Neurodevelopmental Effects of Cannabis and its Epigenetic Regulation

描述（由申请人提供）：越来越多的证据表明，基因和环境之间的相互作用在个体对精神疾病（包括药物成瘾）的易感性中起着关键作用。表观基因组受环境影响，因此是一个高度相关的生物学候选者，以维持持续异常的神经元加工作为发育药物暴露的结果。考虑到这一时期动态的神经可塑性特征，发育中的大脑可能对表观遗传影响特别敏感。大麻是孕妇和青少年最常使用的非法药物。我们对母体使用大麻的人类胎儿的研究显示，纹状体前脑啡肽（PENK）和多巴胺受体D2基因表达（主要富集于纹状体神经元）发生了选择性改变，但前啡肽或多巴胺D1受体（富集于纹状体神经元）没有发生选择性改变。同样的基因表达模式在暴露于？-四氢大麻酚（THC），大麻的精神活性成分，在产前和青春期。重要的是，PENK和D2基因表达障碍在产前或青少年THC暴露后持续到成年期，并且动物表现出增加的海洛因自我给药和抑制控制缺陷，这是预测药物成瘾脆弱性的表型。表观遗传修饰能够维持在整个发育过程中持续存在的修饰基因表达状态，这种机制可能是大麻暴露的长期影响的基础，这是一个有趣的可能性。在本项目中，我们拟研究发育性四氢大麻酚暴露成年大鼠腹侧纹状体PENK和D2基因特定调控区域的染色质修饰。事实上，PENK和D2基因在构成纹状体通路的纹状体神经元亚群中优先表达，这表明与该回路相关的基因可能对thc敏感。我们着手发现受发育性四氢大麻酚暴露影响的新型纹状体基因，并探索调节其表达的表观遗传机制。此外，我们将通过在腹侧纹状体中使用基因操作来研究四氢大麻酚敏感纹状体基因与成瘾相关行为之间的因果关系。总的来说，这些研究将为发育性四氢大麻酚暴露的长期影响提供重要的机制见解，这将有助于开发针对成瘾脆弱性和其他与发育性侮辱相关的相关精神疾病的针对性治疗干预措施。

DESCRIPTION (provided by applicant): Emerging lines of evidence suggest that interactions between genes and the environment play a critical role in individual vulnerability to psychiatric disorders including drug addiction. The epigenome is influenced by environment and thus is a highly relevant biological candidate to maintain persistent aberrant neuronal processing as a result of developmental drug exposure. The developing brain may be particularly sensitive to epigenetic influences, given the dynamic neuroplasticity characteristic of this period. Marijuana (Cannabis sativa) is the illicit drug most commonly used by pregnant women and teenagers. Our studies of human fetuses with maternal cannabis use revealed selective alterations of striatal preproenkephalin (PENK) and dopamine receptor D2 gene expression (predominantly enriched in striatopallidal neurons), but not prodynorphin or dopamine D1 receptors (enriched in striatonigral neurons). Similar gene expression patterns were detected in the ventral striatum of rats exposed to ?-tetrahydrocannabinol (THC), the psychoactive component of cannabis, prenatally as well as during adolescence. Importantly, PENK and D2 gene expression impairments persisted into adulthood following either prenatal or adolescent THC exposure and the animals exhibited increased heroin self-administration and inhibitory control deficit, phenotypes predictive of drug addiction vulnerability. Epigenetic modifications are capable of maintaining modified gene expression states that can persist throughout development and it is an intriguing possibility that such mechanisms would underlie the long-term effects of cannabis exposure. In this project, we propose to study chromatin modification at specific regulatory regions of the PENK and D2 genes in the ventral striatum of adult rats with developmental THC exposure. The fact that PENK and D2 genes are preferentially expressed in subpopulations of striatal neurons that constitutes the striatopallidal pathway suggests a potential THC-sensitivity of genes aligned to this circuit. We set out to discover novel striatopallidal genes that are affected by developmental THC exposure and explore the epigenetic mechanisms that regulate their expression. Furthermore, we will investigate the causal relationship between THC-sensitive striatopallidal genes and addiction-related behaviors by use of gene manipulation in the ventral striatum. Overall, these studies will provide important mechanistic insights into the long-term impact of developmental THC exposure that would enable the development of targeted treatment interventions for addiction vulnerability and other related psychiatric disorders associated with developmental insults. PUBLIC HEALTH RELEVANCE: Marijuana is the illicit drug most used by pregnant women and teens. Expanding knowledge regarding the long-term impact of developmental marijuana exposure on specific neurobiological events causally linked to behavioral disturbances will provide significant insights as to the discrete neurobiological mechanisms that may underlie the vulnerability to neuropsychiatric disorders.