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The reconsolidation-impairing effect of \u0394\u2079-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 (PPAR\u03b3), and both CB1 and PPAR\u03b3 modulate neuroimmune processes, including microglial activity. This dual mechanism suggests that THC\u2019s 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 PPAR\u03b3. Adult male and female Wistar rats underwent contextual fear conditioning, followed by THC (0.002\u2009mg\/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 PPAR\u03b3 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 PPAR\u03b3 antagonism, blocked THC\u2019s 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\u2019s reconsolidation impairment, offering a mechanistic basis for novel sex-tailored therapeutic opportunities.<\/jats:p>","DOI":"10.1038\/s41386-026-02434-x","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T15:37:39Z","timestamp":1778341059000},"page":"2163-2174","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex-specific role of microglia in \u03949-tetrahydrocannabinol-induced disruption of fear memory reconsolidation"],"prefix":"10.1038","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8012-4104","authenticated-orcid":false,"given":"Ana Maria","family":"Raymundi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie Carla","family":"Cardoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6465-6707","authenticated-orcid":false,"given":"Gabriel Costa","family":"Louren\u00e7o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruliam","family":"Queiroz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maressa D.","family":"Dolzan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Vitali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8425-6358","authenticated-orcid":false,"given":"Erika","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2069-3524","authenticated-orcid":false,"given":"Sabrina Francesca","family":"Lisboa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4092-7778","authenticated-orcid":false,"given":"Francisco Silveira","family":"Guimar\u00e3es","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7541-4855","authenticated-orcid":false,"given":"Graziano","family":"Pinna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2876-1146","authenticated-orcid":false,"given":"Leandro Jos\u00e9","family":"Bertoglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1736-5503","authenticated-orcid":false,"given":"Cristina Aparecida Jark","family":"Stern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"2434_CR1","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/35044580","volume":"1","author":"K Nader","year":"2000","unstructured":"Nader K, Schafe GE, LeDoux JE. 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