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，导致大麻合法化， 医疗化和大麻使用合法化，这有助于降低对大麻危害的风险认识。 然而，这一转型时期对健康产生了影响，特别是对与以下方面有关的弱势群体： 大麻对神经发育的影响很大，因为孕妇和育龄妇女通常使用大麻。 从我们长期的研究中积累的证据清楚地表明，产前暴露于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，负面影响和决策有关，以及与 突触可塑性与深刻的表观遗传失调，加剧了压力。我们还确定 与突触可塑性和行为相关的特异性表观遗传修饰 四氢大麻酚暴露的风险最近的结果强调了免疫系统与 发育大麻/THC，因为对使用大麻的妇女的胎盘进行了初步基因表达分析， 怀孕期间的大麻揭示了免疫转录组的显著重组， 后来的童年行为。免疫相关基因在成年大鼠中皮质边缘结构也发生了改变 与发育THC暴露，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制的见解，我们将进行整合和转化研究 （人类和大鼠模型），以：（1）确定产前大麻/THC暴露对免疫相关的影响 （2）描绘不同中皮质边缘细胞内的分子网络 通过发育大麻/THC暴露改变的高分辨率单细胞策略 与免疫功能相关;以及（3）识别早期生物学紊乱（持续到成年）预测 对大脑的长期影响和由于产前大麻/THC暴露引起的因果介导行为。的 从该项目中获得的翻译知识和产生的人类和啮齿动物数据库将大大 推进我们对精神病理学风险的理解，这种风险通常在发展过程中产生。

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.