Sylvina E. Mullins - US grants

DESCRIPTION (provided by applicant): Adolescence is a period of extensive neocortical maturation during which dynamic neocortical networks are supremely vulnerable to the lasting effects of illicit substances such as marijuana. Marijuana use is higher in adolescents than in the adult population, and initiation of marijuana use during adolescence confers an elevated risk for developing psychiatric diseases, such as schizophrenia and depression, as an adult. By some accounts, the risk for schizophrenia is over six times higher in adults with a history of adolescent marijuana consumption than in drug-naive individuals, indicating the particularly strong association between early marijuana use and adulthood psychoses. Impaired synchrony of electrical activity in cortical networks is a hallmark of schizophrenia, and underlies the disorganization of neural circuitry intrinsic to the disease. Individuals with schizophrenia have pronounced abnormalities in the gamma frequency (gamma: >30 Hz) and in other bandwidths in prefrontal and sensory cortical areas. These bandwidths are also affected by delta-9 tetrahydrocannabinol (THC), the main active ingredient in marijuana. THC exerts its psychotropic effects through its action in the endogenous cannabinoid system. This endocannabinoid system is involved in the maintenance of synchronous electrical activity within neural networks, and remains highly plastic during adolescence, particularly within more rostral cortical areas. Due to the dynamic character of the neocortical endocannabinoid system and the association between marijuana and diseases involving impairments in cortical synchrony, we hypothesized that adolescent marijuana use leads to abnormal patterns of cortical oscillations, and alterations in endocannabinoid mediated neurotransmission. These abnormalities are more pronounced in rostral cortical areas that are less developed during adolescence than caudal cortical regions. We will test this hypothesis with experiments performed in adult mice administered THC during adolescence. In vitro electrophysiological recordings will quantify pharmacologically induced cortical oscillations and endocannabinoid mediated neurotransmission, while in vivo recordings of oscillations will be performed in the cortices of awake, behaving adult mice. PUBLIC HEALTH RELEVANCE: Narrative Adolescence is a period during which the neocortex is highly dynamic and susceptible to environmental insults such as marijuana use. Exposure to this widely abused illicit substance during adolescence corresponds to impaired neocortex-dependent cognitive processes in adulthood, and has been identified as an environmental risk factor for the development of the debilitating psychiatric disease of schizophrenia. Through this proposal, we seek to understand potential mechanisms accounting for the detrimental effects of adolescent marijuana use on adult cognition and its association with psychiatric illnesses.