Psilocybin restores spatial memory but not fronto-hippocampal synchrony in a rat model of Alzheimer's disease

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

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.

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.

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.