Psilocybin Restores Spatial Memory but Not Fronto-Hippocampal Synchrony in a Rat Model of Alzheimer's Disease

ABSTRACT Background Fronto-hippocampal desynchronization is linked to cognitive decline in Alzheimer's-like pathology, but whether psilocybin can restore this dysfunction is unknown.

Methods: Male rats received intracerebroventricular streptozotocin (ICV-STZ) to induce neurotoxicity, followed by a single dose of psilocybin (2.5 mg/kg, the maximum tolerated dose). Spatial memory, recognition memory, spatial learning, anxiety-like behavior, and depressive-like behavior were assessed (Y-maze, novel object recognition, Barnes maze, elevated plus maze, forced swim test), alongside resting-state local field potentials from the prefrontal cortex and hippocampus.

Results: ICV-STZ impaired spontaneous alternation and Barnes maze learning (both p<0.01), without affecting anxiety-like behavior or locomotion. Novel object discrimination index showed a similar but non-significant pattern (p=0.155). Forced swim test immobility was numerically higher after ICV-STZ but not significantly different from Control (p=0.068); psilocybin significantly reduced immobility versus STZ (p<0.001) and normalized alternation and escape latency to control levels. Spectral power, coherence, and cross-correlation did not differ significantly among groups at most sessions and bands (p>0.08), except one elevated mPFC-ventral hippocampal correlation in STZ animals (p=0.029, small cohort), not replicated with psilocybin.

Conclusion: A single psilocybin dose reversed spatial memory and learning deficits and reduced depressive-like immobility, without altering anxiety-like behavior or locomotion, but this behavioral rescue was not accompanied by a robust electrophysiological signature. This dissociation warrants replication using larger, artifact-robust cohorts and reference-free connectivity metrics.