Molecular underpinnings of the developmental Effects of Cannabis

大麻发育影响的分子基础

• 批准号: 10467546
• 负责人: YASMIN L. HURD
• 金额: $ 85.1万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467546
• 关键词: Adolescent; Adult; Amygdaloid structure; Animal Model; Anxiety; Astrocytes; Attention; Behavior; Behavioral; Bioinformatics; Biological; Brain; Cannabidiol; Cannabis; Cells; Characteristics; Child; Child Behavior; Childhood; Collection; Complement; Data; Data Set; Databases; Decision Making; Development; Elderly; Epigenetic Process; Evaluation; Event; Exposure to; Female; Female of child bearing age; Future; Gene Expression; Gene Expression Profiling; Gene Proteins; Genes; Genetic Transcription; Growth; Health; Homing Behavior; Human; Immune; Immune system; Inflammatory; Knowledge; Life; Link; Long-Term Effects; Mediating; Medical; Modeling; Modification; Molecular; Molecular Profiling; Motivation; Neurobiology; Neuroglia; Neurons; Nuclear RNA; Nucleus Accumbens; Outcome; Pharmaceutical Preparations; Placenta; Play; Policies; Population; Pregnancy; Pregnant Women; Process; Proteins; Proteome; Proteomics; Psychopathology; Rattus; Regulation; Research; Resolution; Rewards; Risk; Rodent; Rodent Model; Role; Small Nuclear RNA; Specimen; Stress; Structure; Synapses; Synaptic plasticity; THC exposure; Tetrahydrocannabinol; Time; United States; Viral; Vulnerable Populations; Woman; Youth; addiction; behavioral phenotyping; behavioral study; cytokine; differential expression; endogenous cannabinoid system; endophenotype; experience; gene network; human fetal brain; human model; human subject; immune function; infancy; insight; male; marijuana legalization; marijuana use; marijuana use in pregnancy; maternal marijuana use; multidisciplinary; multiple omics; negative affect; neurobiological mechanism; neurodevelopment; neuropsychiatric disorder; novel; postnatal; pregnant teen; prenatal; prenatal exposure; programs; public education; risk perception; substance use treatment; synaptic function; transcription factor; transcriptome; transcriptome sequencing; translational study; virtual

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.

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， 大麻使用的医疗化和合法化，有助于降低对其危害的风险认知。 然而，这一转型时期对健康产生了影响，特别是对于与以下方面相关的弱势群体： 神经发育，因为大麻通常被孕妇和育龄妇女使用。 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，对行为具有长期影响 — 与奖励、动机、负面影响和决策以及与相关的分子干扰有关 突触可塑性具有严重的表观遗传失调，而压力会加剧这种失调。我们还确定了 与突触可塑性和与持久效应相关的行为相关的特定表观遗传修饰 发育性 THC 暴露。最近的结果强调了免疫系统与 自从对使用过大麻的妇女的胎盘进行初步基因表达分析以来，发育大麻/四氢大麻酚 怀孕期间吸食大麻揭示了免疫转录组的显着重组，这与 童年后期的行为。成年大鼠中皮质边缘结构中的免疫相关基因也发生了改变 随着发育性 THC 暴露的增加，这增强了免疫相关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，我们将进行综合和转化研究 （人类和大鼠模型）：(1) 确定产前大麻/四氢大麻酚暴露对免疫相关的影响 紊乱（胎盘和大脑）； (2) 描绘不同中皮质边缘细胞内的分子网络 通过高分辨率单细胞策略对因发育中的大麻/四氢大麻酚暴露而改变的人群进行研究 与免疫功能有关； (3) 识别早期生物紊乱（持续到成年期）的预测性 产前大麻/四氢大麻酚暴露对大脑的长期影响和因果介导行为。这 该项目获得的转化知识以及生成的人类和啮齿动物数据库将显着 增进我们对精神病理学风险的理解，这种风险通常在发育过程中产生。