LASSALLE, O. | Search bioRxiv

bioRxiv2026

Prenatal Cannabidiol and Δ9-Tetrahydrocannabinol exposure lead to sex-specific disruptions in risk assessment and behavioral switching via divergent rewiring of the adult mPFC

BackgroundPrenatal cannabidiol (CBD) consumption is increasing, driven by a perception of safety relative to {Delta}9-tetrahydrocannabinol (THC). However, the neurodevelopmental risks of gestational CBD remain largely uncharacterized. MethodsUsing a sex-disaggregated framework, we investigated adult (P100-140) mouse offspring following in utero exposure (GD5-18; 3 mg/kg) to THC or CBD. Behavioral strategies were evaluated through risk-assessment and repetitive behavior tasks, coupled with targeted electrophysiological mapping of medial prefrontal cortex Layer 5 neurons, the primary hub for approach-avoidance arbitration. ResultsWe found that increased repetitive behavior was a universal feature of prenatal cannabinoids exposure. Alterations in risk appraisal emerged uniquely in CBD-exposed females and appeared dissociated from classical anxiety metrics. At the circuit level, THC and CBD were linked to an absence of endocannabinoid long-term depression (eCB-LTD). In males, CBD exposure coincided with a bidirectional plasticity collapse characterized by functional saturation, elevated AMPA/NMDA ratios, and slowed NMDAR activation kinetics. This ceiling effect may represent a top-down constraint on the prefrontal output circuit, potentially limiting the synaptic flexibility typically associated with adaptive behavioral transitions. In contrast, females exhibited compound-specific reorganizations of E/I balance. CBD-exposed females displayed a scaled-up architecture that preserved net E/I balance, whereas THC was associated with a pro-excitatory phenotype through the collapse of inhibitory control. ConclusionsDespite a shared loss of eCB-LTD, distinct synaptic remodeling might underlie divergent alterations in risk assessment and behavioral flexibility. This sex-specific circuit rewiring provides a neurobiological framework for the long-term behavioral risks associated with gestational cannabinoid exposure.

neuroscience↗

bioRxiv2021

Sex-specific divergent maturational trajectories in the post-natal rat basolateral amygdala

The basolateral amygdala (BLA), the part of the amygdala complex involved in the transduction of perceptual stimuli into emotion, undergoes profound reorganization at adolescence in rodents and humans. How cellular and synaptic plasticity evolve throughout postnatal development in both sexes is only partially understood. We used a cross-sectional approach to compare the morphology, neuronal, and synaptic properties of BLA neurons in rats of both sexes at adolescence and adulthood. While BLA pyramidal neurons from rats of both sexes displayed similar current-voltage relationships, rheobases, and resting potentials during pubescence, differences in these parameters emerged between sexes at adulthood: BLA neurons were more excitable in males than females. During pubescence, BLA neuron excitability was highest in females and unchanged in males; male action potentials were smaller and shorter than females and fast afterhyperpolarizations were larger in males. During post-natal maturation, no difference in spine density was observed between groups or sexes but spine length increased and decreased in females and males, respectively. A reduction in spine head diameter and volume was observed exclusively in females. Basic synaptic properties also displayed sex-specific maturational differences. Stimulus-response relationships and maximal fEPSP amplitudes where higher in male adolescents compared with adults but were similar in females of both ages. Spontaneous excitatory postsynaptic currents mediated by AMPA receptors were smaller in BLA neurons from adolescent female compared with their adult counterparts but were unchanged in males. These differences did not directly convert into changes in overall synaptic strength estimated from the AMPA/NMDA ratio, which was smaller in adolescent females. Finally, the developmental courses of long-term potentiation and depression (LTP, LTD) were sexually dimorphic. LTP was similarly present during the adolescent period in males and females but was not apparent at adulthood in females. In contrast, LTD followed an opposite development: present in adolescent females and expressed in both sexes at adulthood. These data reveal divergent maturational trajectories in the BLA of male and female rats and suggest cellular substrates to the BLA linked sex-specific behaviors at adolescence and adulthood.

neuroscience↗