Effects of adolescent cannabinoid exposure on cortical development

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Project Summary / Abstract Adolescence is a critical period for neuronal development, and exposure to drugs of abuse during this period of vulnerability can alter the course of normal neurodevelopment causing changes that persist into adulthood. Initial exposure to cannabinoids, such as Δ-9-tetrahydrocannabinol (THC), often occurs during adolescence and this exposure can alter development on a neuronal and molecular level. Previous preclinical studies have indicated that repeated exposure to THC during adolescence can produce learning and memory deficits. These studies were performed using experimenter-administered doses of THC, as rodent self-administration of THC has been notoriously hard to achieve. Thus, the effects of cannabinoid exposure at self-administered doses of THC where the animal can choose how much drug to receive over time may differ from the effects of experimenter-administered doses. Additionally, THC administered in this manner may result in alternate effects on learning and memory than have been demonstrated by other paradigms. To address this gap in knowledge, the proposed studies will test the prolonged effects of adolescent THC self-administration on behavior, receptor expression, and neuronal activity in adulthood. Rats will be given access to low or high dose THC throughout adolescence, and once they reach adulthood, they will be tested on a delayed-match-to-sample working memory task. In some rats, we will then measure the expression of dopaminergic and cannabinoid receptors as the expression of these receptors is developing during adolescence and may be disrupted by chronic activation due to high THC exposure. Additionally, we will use in vivo calcium imaging during the working memory task to measure neuronal activity, tracking individual PFC neurons and measuring dynamic fluctuations in activity during learning. Our central hypothesis is that chronic THC exposure during adolescence will cause dose-dependent neuroadaptations in cortical dopaminergic and cannabinoid signaling, leading to alterations in neuronal activity that impact the performance of a cognitively demanding behavior. The proposed training plan will allow me to develop new and necessary skills in cell and molecular techniques, as well as in the statistical analysis of complex neuronal datasets. I will be able to draw on the expertise of strong faculty mentors and collaborators at the University of Pittsburgh and Carnegie Mellon University to ensure the successful completion of my research training plan. These innovative longitudinal studies will significantly advance our knowledge of the protracted neurobiological effects of adolescent exposure to THC. The proposed experiments will provide a detailed characterization of the progression activity in individual prefrontal neurons and ensembles during the learning of a complex task, in both drug and non-drug exposed animals. Given the recent political and health-related interest in the effects of cannabinoids for recreational and therapeutic use, the research proposed within this application will provide useful knowledge to the scientific community, as well as being indispensable as I embark on a productive career as an independent investigator.