Early spatial and contextual memory deficits in hippocampal CA1 precede performance decline in an Alzheimer's disease model
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Alzheimer’s disease (AD) is characterized by progressive memory decline, yet how hippocampal representations change at early AD stages remains largely unknown. In this study, we utilized a real-world head-fixed spatial alternation task combined with in vivo
two-photon imaging to investigate hippocampal CA1 representations in 5xFAD mice. While 7-9 month old 5xFAD mice showed significant deficits in task learning, 2-4 month old mice performed normally, enabling assessment of hippocampal coding prior to behavioral decline. At this early stage, CA1 neurons exhibited intact global spatial encoding but demonstrated impaired task-related place cell representations. Contextual
representations revealed by trajectory-dependent coding were weakened at both the population and single cell levels, accompanied by a notable shift from predominantly retrospective to more prospective encoding during behavioral choices. During task
learning, longitudinally unstable place cells showed greater impairments in spatial coding, whereas stable place cells remained largely preserved in early-stage AD mice. Additionally, chemogenetic activation of basal forebrain cholinergic neurons increased spatial information and within-session stability, while promoting trajectory-dependent coding in these early-stage 5xFAD mice. Together, these findings reveal selective early
impairments in hippocampal task-related spatial and contextual representations in AD that precede overt deficits in spatial alternation performance and remains amenable to cholinergic modulation.
two-photon imaging to investigate hippocampal CA1 representations in 5xFAD mice. While 7-9 month old 5xFAD mice showed significant deficits in task learning, 2-4 month old mice performed normally, enabling assessment of hippocampal coding prior to behavioral decline. At this early stage, CA1 neurons exhibited intact global spatial encoding but demonstrated impaired task-related place cell representations. Contextual
representations revealed by trajectory-dependent coding were weakened at both the population and single cell levels, accompanied by a notable shift from predominantly retrospective to more prospective encoding during behavioral choices. During task
learning, longitudinally unstable place cells showed greater impairments in spatial coding, whereas stable place cells remained largely preserved in early-stage AD mice. Additionally, chemogenetic activation of basal forebrain cholinergic neurons increased spatial information and within-session stability, while promoting trajectory-dependent coding in these early-stage 5xFAD mice. Together, these findings reveal selective early
impairments in hippocampal task-related spatial and contextual representations in AD that precede overt deficits in spatial alternation performance and remains amenable to cholinergic modulation.
Date Acceptance
2026-08-17
Citation
Advanced Science
ISSN
2198-3844
Publisher
Wiley
Journal / Book Title
Advanced Science
Copyright Statement
Copyright This paper is embargoed until publication. Once published the Version of Record (VoR) will be available on immediate open access.
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Publication Status
Accepted