PROJECT SUMMARY / ABSTRACT Cannabis use continues to be high among adolescents and is increasing in young adults. This is a significant public health issue as heavy cannabis use during this period is linked to an increased risk for developing affective, addictive, or psychotic disorders later in life. Adolescence and early adulthood are also when the prefrontal cortex (PFC), which plays a key role in executive function and working memory, is maturing. Interestingly, psychiatric disorders seen following early cannabis use often involve the PFC and deficits in executive function are common in these disorders. This suggests that adolescent cannabis use disrupts PFC maturation, impairing working memory/executive function and increasing risk for later psychiatric disorders. This hypothesis is supported by functional imaging studies of individuals who heavily used cannabis during adolescence that have identified defects in functional connectivity between PFC and several brain regions. Thus, cannabis use may cause miswiring of PFC circuits, increasing the risk for psychiatric disorders. 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. These studies robustly demonstrate enduring deficits in PFC- mediated behaviors following adolescent THC that are lacking if similar doses of THC are given to adults, emphasizing a specific window of vulnerability. Our preliminary data investigating potential mechanisms have identified three, likely-interrelated processes. The first is that adolescent THC treatment decreases projections from the mediodorsal thalamus to the medial PFC (mPFC). The second is that adolescent THC treatment causes neuroinflammation, including increased IL-6 and activated microglia. The third is that co-treatment with cannabidiol prevents the behavioral and neuroinflammatory effects of adolescent THC. In the proposed studies we will investigate the mechanisms underlying these findings and evaluate mechanism-based potential therapies to reverse the behavioral and cognitive abnormalities caused by adolescent THC. We propose to develop a mechanistic understanding of the consequences of adolescent cannabis use by combining molecular, anatomical, electrophysiological, and behavioral approaches to complete three aims: Aim 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. Aim 2. Test the hypothesis that adolescent THC exposure reduces MD thalamus/mPFC connectivity to impair working memory. Aim 3. Test the hypothesis that adolescent THC activates microglia to excessively prune mPFC inputs from the MD thalamus to impair working memory.

PUBLIC HEALTH RELEVANCE Cannabis is widely used recreationally by adolescents and young adults, thus exposing the brain to delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) as it goes through its final development. Our studies will examine the impact of THC, CBD, and THC + CBD on the developing adolescent brain to determine their individual effects and potential interactions. We will also evaluate potential therapeutic strategies to treat the long-lasting behavioral and cognitive deficits that emerge in adults after adolescent cannabis use.