Adolescent marijuana use and maturation of cortical functions

描述(申请人提供)：青春期是广泛的新皮质成熟期，在此期间，动态的新皮质网络极易受到大麻等非法物质的持久影响。青少年的大麻使用率高于成年人，而在青春期开始吸食大麻会增加成年后患精神分裂症和抑郁症等精神疾病的风险。根据一些说法，有青少年吸食大麻史的成年人患精神分裂症的风险是吸食毒品的人的六倍多，这表明早期吸食大麻与成年后的精神病之间存在着特别强的关联。皮层网络中电活动的同步性受损是精神分裂症的一个特征，也是该疾病固有的神经回路紊乱的基础。精神分裂症患者在伽马频率(伽马：30赫兹)以及前额叶和感觉皮质区域的其他带宽上都有明显的异常。这些带宽还受到大麻的主要活性成分--三角洲-9四氢大麻酚(THC)的影响。THC通过其在内源性大麻素系统中的作用发挥其精神药物作用。这种内源性大麻素系统参与维持神经网络中的同步电活动，并在青春期保持高度可塑性，特别是在更多的吻侧皮质区域。由于新皮质内源性大麻素系统的动态特征，以及大麻与涉及皮质同步性损伤的疾病之间的关联，我们假设青少年使用大麻会导致皮质振荡的异常模式，以及内源性大麻素介导的神经传递的改变。这些异常在吻侧皮质区域比尾侧皮质区域更明显，这些区域在青春期不太发达。我们将通过在青春期给药的成年小鼠身上进行的实验来验证这一假设。体外电生理记录将量化药物诱导的皮质振荡和内源性大麻素介导的神经传递，而体内振荡记录将在清醒、行为正常的成年小鼠的皮质中进行。 公共卫生相关性： 叙述性青春期是大脑皮层高度活跃的时期，容易受到环境的侮辱，如吸食大麻。在青春期接触这种被广泛滥用的非法物质，相当于成年后新皮质依赖的认知过程受损，并已被确定为精神分裂症这种衰弱精神疾病发展的环境风险因素。通过这项提议，我们试图了解青少年吸食大麻对成人认知的有害影响及其与精神疾病的关联的潜在机制。

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.