Changes in Hippocampal Coding of Very Large Spaces from Adulthood to Senescence

There is currently an approximate 60% success rate in diagnosing Alzheimer’s disease (AD) using cognitive tests. New FDA approved blood tests testing for amyloid plaque byproducts could soon bring this number to 90%, among patients with cognitive deficits. AD will now be detected earlier, and will consequently be more likely to be treated effectively. As amazing as these new indicators might be, effective treatments will still require an understanding of how the disease progresses, and how it affects the prefrontal and hippocampal structures, on a case-by-case basis. The ventral hippocampus (vHPC) is in bi-directional interactions with both the prefrontal cortex and the dorsal hippocampus (dHPC) and is likely to be an early locus of cognitive dysfunction. The traditional view is that vHPC and dHPC, even though they are part of the same anatomical structure, may perform different functions and that vHPC is much less involved in spatial navigation than dHPC. We propose that this view emanate from the fact that most of the studies in spatial navigation were conducted in relatively small environments where the large place fields of vHPC are not functionally relevant, because they do not discriminate between spatial locations (low position information content). Based in part on these findings, very little attention has been placed on the role of vHPC in normal or abnormal aging. In this 2-year proposal, we aim to fill this gap by characterizing the role of dHPC and vHPC in very large environments where the large place fields of vHPC are likely to be functionally relevant to spatial navigation. We further hypothesize that the encoding of space at both levels of the structure will be related to the complexity of the tasks. We propose to test these ideas by contrasting the multi-field and multi-scale neural encoding by place cells and the behavior of the animals in two tasks with low (foraging) and high (multi-goal maze) cognitive loads respectively. To measure the complexity of the multi-goal mazes, we propose to use the quantitative tools of Space Syntax, a common framework in Architectural Sciences that is rarely used in Neuroscience, if at all. We also propose to sample hippocampal activity in animals with increasing amount of experience and training, as in human aging, throughout their life span, starting from young adulthood until senescence. Whether differences in encoding between ventral and dorsal levels vary with complexity and age are observed or not, this study will likely provide important information and motivation for further studies of this and related structures not only in the context of spatial navigation in complex environments, but also in the manner in which they differentially processes simple and complex memories. Altogether, this proposal will advance our understanding to the role of the longitudinal axis of the hippocampus in complex spatial information processing and its changes as subjects age. It will shed further light of the contribution of this axis, as a whole, into the deficits observed during AD, dementia or mild Cognitive Impairments in humans. Project Number: 1R21AG101586-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Jean-Marc Fellous | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $439,750 | Activity Code: R21 | Study Section: Learning, Memory and Decision Neuroscience Study Section[LMDN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11355737