Frontal and Temporal Lobe Interactions in Rat Models of Normative Aging and Alzheimer's Disease

ABSTRACT Dramatic advances have been made in recent years in the theory of how information is 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-dependent episodic memory, 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. 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 over 71. It is also critical to understand the mechanisms that underly devastating neurodegenerative disorders such as Alzheimer's disease. The two Aims of this proposal use two different animal models – one that represents a model of normative human aging and another that models many of the

pathological characteristics of Alzheimer's disease. The goal is to understand how brain circuit interactions critical for memory are altered in both normal aging and in neurodegenerative disease. This proposal focuses on the interactions between the hippocampus and the medial prefrontal cortex (mPFC). Both structures are

known 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 interactions between the hippocampus and prefrontal cortex in young and aged rats while performing a continuous alternation task on a W-track apparatus. The questions addressed in this Aim include how the normative aging

brain adapts to changes in intrinsic network dynamics within each structure, between the direct projection from ventral hippocampus to mPFC, and how these structures interact or compete during aging to find solutions to this spatial working memory problem. Aim 2 uses a relatively newly established rat genetic model of AD, the

TgF344-AD rat, that carries the mutant human APP and PS1 genes, but spontaneously manifests tau pathology, hippocampus cell loss and cognitive dysfunction by 15 mo of age. We have developed a more constrained spatial sequence memory task, modeled after the W-track, that we call the Fan Maze. The smaller

apparatus allows us to adapt a massively high-density recording technology (the Neuropixels probe) to chronically implanted freely behaving rats. The ability to record from ensembles of cells across the hippocampus and mPFC while rats perform tasks dependent on the interactions between these brain structures, will allow us to bridge the gap between principles learned from studying animal models of normative

aging and Alzheimer's disease, to those that underlie the neural basis of human cognitive aging and disease.