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。大麻的使用会严重损害包括工作记忆在内的认知过程，而工作记忆在灵长类动物中依赖于背外侧前额皮质（DLPFC）的回路。大麻的使用也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，青春期代表了一个对大麻影响特别敏感的发育时间窗口。大麻的作用主要是由大麻素受体1 （CB1R）介导的。在灵长类动物中，DLPFC被cb1r免疫反应（CB1R-IR）轴突密集支配，这些轴突来自于含有胆囊收缩素（CCK）的一类GABA篮状神经元和锥体神经元体上的突触。因此，cb1r阳性轴突终末与含有小白蛋白（PV）的GABA神经元的输入汇合到锥体细胞的体周区域，这两种体周输入来源在工作记忆所需的锥体细胞活动同步中起互补作用。由于CB1R的刺激强烈抑制CCK阳性篮状神经元对锥体神经元的GABA输入，我们假设青春期使用大麻改变了CCK/CB1R和PV抑制输入DLPFC锥体神经元之间的平衡。这些细胞周围GABA输入的发育轨迹的干扰产生了持续的电路改变，损害了工作记忆表现的成熟。为了验证这一假设，我们将确定猕猴DLFPC中CB1R mRNA和蛋白表达的出生后发育变化（Aim 1）， CB1R- ir轴突的神经支配模式（Aim 2）以及CB1R激活的电生理后果（Aim 3），该模型系统独特地概括了人类DLPFC的电路和长期发育。我们还将评估青少年时期长期接触大麻对猴子工作记忆表现的影响（目的4），以及对DLPFC锥体神经元周围输入成熟的影响（目的5）。因此，这些研究将为使青少年大脑特别容易受到大麻影响的生物学事件和机制提供明确的测试。

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.