Concurrent maternal stress and THC exposure alters maternal regulation and downstream adolescent corticolimbic programs.

Cannabis use during pregnancy is increasing, often to alleviate stress and anxiety, yet the impact of prenatal cannabis exposure alone, or in combination with psychosocial stress on maternal regulation and downstream offspring neurodevelopment remains unclear. Here, we developed a translational rodent model combining prenatal Δ⁹-tetrahydrocannabinol (THC) exposure with chronic psychosocial stress using the maternal witness defeat stress (MWDS) paradigm. Pregnant C57BL/6 mice were exposed to MWDS from gestational day (GD) 3-12 and received daily subcutaneous THC (2 mg/kg) or vehicle until birth. All exposure groups exhibited disrupted maternal caregiving and adverse postnatal outcomes, with combined THC and stress exposure producing the most pronounced maternal impairments. To assess downstream consequences, adolescent male and female offspring were evaluated for behavioral and molecular alterations. Prenatal stress and combined exposures were associated with increased anxiety-like behavior and reduced motivated behavior in both sexes, while THC alone primarily impacted female self-care and social behavior. Transcriptomic profiling of the prefrontal cortex (PFC) and nucleus accumbens (NAc) of adolescent offspring using a custom NanoString panel revealed sex- and region-specific gene expression changes across exposure groups. Prenatal THC, stress, and combined exposures altered molecular pathways related to mitochondrial function, synaptic organization, and glial signaling. Comparative analysis with a perinatal fentanyl model identified shared transcriptional substrates involved in synaptic signaling and circadian regulation. Collectively, these findings demonstrate that concurrent prenatal stress and THC exposure disrupt maternal regulation, with associated and enduring neurodevelopmental signatures in offspring.