Supplement to Support Addiction Science and Related Neuroscience Pilot Research Projects (Al-Hilal and Moschak)

摘要--试点项目1(Al-Hilal) 近年来，几种蒸发产品投放市场，在青少年中迅速赢得了消费者， 育龄妇女，尤其是怀孕妇女。电子尼古丁传递系统或电子烟 (e-Cigs)已成为孕妇的首选产品，因为她们上瘾并相信自己是 比传统香烟安全得多。临床前研究表明，尼古丁(主要的电子液体) 成分)可引起血管内皮细胞功能障碍，加重脑缺血，增加血管内皮细胞 继发性脑损伤的易感性。同样，慢性e-Cig蒸发可能是脑血管疾病的前驱症状。 损伤和促进脑血管状况有利于脑缺血后继发性脑的发病 受伤。发育调节基因受出生前吸烟的影响比 成人期。母体e-Cig暴露导致认知和表观遗传学改变并恶化脑部结局 子代的损伤；然而，它们与脑血管发育的关系尚不清楚。广为传播 使用母体e-Cig，作为烟草烟雾的替代品，迫切需要方法学研究来确定 E-Cig对调节后代脑血管生成和发育过程中血脑屏障的基因的真正影响。因此，在 针对BBRC试点项目的项目范围和研究目标，我们提出如下建议：1) 评估产前暴露于E-Cig对子代脑血管内皮细胞的作用，并开发一组 潜在的血管生成生物标志物，以确定这些产品的危害和2)评估分子机制 驱动E-Cig介导的子代血脑屏障损伤及其对二次脑模型的影响 受伤。总体而言，我们将评估母体e-Cig蒸发对子代脑血管发育的影响。 我们的研究还将集中于它们对继发性脑损伤风险和结局的影响。监管的匮乏 由于我们对孕妇电子烟对健康影响的了解有限，指南已成为一个关键 我们希望通过这项研究解决公众和监管机构的关切。 摘要--试点项目2(莫沙克) 物质使用是拉美裔和其他人群之间存在健康差距的主要驱动因素 人群，行为内表型和物质使用之间的关系可能不同 西班牙裔和非西班牙裔个人。几种不同的行为内表型可以预测成瘾行为， 包括冲动性、耐受性、激励性和求新性。重要的是，这些行为 他们预测上瘾行为的能力经常相互作用或重叠。因此，迫切需要对这些进行测试 行为结合在一起，给出了与物质使用障碍最准确的关系。此外， 确定这些行为背后的神经底物是开发有效的 治疗上瘾的方法。然而，尽管包括我们自己在内的许多研究都评估了神经 这些行为表型的基础是孤立的，技术限制到目前为止限制了这种能力 以评估多个行为预测因子和药物寻找行为组合的神经活动。 幸运的是，体内钙成像的最新进展允许神经元跨多个 会议，并使这类研究成为可能。出于两个原因，这项研究是必要的。首先，它会 确定多个行为预测指标和药物寻找的共同神经底物。这 将分离所有表型中对药物寻找最关键的神经群，从而提炼候选 治疗发展的目标。其次，这项研究将确定独特的神经底物 与特定的行为和毒品有关。对这些独特的神经群体的了解将有助于 开发可针对个人行为特征量身定做的治疗方法。最后，确定 这些共同和独特的神经种群跨越不同的药物滥用类别，如可卡因和 海洛因是开发适当的针对毒品的治疗方法所必需的。作为研究这些问题的初始起点 初级皮质(PRL)是一种常见而独特的神经底物，是一种理想的候选者。首先， PRL是寻求毒品行为表达所必需的，在延长的过程中表现出神经适应 戒除滥用毒品。此外，PRL关键地参与了上述每一种行为 寻找毒品的预测因素，研究表明，在这些行为中PRL活动与毒品之间存在联系 使用。最后，PRL是在寻找可卡因和海洛因时激活的一个共同的大脑区域。因此，要 建立成瘾的多行为神经模型，我们计划用大鼠体内的钙成像来评估 寻找可卡因(目标1)和寻求海洛因(目标2)的多个行为预测因子之间的催乳素活动。 总的来说，这些研究将确定几种行为的独特和共同的神经贡献 成瘾的预测者。这反过来将有助于NIDA的使命，以确定生物和行为原因 以及药物使用和成瘾的后果，以及确定行为的生物学基础 在拉美裔和其他群体之间区分物质使用结果的内在表型。

ABSTRACT – Pilot Project 1 (Al-Hilal) In recent years several vaping products have hit the market, rapidly gaining consumers among adolescent, women of reproductive age, and especially pregnant women. Electronic nicotine delivery systems or e-cigarettes (e-Cigs) have become the preferred product to pregnant women due to the addiction and belief that they are much safer than traditional cigarettes. Preclinical studies have shown that nicotine (the principal e-liquid's ingredient) can cause vascular endothelial dysfunction, exacerbation of cerebral ischemia, and increase the susceptibility of secondary brain injuries. Likewise, chronic e-Cig vaping could be prodromal to cerebrovascular impairment and promote cerebrovascular conditions that favor the onset of post-ischemic secondary brain injuries. Developmentally regulated genes are more affected by smoke-exposure during prenatal life than adulthood. Maternal e-Cig exposure causes cognitive and epigenetic changes and worsens outcome to brain injuries in the offspring; however, their relationship with brain vasculature development is unknown. Widespread use of maternal e-Cig, alternative to tobacco smoke, strongly demands methodological studies to determine the real impact e-Cig on genes that regulate offspring’s brain angiogenesis and BBB during development. Thus, in response to the program scope and research objective of BBRC Pilot projects, we propose the following: 1) Assess the role of prenatal E-Cig exposure on the offspring brain endothelial cells and develop a panel of potential angiogenic biomarkers to determine harm of these products and 2) assess the molecular mechanisms that driving E-Cig-mediated impairment of the BBB in the offspring and its impact in a model of secondary brain injury. Overall, we will assess the impact of maternal e-Cig vaping on brain vascular development in the offspring. Our study will