Mechanisms and Treatment of Adolescent Phytocannabinoid Impairment of Prefrontal Cortex Function
The major goal of our NIDA-funded project (R01 DA053746) entitled “Mechanisms and treatment of adolescent phytocannabinoid impairment of prefrontal cortex function” is to better understand the consequences and mechanisms of cannabis use during adolescence and early adulthood. We model this process in rodents by adolescent administration of Δ-9-tetrahydrocannabinol (THC), the primary intoxicating component of cannabis.
Our behavioral studies find enduring deficits in the medial prefrontal cortex (mPFC)- mediated behaviors following adolescent, but not adult, THC exposure. These findings emphasize a specific window of vulnerability of the mPFC to chronic THC exposure.
Our aims include the following: (1) Test the hypothesis that CB1 receptors are required for the detrimental effects of adolescent THC on working memory and evaluate potential therapies to reverse these deficits; (2) Test the hypothesis that adolescent THC exposure reduces the connectivity of the mediodorsal thalamus to mPFC to impair working memory; (3) Test the hypothesis that adolescent THC activates microglia to excessively prune mPFC inputs from the MD thalamus to impair working memory. Recently, our studies using whole-cell electrophysiological recordings with cortical layer V pyramidal neurons located in the prelimbic mPFC region identified significant synaptic functional alterations following adolescent THC exposure. To elucidate the mechanism mediating lasting synaptic and behavioral changes caused by adolescent THC exposure, we would like to conduct unbiased proteomic and post-translational modifications (PTMs) analyses with the support of the Yale/NIDA Neuroproteomics Center. Specifically, we plan to submit two groups of brain tissue punchouts from adult mPFC harvested from both male and female mice with adolescent THC exposure versus mice with vehicle exposure from postnatal day 28-49. The quantitative proteomic data will allow us to generate testable hypotheses on specific signaling cascades. This knowledge will enable us to identify putative pharmacological therapeutic tools and to test their efficacy in reversing the working memory deficits caused by adolescent THC exposure.
We believe our study matches the Yale/NIDA Neuroproteomics Center’s goal of using cutting-edge proteomic technologies to analyze neuronal signal transduction mechanisms and the adaptive changes in these processes that occur in response to drugs of abuse.