Declines in spatial cognition and function of brain circuits responsible for these behaviors are among the hallmark signs of normative biological aging across species. The objective of this research program is to understand the basis of these memory impairments, and rodent and nonhuman primate models each can provide unique windows into understanding how age impacts networks critical for cognition, at cellular resolution. The experiments proposed in the present application are guided by two primary aims.
Aim 1 is to understand how brain circuits responsible for spatial cognition are altered in the aged rat. While empirical focus on the hippocampus is justified because of this structure's critical role in memory, the extent to which changes in upstream cortico-hippocampal inputs, such as the entorhinal cortex, contribute to these age- related behavioral deficits is unknown. Two approaches are taken in this aim to answer these questions. We have developed a novel spatial task (the Instantaneous Cue Rotation arena, ICR) that enables precise measurement of spatial behavior accuracy and flexibility in the rat. Additionally, the hippocampus and its primary afferent input, the entorhinal cortex, are recorded simultaneously in order to examine age-related changes in bi-directional interactions between these structures. The dual-structure recordings will enable identification of changes within the hippocampus proper that are driven by upstream entorhinal cortical inputs, as well as changes in the entorhinal cortex driven by degraded hippocampal feedback signals. This multi-site recording method also allows examination of neural dynamics thought to be involved in memory consolidation.
Aim 2 is to understand how hippocampal representations are altered in aged freely-behaving primates. While other important questions about circuit dysfunction in aging remain to be addressed in rodent models of aging, recent advances in wireless recording technologies enable new experimental designs for primates that have the potential to test directly assumptions that our discoveries in the rat will find an analogue in the aging human brain. Free locomotion is an important missing link between the behavioral conditions employed to study place cells in rodents, and more constrained conditions under which human studies must be conducted. The experiments under this aim will implement the behavior and electrophysiological tools that allow us to determine the neural impact that aging and level of restraint has on the function of hippocampal networks in the nonhuman primate. Our hypotheses are that old monkeys will show faulty retrieval of hippocampal network patterns (similar to map retrieval failures in old rats) and that the global network activity state will be altered in both age groups when the animals are restrained, compared to when completely unrestrained and free to move. Taking advantage of new behavior and recording approaches in rodents and primates, we believe significant advances will be made in our understanding of the aging brain that will contribute substantively to the development of therapeutic or preventative treatments for cognitive decline in the elderly.
The outcome of the proposed project will have a significant impact on our understanding of the neural basis of episodic and semantic memory and how specific brain regions contribute to age-associated memory deficits. This is a prerequisite for successful development of therapeutic or preventative treatments for cognitive decline in the elderly, and will provide new approaches to studying, and ultimately ameliorating, memory disorders arising from other sources, such as developmental disorders, stress, drug abuse and brain trauma.
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