Neurodevelopmental Effects of Cannabis and its Epigenetic Regulation

大麻在全世界的普遍使用，加上其相对较低的致命性，导致许多人 相信它几乎没有什么害处。因此，大麻的使用量目前超过了烟草的吸烟量 美国的青少年。然而，现在人们承认，发育中的大脑对 会影响成年后行为的药物。这一点特别令人担忧，因为大麻是最 青少年和孕妇经常滥用的非法药物。我们的研究继续集中在 Δ9-四氢大麻酚，大麻的主要精神活性成分，与奖励和 精神脆弱。我们证明，在发育中的大脑中暴露于THC具有持久的影响 在成年后，分子和行为结果与奖励敏感性、动机行为有关 和负面影响。我们建立的产前动物模型模拟了中皮质边缘的分子变化 与我们在使用母体大麻的人类胎儿标本中看到的结构相似。此外，还有一些 与表观遗传障碍和突触可塑性相关的分子变化在 青春期接触THC的成年人强调发育THC的共同潜在机制 效果。我们确定了一个特定的表观遗传分子靶点(mll1；多发性白血病)，它直接与 由发育性THC引起的异常动机行为并制定了最先进的策略 例如激光捕获显微切割(LCM)以分离转录组和表观遗传学改变 神经通路。我们现在使用这样的策略来描绘表观遗传学的路径特异性改变。 整个基因组中与发育相关的THC机制。我们的研究主要集中在核上 伏隔神经(NAC)，它调节与成瘾有关的奖赏、动机行为和情绪调节 脆弱性和相关的精神病态。我们建议(1)刻画表观基因组中的变化 发育相关的成人NAC通路与THC的接触及其与转录的关系 使用LCM和染色质深度测序的可及性和与转录组数据重叠。(2)建立 特定NAC输出通路中识别的分子改变与行为之间的因果联系 与成瘾精神病理学相关的表型。(3)研究成人体内神经活动的模式。 利用创新技术研究发育过程中THC暴露的特定NAC途径 纤维光度法钙成像以特定途径的方式。从这一深入研究中生成的数据库 工作主体将是宝贵的资源，结果将提供关于特定NAC角色的新见解 神经回路潜伏着精神病理上的脆弱性。

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.