Molecular underpinnings of the developmental Effects of Cannabis

近年来，大麻的社会政治格局发生了巨大变化，导致了大麻合法化， 大麻使用的医学化和合法化，有助于降低对其危害的风险认识。 然而，这一转型时期具有健康影响，特别是对与以下相关的脆弱人群 由于大麻是孕妇和育龄妇女普遍使用的神经发育药物。 我们长期研究积累的证据清楚地表明，产前接触D9- 四氢大麻酚(THC)是大麻的主要精神活性成分，对行为有长期影响 -与奖励、动机、负面情绪和决策有关，以及与以下方面有关的分子干扰 突触可塑性与严重的表观遗传失调，这会因应激而加剧。我们还确认了 与突触可塑性相关的特定表观遗传修饰和与延长效应相关的行为 发育中的THC暴露。最近的研究结果表明，免疫系统与 吸毒妇女胎盘基因表达初步分析后发育性大麻/THC 怀孕期间吸食大麻显示出免疫转录组的显著重组，这与 童年后期的行为。成年大鼠中皮质边缘结构中免疫相关基因也发生了改变 与发育中的THC接触，这增强了免疫和突触相关之间的相关性 基因。为了获得神经生物学和机械学方面的见解，我们将进行综合和翻译研究 (人和大鼠模型)：(1)确定产前大麻/THC暴露对免疫相关的影响 紊乱(胎盘和脑)；(2)描绘不同的中皮质边缘细胞内的分子网络 通过高分辨率单细胞策略改变发育中的大麻/THC暴露 与免疫功能相关；以及(3)识别早期生物障碍(持续到成年)预测性 关于产前大麻/THC暴露对大脑的长期影响和因果中介行为的研究。这个 从该项目获得的翻译知识以及生成的人类和啮齿动物数据库将大大 促进我们对精神病理风险的理解，这种风险往往在发育过程中产生。

The cannabis sociopolitical landscape has dramatically shifted in recent years leading to the decriminalization, medicalization, and legalization of cannabis use, which has contributed to the reduced risk perception of its harm. This transformational time, however, has health implications particularly for vulnerable populations related to neurodevelopment since cannabis is commonly used by pregnant women and women of childbearing age. Accumulating evidence from our long-standing research has clearly demonstrated that prenatal exposure to D9- tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has long-term effects on behaviors — relevant to reward, motivation, negative affect and decision-making, and molecular disturbances linked to synaptic plasticity with profound epigenetic dysregulation that are exacerbated by stress. We have also identified specific epigenetic modifications linked to synaptic plasticity and behaviors associated with the protracted effects of developmental THC exposure. Recent results have highlighted the immune system as relevant to developmental cannabis/THC since preliminary gene expression analysis of the placenta from women who used cannabis during pregnancy revealed marked reorganization of the immune transcriptome that correlated with later childhood behavior. Immune-related genes were also altered in mesocorticolimbic structures of adult rats with developmental THC exposure, which enhances the correlation between immune- and synaptic-related genes. To gain neurobiological and mechanistic insights, we will conduct integrative and translational studies (human and rat models) to: (1) Determine the impact of prenatal cannabis/THC exposure on immune-related disturbances (placenta and brain); (2) Delineate molecular networks within distinct mesocorticolimbic cell populations through high resolution single-cell strategies altered by developmental cannabis/THC exposure relevant to immune function; and (3) Identify early biological disturbances (sustained into adulthood) predictive of long-term effects on brain and causally mediate behavior due to prenatal cannabis/THC exposure. The translational knowledge gained and the human and rodent databases generated from this project will significantly advance our understanding of psychopathology risk that often has its genesis during development.