Cannabis and Adolescent Brain Development

描述（由申请人提供）：大麻是当今滥用最广泛的非法药物。吸食大麻会严重损害认知过程，包括工作记忆，而灵长类动物的工作记忆依赖于背外侧前额叶皮层的回路。大麻的使用还与精神分裂症的风险增加有关，精神分裂症是一种以工作记忆受损和DLPFC功能障碍为特征的疾病。有趣的是，在青春期使用大麻似乎特别增加了这两种不良后果的风险。因此，青春期是对大麻的影响特别敏感的发育时间窗口。大麻的作用主要由大麻素受体1（CB 1 R）介导。在灵长类动物中，DLPFC由CB 1 R免疫反应性（CB 1 R-IR）轴突密集支配，这些轴突来自含胆囊收缩素（CCK）的GABA篮神经元类，并与锥体神经元的索马突触。因此，CB 1 R阳性轴突终末收敛与输入从小白蛋白（PV）含有GABA神经元上的锥体细胞的体周区域，这两个来源的体周输入发挥互补的作用，在同步的锥体细胞活动所需的工作记忆。由于CB 1 R的刺激强烈抑制GABA的输入，从CCK阳性篮神经元的锥体神经元，我们假设，在青春期大麻的使用改变了CCK/CB 1 R和PV抑制输入DLPFC锥体神经元之间的平衡。这些体周GABA输入的发展轨迹中产生的干扰产生持久的电路改变，损害工作记忆性能的成熟。为了验证这一假设，我们将确定出生后的发育变化的表达CB 1 R的mRNA和蛋白质（目的1），CB 1 R-IR轴突（目的2）的神经支配模式，和CB 1 R激活的电生理后果（目的3）在猕猴DLFPC，一个模型系统，独特的重演的电路和人类DLPFC的长期发展。我们还将评估青春期慢性大麻暴露对猴子工作记忆表现（目标4）和DLPFC锥体神经元（目标5）的体周输入成熟的影响。因此，这些研究将提供一个明确的测试的生物事件和机制，使青少年的大脑特别容易受到大麻的影响。

DESCRIPTION (provided by applicant): Cannabis is the most widely abused illicit drug today. Cannabis use can substantially impair cognitive processes, including working memory, which in primates is dependent upon the circuitry of the dorsolateral prefrontal cortex (DLPFC). Cannabis use has also been associated with an increased risk of schizophrenia, a disorder characterized by impairments in working memory and dysfunction of the DLPFC. Interestingly, cannabis use during adolescence appears to especially increase the risk of both of these adverse consequences. Thus, adolescence represents a developmental time window of particular sensitivity to the effects of cannabis. The effects of cannabis are primarily mediated by the cannabinoid receptor 1 (CB1R). In primates, the DLPFC is densely innervated by CB1R-immunoreactive (CB1R-IR) axons that arise from the cholecystokinin (CCK)-containing class of GABA basket neurons and that synapse on the soma of pyramidal neurons. Thus, CB1R-positive axon terminals converge with inputs from parvalbumin (PV)-containing GABA neurons onto the perisomatic region of pyramidal cells, and these two sources of perisomatic inputs play complementary roles in the synchronization of pyramidal cell activity required for working memory. Because stimulation of the CB1R strongly suppresses the GABA inputs to pyramidal neurons from CCK-positive basket neurons, we hypothesize that cannabis use during adolescence alters the balance between the CCK/CB1R and PV inhibitory inputs to DLPFC pyramidal neurons. The resulting disturbance in the developmental trajectories of these perisomatic GABA inputs produces persistent circuitry alterations that impair the maturation of working memory performance. To test this hypothesis we will determine the postnatal developmental changes in the expression of CB1R mRNA and protein (Aim 1), the innervation patterns of CB1R-IR axons (Aim 2), and the electrophysiological consequences of CB1R activation (Aim 3) in the macaque monkey DLFPC, a model system that uniquely recapitulates the circuitry and protracted development of the human DLPFC. We will also assess the impact of chronic cannabis exposure during adolescence on working memory performance in monkeys (Aim 4) and on the maturation of perisomatic inputs to DLPFC pyramidal neurons (Aim 5). Thus, these studies will provide an explicit test of the biological events and mechanisms that make the adolescent brain especially vulnerable to the effects of cannabis.