments that result from normal aging. Over the past 19 years we have discovered links between spatial memory deficits and age-related changes in hippocampal connectivity and plasticity at the cellular and network levels. While empirical focus on the hippocampus is justified because of this structures critical role in memory, the extent to which changes in upstream cortico-hippocampal inputs contribute to these age-related behavioral deficits is unknown. The perirhinal cortex is at the highest level of the ventral visual processing stream. It carries polymodal sensory information to the hippocampus, is extensively reciprocally connected with it, and is critical for memory in its own right. Whether it transmits degraded information to the aged hippocampus, resulting in deficits in visual perception or stimulus associations is thus a major question addressed in the present grant. A complementary question is whether the breakdown during aging in the connectivity and plasticity mechanisms of hippocampal circuits leads to defective associative binding among neocortical areas, and hence less robust stabilization of episodic memories. Understanding how the bi-directional interactions between these structures are altered by the aging process, and how such failures in network communication may contribute to behavioral deficits, could provide insights into the neural mechanisms of memory at all ages. To begin the process of integrating the past two decades of rodent work towards an understanding of human aging, the scope of the project will be expanded to include young and aged monkeys in addition to rodents. The animals will be behaviorally tested on a battery of tasks that are adaptable to both species and known to be sensitive to lesions of the hippocampus and to the perirhinal cortex. In the monkeys, high resolution quantitative structural MRI and eventual microscopic stereological analysis will be used to begin to define structural changes associated with physiological changes and memory impairments in the aged non-human primate. Electrophysiological experiments will focus on ensemble recordings from hippocampus and perirhinal cortex of behaving young and old monkeys, and on synaptic connectivity and plasticity of the hippocampal - perirhinal cortex in young and old rats. The combination of ensemble recordings in the awake, behaving, aged non-human primate, and functional electrophysiological characterization of connections in behaviorally-screened young and old rats, should lead to insights into the respective involvement of hippocampal and neocortical association areas to age-associated memory deficits. This is a prerequisite for successful development of therapeutic or preventative treatments for cognitive decline in the elderly.
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