Neurodevelopmental Effects of Cannabis and its Epigenetic Regulation

描述（由申请人提供）：新出现的证据表明，基因与环境之间的相互作用在个体易患精神疾病（包括药物成瘾）方面起着关键作用。表观基因组受环境的影响，因此是一个高度相关的生物学候选人，以维持持续异常的神经元加工作为发育药物暴露的结果。发育中的大脑可能对表观遗传的影响特别敏感，因为这一时期的动态神经可塑性特征。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，纹状体前脑啡肽原（PENK）和多巴胺受体D2基因表达（主要富集在纹状体苍白球神经元中）的选择性改变，但不是强啡肽原或多巴胺D1受体（富集在纹状体黑质神经元中）。类似的基因表达模式被检测到在大鼠腹侧纹状体暴露？-四氢大麻酚（THC），大麻的精神活性成分，产前以及在青春期。重要的是，在产前或青少年THC暴露后，PENK和D2基因表达障碍持续到成年期，并且动物表现出增加的海洛因自我管理和抑制控制缺陷，这些表型预测药物成瘾的脆弱性。表观遗传修饰能够保持修饰的基因表达状态，这种状态可以在整个发育过程中持续存在，并且这种机制可能是大麻暴露的长期影响的基础，这是一种有趣的可能性。在这个项目中，我们建议研究染色质修饰在特定的调控区域的PENK和D2基因在腹侧纹状体的成年大鼠发育THC暴露。事实上，PENK和D2基因优先表达的纹状体神经元的亚群，构成了striatopallidal通路表明一个潜在的THC敏感性的基因对齐到这个电路。我们着手发现新的striatopallidal基因，这些基因受到发育中THC暴露的影响，并探索调节其表达的表观遗传机制。此外，我们将调查THC敏感的纹状体基因和成瘾相关行为之间的因果关系，通过使用基因操作在腹侧纹状体。总的来说，这些研究将为THC暴露的长期影响提供重要的机制性见解，这将有助于开发针对成瘾脆弱性和其他与发育性损伤相关的相关精神疾病的有针对性的治疗干预措施。 公共卫生相关性：玛丽莎克是孕妇和青少年使用最多的非法药物。扩大知识的长期影响，发展大麻暴露在特定的神经生物学事件因果关系到行为障碍将提供重要的见解离散的神经生物学机制，可能是神经精神疾病的脆弱性。

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.