Early Stress, Sensitive Periods and the Neurobiology of Addiction

说明(由申请人提供)：儿童期虐待(即父母、同龄人或兄弟姐妹的身体、性或情感虐待、身体和情感忽视)对药物滥用和依赖的风险有巨大影响。不良童年经历研究报告指出，暴露于与虐待有关的逆境中，占药物滥用人群归因风险的%。了解这种联系可能对我们预防、预防或治疗药物滥用的努力至关重要。在前一次筹资期间，我们进行了一系列研究，以更好地了解儿童期虐待与药物使用之间的联系。我们在横断面研究中发现，与情感虐待相比，身体虐待是大量使用药物和酒精的更重要的风险因素，而且身体虐待(但不是情感虐待)与提升多巴胺系统主要组成部分的T2-松弛时间(通过MRI评估的脑血量的间接测量)的显著变化有关。两个成分(背外侧前额叶和前扣带回皮质)的T2-松弛时间与药物和酒精的使用程度有关。此外，我们还发现，身体虐待受试者小脑第一小叶(舌状叶)的大小与物质使用程度之间存在很强的统计学关系。我们还发现，受虐待的个人在20-21岁时使用药物的人数激增。这项拟议研究的关键目的是在一项前瞻性研究中测试前额叶和扣带前皮质背外侧的T2-松弛时间，以及较大的舌头大小是否可以预测受虐待个人使用药物和酒精的程度。此外，我们将检验这样一种假设，即接触虐待的类型和时间很重要，而且在某些敏感期，接触特定类型的虐待最有可能影响这些大脑区域的发育，并增加药物滥用的风险。这些信息将通过从发育神经科学的角度研究虐待和药物滥用之间的现象，为我们理解虐待和药物滥用之间的关系提供新的线索。这些研究可能会提供必要的关键见解，以设计计划，在儿童最脆弱的时期保护他们，并制定先发制人的战略，在暴露于危险中的个人变得明显之前帮助他们。

DESCRIPTION (provided by applicant): Childhood maltreatment (i.e., physical, sexual or emotional abuse by parents, peers or siblings, physical and emotional neglect) has an enormous impact on risk for substance abuse and dependence. The Adverse Childhood Experience Study reported that exposure to maltreatment-related adversity accounted for 64% of the population attributable risk for substance abuse. Understanding this association may be crucial to our efforts to prevent, preempt or treat drug abuse. During the previous funding period we conducted a series of studies to better understand the association between childhood maltreatment and substance use. We found in cross-sectional studies that exposure to physical maltreatment was a more significant risk factor for high levels of drug and alcohol use than emotional maltreatment, and that physical maltreatment (but not emotional maltreatment) was associated with marked alterations in T2-relaxation time (an indirect measures of cerebral blood volume assessed by MRI) in major components of the ascending dopamine system. T2-relaxation time in two components (dorsolateral prefrontal and anterior cingulate cortex) correlated with degree of drug and alcohol use. Further we found a strong statistical relationship between the size of the first lobule (lingula) of the cerebellar vermis in physically maltreated subjects and degree of substance use. We also found that substance use by maltreated individuals spiked at 20-21 years of age. The key aims of the proposed study are to test in a prospective study whether T2-relaxation time in dorsolateral prefrontal and anterior cingulate cortex, and large lingula size can predict degree of drug and alcohol use by maltreated individuals. Moreover, we will test the hypothesis that type and timing of exposure to maltreatment matters, and that there are sensitive periods when exposure to specific types of maltreatment are most likely to effect the development of these brain regions¿ and to increase risk for drug abuse. This information will shed new light on our understanding of the relationship between maltreatment and drug abuse by examining the phenomenon from a developmental neuroscience perspective. These studies may provide the critical insights necessary to design programs to protect children during their most vulnerable periods, and to develop preemptive strategies to aid exposed individuals before their vulnerability becomes manifest.