ABSTRACTDramatic advances have been made in recent years in the theory of how information is represented storedand 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 thehippocampus contribute to altered network function associated with changes in spatial cognition. In addition tochanges in temporal lobe-dependent episodic memory some of the earliest alterations detected in memoryacross the lifespan occur in frontal lobe-dependent tasks including working memory and attention. Each ofthese cognitive functions of course is essential for effective interaction with our environment. In humans theproportion of people across the USA over 71 who are demented from all causes is 14%. This suggests that itis critical to understand normal cognitive aging processes in their own right as this reflects 86% of agedindividuals over 71. It is also critical to understand the mechanisms that underly devastatingneurodegenerative disorders such as Alzheimer's disease. The two Aims of this proposal use two differentanimal models one that represents a model of normative human aging and another that models many of thepathological characteristics of Alzheimer's disease. The goal is to understand how brain circuit interactionscritical for memory are altered in both normal aging and in neurodegenerative disease. This proposal focuseson the interactions between the hippocampus and the medial prefrontal cortex (mPFC). Both structures areknown to be critical for cognition and are vulnerable in aging and in neurodegenerative disease.Aim 1 examines spatial working memory and the effect of age on the dynamics of network interactionsbetween the hippocampus and prefrontal cortex in young and aged rats while performing a continuousalternation task on a W-track apparatus. The questions addressed in this Aim include how the normative agingbrain adapts to changes in intrinsic network dynamics within each structure between the direct projection fromventral hippocampus to mPFC and how these structures interact or compete during aging to find solutions tothis spatial working memory problem. Aim 2 uses a relatively newly established rat genetic model of AD theTgF344-AD rat that carries the mutant human APP and PS1 genes but spontaneously manifests taupathology hippocampus cell loss and cognitive dysfunction by 15 mo of age. We have developed a moreconstrained spatial sequence memory task modeled after the W-track that we call the Fan Maze. The smallerapparatus allows us to adapt a massively high-density recording technology (the Neuropixels probe) tochronically implanted freely behaving rats. The ability to record from ensembles of cells across thehippocampus and mPFC while rats perform tasks dependent on the interactions between these brainstructures will allow us to bridge the gap between principles learned from studying animal models of normativeaging and Alzheimer's disease to those that underlie the neural basis of human cognitive aging and disease.