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

摘要-试点项目1 （Al-Hilal）

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.