Adolescent marijuana use and maturation of cortical functions

描述（由申请人提供）：青春期是一个广泛的新皮层成熟的时期，在此期间，动态的新皮层网络非常容易受到大麻等非法物质的持久影响。青少年使用大麻的比例高于成年人，在青少年时期开始使用大麻会增加成年后患精神疾病的风险，如精神分裂症和抑郁症。根据一些说法，有青少年大麻消费史的成年人患精神分裂症的风险比未吸毒的人高出六倍以上，这表明早期大麻使用与成年精神病之间存在特别强的关联。皮层网络中电活动的同步性受损是精神分裂症的一个标志，并且是该疾病固有的神经回路紊乱的基础。精神分裂症患者在前额叶和感觉皮层区域的伽马频率（伽马：> 30 Hz）和其他带宽方面有明显的异常。这些带宽也受到δ-9四氢大麻酚（THC）的影响，THC是大麻的主要活性成分。THC通过其在内源性大麻素系统中的作用发挥其精神作用。这种内源性大麻素系统参与维持神经网络内的同步电活动，并在青春期保持高度可塑性，特别是在吻侧皮层区域。由于新皮质内源性大麻素系统的动态特征和大麻与涉及皮质同步性损伤的疾病之间的关联，我们假设青少年大麻使用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。这些异常在青春期发育较晚的吻侧皮质区比尾侧皮质区更明显。我们将通过在青春期给予THC的成年小鼠中进行的实验来验证这一假设。体外电生理记录将量化大麻素诱导的皮层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的成年小鼠的皮层中进行。 公共卫生相关性： 叙事青春期是一个新皮层高度活跃的时期，容易受到大麻使用等环境伤害。在青春期接触这种被广泛滥用的非法物质，相当于成年后依赖新皮层的认知过程受损，并已被确定为发展精神分裂症这种使人衰弱的精神疾病的一个环境风险因素。通过这一提议，我们试图了解青少年大麻使用对成人认知及其与精神疾病相关性的有害影响的潜在机制。

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.