Delayed psilocybin treatment after repeated mild traumatic brain injury recovers chronic behavioural deficits, reduces microglial density, and enhances hippocampal neurogenesis in rats

Repeated mild traumatic brain injury (RmTBI) can produce lasting cognitive, emotional, and social deficits (e.g., persistent post-concussion symptoms; PPCS). Despite the prevalence of RmTBI in sports, military, and domestic violence settings, effective treatments to alleviate the neurological consequences of RmTBI remain limited. Psilocybin, a serotonergic psychedelic, can enhance neuroplasticity and reduce neuroinflammation and has shown efficacy in psychiatric conditions that share overlapping pathophysiological and symptomatic features with RmTBI and PPCS. Here we examined whether delayed administration of psilocybin after RmTBI could improve long-term recovery in rats. Adult male rats received either five mTBIs delivered once daily via a lateral impactor or underwent sham procedures. After an 8-week recovery period, rats were administered psilocybin (1 mg/kg, i.p.) or saline. Behavioural testing began 24 hours later to evaluate psilocybin’s potential therapeutic effects. Afterwards, rats were perfused for immunohistochemical analysis of Cd11b and doublecortin to assess the density and morphology of microglia and newborn neurons, respectively, in the dorsal dentate gyrus. RmTBI produced persistent behavioural deficits across affective, social, and cognitive domains. Psilocybin treatment reversed several of these alterations, exhibiting antidepressant-like effects in the forced swim and sucrose preference tests, promoting pro-social behaviour, and increasing nociceptive thresholds in the hot plate test. Psilocybin also partially recovered RmTBI-induced increases in microglial density and, while RmTBI had minimal impact on the number of newborn neurons, psilocybin increased their abundance and enhanced their dendritic complexity. These results support the potential of psilocybin as a novel intervention for the enduring consequences of RmTBI.