Microstrokes Disrupt Hippocampal Place Cell Stability and Spatial Memory

Heiser H, Kiessler F, Roggenbach A, Ibanez V, Wieckhorst M, Helmchen F, Gjorgjieva J, Wahl AS. Brain-wide microstrokes affect the stability of memory circuits in the hippocampus. Nat Commun 2025;16(1):3462. doi: 10.1038/s41467-025-58688-4.

Background: Small-vessel disease–related microstrokes are a major cause of cognitive decline and vascular dementia. The hippocampus, central to spatial and episodic memory, is particularly vulnerable to microvascular insults. However, how such microscopic lesions disrupt hippocampal network stability and memory encoding over time remains unclear.

Hypothesis: This study hypothesized that distributed microstrokes impair spatial memory by destabilizing hippocampal place cell networks, and that preservation of stable spatial coding predicts recovery of cognitive function.

Methods: The authors used chronic two-photon calcium imaging to repeatedly record the same hippocampal CA1 neurons in head-fixed mice navigating a virtual reality corridor. Microstrokes were induced by unilateral intra-arterial microsphere injections. Imaging was performed with a galvo-resonant two-photon system controlled by ScanImage. Neural data were preprocessed with automated motion correction, and neuronal activity was classified into stable, unstable or non-coding cells. Bayesian decoding and correlation analyses assessed network stability and spatial coding precision.

Results: Microstrokes significantly reduced task performance, mean firing rates and within-session stability of place cells without affecting motor behavior. The loss of stable place cells correlated with lesion load and chronic spatial memory deficits. Mice that recovered behaviorally showed restoration of stable place cells and improved decoder accuracy in later sessions. Recovery animals displayed increased spatial synchronization near reward zones, indicating functional reorganization of salient locations.

Conclusions: Microstrokes disrupt hippocampal spatial coding and network stability, leading to memory loss. Maintenance or reestablishment of stable, synchronously active place cells supports functional recovery after microvascular brain injury.