Neurodevelopmental Effects of Cannabis and its Epigenetic Regulation

大麻（cannabis sativa）在全世界的普遍使用，沿着其相对较低的致命性，导致许多人 相信它是没有什么害处的。因此，大麻的使用目前超过了吸烟， 美国的青少年。然而，现在公认的是，发育中的大脑对 影响成年人行为的药物这一点尤其令人关切，因为大麻是最常见的毒品。 青少年和孕妇经常滥用非法药物。我们的研究继续关注 Δ9-四氢大麻酚（THC），大麻的主要精神活性成分，与奖励有关， 精神脆弱性我们证明了THC暴露在发育中的大脑中会产生长期影响， 长期到成年期的分子和行为结果与奖励敏感性，动机行为 负面影响。我们建立的产前动物模型模拟了中皮质边缘细胞的分子变化， 结构与我们在母亲使用大麻的人类胎儿标本中看到的结构相似。此外，一些 与表观遗传紊乱和突触可塑性相关的分子变化也很明显， 青少年THC暴露的成年人，强调THC发育的共同潜在机制 方面的影响.我们确定了一个特定的表观遗传分子靶点（Mll 1;多发性白血病）， 发展性THC引起的异常动机行为，并已开发出最先进的策略 例如激光捕获显微切割（LCM），以切割离散细胞中转录组和表观遗传改变 神经通路我们现在采用这样的策略来描绘表观遗传的途径特异性改变， 与发育THC相关的基因组机制。我们的研究集中在细胞核上 NAc介导与成瘾相关的奖励、动机行为和情绪调节 脆弱性和相关的精神病理学。我们建议（1）表征表观基因组中的变化， 与发育中THC暴露相关的独立成人NAc通路及其与转录的关系 使用LCM和染色质可及性的深度测序以及与转录组数据的重叠。(2)建立 在特定NAc输出途径中鉴定的分子改变与行为 与成瘾精神病理学相关的表型。(3)研究成年人体内神经活动的模式， 特定的NAc途径作为发展THC暴露的结果，使用创新技术， 纤维光度钙成像在特定途径的方式。从这个深度生成的数据库 大量的工作将是宝贵的资源，其结果将提供有关特定NAc作用的新见解 神经回路潜在的精神病理脆弱性。

The pervasive use of marijuana (cannabis sativa) worldwide, along with its relatively low lethality, has led many to believe that it is of little harm. As such cannabis use currently exceeds that of tobacco smoking among adolescents in the USA. However, is now acknowledged that the developing brain is particularly sensitive to drugs that can impact behavior in adulthood. This is of particular concern given that cannabis is the most commonly abused illicit drug by teens and pregnant women. Our research continues to focus on the impact of Δ9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis associated with reward and psychiatric vulnerability. We demonstrated that THC exposure in the developing brain has protracted effects long into adulthood on molecular and behavioral outcomes relevant to reward sensitivity, motivated behavior and negative affect. Our established prenatal animal model mimiced molecular changes in mesocorticolimbic structures to that seen in our human fetal specimens with maternal cannabis use. Moreover, a number of molecular changes relevant to epigenetic disturbances and synaptic plasticity are also commonly evident in adults with adolescent THC exposure emphasizing common underlying mechanisms of developmental THC effects. We identified a specific epigenetic molecular target (Mll1; multiple leukemia ) directly linked to abnormal motivated behavior induced by developmental THC and have developed state-of-the-art strategies such as laser capture microdissection (LCM) to dissect transcriptome and epigenetic alterations in discrete neuronal pathways. We now employ such strategies to delineate pathway-specific alterations of epigenetic mechanisms across the genome associated with developmental THC. Our study focuses on the nucleus accumbens (NAc), which mediates reward, motivated behavior and emotional regulation linked to addiction vulnerability and related psychopathologies. We propose to (1) characterize changes in the epigenome within discrete adult NAc pathways associated with developmental THC exposure and its relationship to transcription using LCM and deep sequencing of chromatin accessibility and overlap with transcriptome data. (2) Establish causal links between molecular alterations identified in specific NAc output pathways wtih behavioral phenotypes relevant to addiction psychopathology. (3) Investigate patterns of adult in vivo neural activity within specific NAc pathways as a consequence of developmental THC exposure using the innovative technique of fiber photometry calcium imaging in a pathway-specific manner. The databases generated from this in-depth body of work will be valuable resources and the results will provide novel insights about the role of specific NAc neural circuits underlying psychopathological vulnerability.