also focus on their impact on secondary brain injury risk and outcome. The dearth of regulatory guidelines, due to our limited knowledge on the health impact of maternal e-Cig vaping, has become a critical public and regulatory concern that we want to address with this research. ABSTRACT – Pilot Project 2 (Moschak) Substance use is a major driver of health disparities that exist between Hispanics and other segments of the population, and the relationships between behavioral endophenotypes and substance use can differ between Hispanic and non-Hispanic individuals. Several distinct behavioral endophenotypes predict addictive behavior, including impulsivity, distress tolerance, incentive salience, and novelty seeking. Importantly, these behaviors often interact or overlap in their ability to predict addictive behaviors. Thus, there is a strong need to test these behaviors in combination to give the most accurate relationship to substance use disorder. Furthermore, determining the neural substrates underlying these behaviors is an important step in developing effective treatments for addiction. However, while many studies including our own have assessed the neural underpinnings of these behavioral phenotypes in isolation, technical constraints have thus far limited the ability to assess neural activity across multiple behavioral predictors and drug-seeking behavior in combination. Fortunately, recent advances with in vivo calcium imaging allow for the registration of neurons across multiple sessions and render such research feasible. This research is necessary for two reasons. First, it would determine the neural substrates that are common to multiple behavioral predictors and drug-seeking. This would isolate the neural populations most critical to drug-seeking across all phenotypes and thus refine candidate targets for treatment development. Second, this research would determine the neural substrates that are unique to a particular behavior and drug-seeking. The knowledge of these unique neural populations would aid development of therapeutics that could be tailored to the behavioral profile of an individual. Finally, determining these common and unique neural populations across distinct classes of drugs of abuse such as cocaine and heroin is needed to develop appropriate drug-specific treatments. As an initial starting point to investigate these common and unique neural substrates, the prelimbic cortex (PrL) stands out as an ideal candidate. For one, the PrL is necessary for the expression of drug-seeking behavior and shows neuroadaptations during extended withdrawal from drugs of abuse. Further, the PrL is critically involved in each of aforementioned behavioral predictors of drug seeking, and studies have shown a link between PrL activity during these behaviors and drug use. Finally, the PrL is a common brain area activated during both cocaine and heroin seeking. Therefore, to establish a multi-behavioral neural model of addiction, we plan to use in vivo calcium imaging in rats to assess PrL activity across multiple behavioral predictors for cocaine-seeking (Aim 1) and heroin-seeking (Aim 2). Collectively, these studies will determine the unique and common neural contributions of several behavioral predictors of addiction. This in turn will assist NIDA’s mission to identify the biological and behavioral causes and consequences of drug use and addiction as well as determine the biological underpinnings of the behavioral endophenotypes that differentiate substance use outcomes between Hispanics and other groups.