Ana Maria Raymundi

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.

The persistence of newly acquired memories is supported by the activity of PKMζ, an atypical isoform of protein kinase C (PKC). Whether the activity of conventional and atypical PKC isoforms contributes to reactivated memories to persist is still unknown. Similarly, whether memory reactivation is a prerequisite for interventions to be able to change memory persistence is scarcely investigated. Based on the above, we examined the role of conventional and atypical PKC isoforms in the prelimbic cortex in reconsolidation and persistence of a reactivated contextual fear memory in male Wistar rats. It is shown that (i) inhibiting the PKC activity with chelerythrine or the PKMζ activity with ZIP impaired the persistence of a reactivated memory for at least 21 days; (ii) ZIP given immediately after memory reactivation affected neither the reconsolidation nor the persistence process. In contrast, when given 1 h later, it impaired the memory persistence; (iii) chelerythrine given immediately after memory reactivation impaired the reconsolidation; (iv) omitting memory reactivation prevented the chelerythrine- and ZIP-induced effects: (v) the ZIP action is independent of the time elapsed between its administration and the initial memory test. The results indicate that prelimbic cortex PKC and PKMζ are involved in memory reconsolidation and persistence.

Background and Purpose: In preclinical studies, cannabidiol (CBD) mitigates fear memories by facilitating their extinction or interfering with their generalization and reconsolidation. The brain regions and mechanisms underlying these effects, and their temporal window, are still poorly understood. Here, we have investigated related questions in the dorsal hippocampus (DH) during contextual fear consolidation.Experimental Approach: Adult male Wistar rats received CBD (10–30 pmol) intra‐DH immediately, 1 or 3 hr after fear conditioning. Effects of CBD on consolidation were inferred behaviourally and by analysing expression of the activity‐regulated, cytoskeleton‐associated (Arc) protein. The contribution of anandamide, CB₁, CB₂, 5‐HT_1A, A_2A, and PPARγ receptors was also assessed.Key Results: CBD impaired memory consolidation when given immediately or 1 hr after fear conditioning, but not after 3 hr. Expression of Arc protein in DH was reduced by systemic CBD treatment in both cases. Immediately after fear conditioning, CBD effects were abolished by CB₁ or CB₂ receptor blockade, partly reduced by 5‐HT_1A or A_2A antagonism, and remained unchanged after antagonism of PPARγ receptors. One hour after fear conditioning, CBD effects were prevented only by PPARγ receptor antagonism. Also, inhibition of fatty acid amide hydrolase by URB597, impaired memory consolidation when infused immediately, but not 1 hr after fear conditioning.Conclusions and Implications: CBD disrupts memory consolidation up to 1 hr after fear conditioning, allowing an extended window of opportunity to mitigate aversive memories after their acquisition. Our results suggest time‐dependent participation of anandamide, CB₁, CB₂ and PPARγ receptors in the DH, during this process.