Interrogating mechanistic underpinnings of cognitive inflexibility in cannabis-exposed offspring - PROJECT SUMMARY Cannabis is the most used illicit drug among pregnant mothers. As the number of states with legal cannabis continues to increase, there has been a concomitant rise in the rate of maternal cannabis use. This is particularly troubling given that prenatal cannabis exposure could interfere with neurodevelopment and increase the risk for cognitive dysfunction later in life. Preclinical animal models are advantageous in that they provide fine control over potentially confounding variables. However, current models of maternal cannabis use have been plagued by methodological concerns that limit the translatability of these data to human populations. Our laboratory has generated important new data using a novel, translationally relevant model of cannabis vapor exposure in pregnant rat dams. This new method of administration uses custom-designed equipment to deliver discrete ‘puffs’ of vaporized, plant-derived cannabis extracts in a response-contingent manner. Using this approach, we have shown that prenatal cannabis exposure produces marked deficits in cognitive flexibility in offspring by impairing acquisition and maintenance of newly updated strategies. This ability is known to depend on corticostriatal neurons, namely glutamatergic projections from the prelimbic (PL) region of the medial prefrontal cortex to the nucleus accumbens (NAc). Dynamic release of glutamate and dopamine (DA) in the NAc coordinates flexible decision making and is constrained by local endocannabinoid (eCB) signaling. Our data also show sex-dependent alterations in spontaneous glutamate release onto NAc-projecting PL neurons in cannabis- exposed offspring from dams that self-administered cannabis. However, we still do not know 1) whether this corticostriatal circuit and local DA and eCB transmission are differentially recruited during flexible decision making in cannabis-exposed vs. control offspring, 2) whether long-term functional alterations occur within this pathway, and 3) whether early intervention strategies can prevent cannabis-related impairment. To address these gaps, we will use complementary projection-specific approaches to identify long-term alterations that give rise to cognitive flexibility deficits in cannabis-exposed offspring and test novel pharmacologicala and circuit- based treatment strategies for restoring behavioral and synaptic function. In Aim 1, we will conduct in vivo fiber photometry recordings of 1) Ca2+ transients in PLNAc neurons and 2) glutamate, DA, and eCB dynamics in the NAc using novel biosensors. In Aim 2, we will employ viral labeling to examine intrinsic excitability and optically evoked transmission from PLNAc neurons, as well as endocannabinoid-dependent plasticity at PLNAc synapses. In Aim 3, we will test whether in vivo depotentiation of synaptic activity at PLNAc synapses or juvenile administration of the FDA-approved steroid precursor pregnenolone can restore cognitive flexibility and recalibrate corticostriatal synaptic transmission in cannabis-exposed offspring. Completion of this work will have a broad, sustained impact by delineating cognitive effects of maternal cannabis use in exposed offspring and their neurobiological underpinnings, which is very timely given the current wave of cannabis legalization.
