Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit.

Abstract

Prenatal Δ9-tetrahydrocannabinol exposure (PTE) poses long-lasting neuropsychiatric risks, as evidenced by clinical and preclinical studies, yet the neurobiological mechanisms remain poorly defined. Emerging evidence implicates the neurolipidome, a critical mediator of neurodevelopment and endocannabinoid signaling, as a potential contributor. Here, we demonstrate that dietary omega-3 fatty acid supplementation sex-selectively ameliorates neurodevelopmental deficits induced by PTE in a Wistar rat model. Omega-3 supplementation reduced cognitive and emotional disturbances in male offspring and normalized many neuronal and neurochemical abnormalities in the prefrontal cortex, nucleus accumbens, and ventral hippocampus. However, lipidomic analyses, regardless of omega-3 supplementation, uncovered pronounced, sex-specific PTE-induced disruptions in pathways critical for synaptic integrity and neurodevelopment, including those related to the endocannabinoid system. These findings provide new insights into the interplay between lipid metabolism and the endocannabinoid system in the context of PTE.