Neurodevelopmental Effects of Cannabis and its Epigenetic Regulation

描述(由申请人提供)：新出现的证据表明，基因和环境之间的相互作用在个人易受包括药物成瘾在内的精神疾病的影响方面发挥着关键作用。表观基因组受环境的影响，因此是一个高度相关的生物候选，以维持持续的异常神经元处理作为发育药物暴露的结果。考虑到这一时期的动态神经可塑性特征，发育中的大脑可能对表观遗传的影响特别敏感。大麻(大麻)是孕妇和青少年最常用的非法药物。我们对使用母体大麻的人胎儿的研究发现，纹状体前脑啡肽原(Penk)和多巴胺受体D2基因的表达(主要集中在纹状体苍白质神经元中)发生了选择性变化，但强啡肽原或多巴胺D1受体(主要集中在纹状体黑质神经元中)的表达没有变化。在孕期和青春期接触大麻的精神活性成分四氢大麻酚(THC)的大鼠的腹侧纹状体中也发现了类似的基因表达模式。重要的是，在产前或青春期接触THC后，Penk和D2基因表达受损一直持续到成年，动物表现出海洛因自我给药增加和抑制控制缺陷，这些表型预示着药物成瘾的易感性。表观遗传修饰能够维持改变的基因表达状态，这种状态可以在整个发育过程中持续存在，这是一种耐人寻味的可能性，这种机制将是大麻暴露的长期影响的基础。在这个项目中，我们建议研究发育中THC暴露的成年大鼠腹侧纹状体PENK和D2基因特定调控区的染色质修饰。Penk和D2基因在构成纹状体桥联通路的纹状体神经元亚群中优先表达的事实表明，与这一回路对齐的基因具有潜在的THC敏感性。我们开始发现新的纹状体蛋白基因，这些基因受发育过程中THC暴露的影响，并探索调节它们表达的表观遗传机制。此外，我们将通过腹侧纹状体的基因操作来研究纹状体敏感基因与成瘾相关行为之间的因果关系。总体而言，这些研究将对发育中THC暴露的长期影响提供重要的机械性见解，从而能够为成瘾易感性和与发育侮辱相关的其他相关精神障碍开发有针对性的治疗干预措施。 与公共卫生相关：大麻是孕妇和青少年最常使用的非法药物。扩大关于发育性大麻暴露对与行为障碍有因果关系的特定神经生物学事件的长期影响的知识，将为了解可能导致神经精神障碍的离散神经生物学机制提供重要的见解。

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.