Disrupted spatial and contextual memory encoding in the hippocampus of 5xFAD mice precedes cognitive impairment

Abstract

Alzheimers 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.