Sex-specific role of microglia in Δ9-tetrahydrocannabinol-induced disruption of fear memory reconsolidation

In PTSD, microglia are more engaged in fear-related circuits, where they participate in fear memory processing responses. The reconsolidation-impairing effect of Δ⁹-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis, is typically linked to cannabinoid type-1 receptor (CB1) signaling. THC also engages peroxisome proliferator-activated receptor gamma (PPARγ), and both CB1 and PPARγ modulate neuroimmune processes, including microglial activity. This dual mechanism suggests that THC's impact on fear memory reconsolidation may extend beyond classical cannabinoid signaling. We hypothesize that THC disrupts contextual fear memory reconsolidation via microglial recruitment in the dorsal hippocampus (DH) through a sex-specific engagement of CB1 and PPARγ. Adult male and female Wistar rats underwent contextual fear conditioning, followed by THC (0.002 mg/kg, i.p.) or vehicle administration immediately after memory retrieval. Microglial involvement was assessed using immunofluorescence and pharmacological and chemogenetic inhibition in DH. The role of CB1 and PPARγ receptors was assessed via intra-DH selective antagonist infusion. THC impaired reconsolidation in males and females. In males, fear memory retrieval increased microglial engagement in the DH CA1 subfield, which THC further enhanced. Pharmacological and chemogenetic inhibition of microglia, as well as selective CB1 and PPARγ antagonism, blocked THC's effects in males. In females, THC-induced reconsolidation blockade was cycle-dependent, occurring at estrus and diestrus but not at proestrus, and was mediated exclusively through CB1 activation. These findings identified sex-specific neuroimmune pathways mediating THC's reconsolidation impairment, offering a mechanistic basis for novel sex-tailored therapeutic opportunities.