Tuesday, May 7, 2024
5/7/2024
PROJECT SUMMARY/ABSTRACT Cannabis is the most used illicit drug by adolescents, and cannabis vaping is on the rise. Cannabis use during adolescence is concerning as adolescence is a time of considerable development of the medial prefrontal cortex (mPFC)—a brain region that mediates higher-order cognitive functioning. Thus, the mPFC may be vulnerable to long-lasting perturbations from cannabis if use occurs during this particular developmental window. Indeed, human and preclinical studies have reported enduring impairments in mPFC-sensitive cognitive flexibility in adulthood after adolescent cannabis use. Parvalbumin (PV) interneurons regulate mPFC function and are impacted by cannabinoids in adolescence. However, since PV interneurons do not express cannabinoid receptors, these cannabinoid effects must be through an indirect mechanism. Perineuronal nets (PNNs) surround PV interneurons to support their function and are reduced following adolescent cannabinoid treatment. Microglia express cannabinoid receptors and have been reported to degrade and engulf PNNs. Importantly, we have recently found that adolescent vaporized cannabis use leads to increased microglial activation in the mPFC in addition to cognitive flexibility impairment in adulthood. Thus, we propose here to investigate microglia as a mechanism of adolescent cannabis-induced mPFC dysfunction with two aims. The first aim will determine whether microglia activation is necessary for cognitive flexibility deficits induced by adolescent vaporized cannabis exposure. We will use a combination of our rat model of noncontingent vaporized cannabis exposure and chemogenetic inactivation of microglia during adolescence to test the hypothesis that adolescent cannabis- induced microglial activation underlies the mPFC-sensitive cognitive flexibility deficits seen in adulthood. The second aim will determine whether microglia activation influences the effect of adolescent vaporized cannabis exposure on PV interneuron function and their surrounding PNNs. We will chemogenetically inactive microglia during vaporized cannabis exposure in adolescence and use immunohistochemistry and slice electrophysiology in adulthood to test the hypothesis that cannabis-induced microglial activation reduces PNNs around PV interneurons in the mPFC and lowers the intrinsic excitability of PV interneurons. We predict that inactivating microglia during adolescent cannabis exposure will prevent the breakdown of PNNs, thereby preserving PV interneuron function. The proposed studies will allow us to gain insight into the complex interplay between neurons, glia, and the extracellular matrix in mediating mPFC dysfunction as a consequence of adolescent vaporized cannabis exposure. Furthermore, findings from the studies in this proposal may identify potential biological targets for developing strategies aimed at preventing the cognitive consequences of adolescent vaporized cannabis use.
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