Effects of Prenatal Alcohol Exposure on the Neurobiology of Social Behavior

描述(由申请人提供)：胎儿酒精谱系障碍(FASD)是一个总称，指怀孕期间母亲饮酒导致的一系列神经行为和生理损伤。在临床和临床前文献中记录的与产前酒精暴露(PAE)相关的认知、生理和行为损害中，终身社会行为缺陷是整个胎儿酒精谱系障碍(FASD)的统一特征。FASD患者的社交行为受损对其他领域具有广泛的影响，并可能导致学校环境中的困难、社交拒绝、法律问题，以及后来的心理健康问题。与PAE相关的社会行为缺陷在发育早期出现，并在青春期之前和青春期期间变得更加明显，青春期是一个关键的发展时期，在此期间发生了重大的行为、认知和生理变化，包括青春期的开始，使青春期成为社会行为障碍易感性增加的独特时期。然而，由于FASD和其他具有社会行为障碍的儿童障碍--包括自闭症谱系障碍(ASD)--的特征有相当大的重叠，对临床界来说，要想得到明确的诊断是一个挑战。事实上，有人提出，识别受FASD影响的个人的困难导致了 低估了其在普通人群中的高流行率(2%-5%)。当前研究建议的相关性取决于需要建立更具体的社会神经行为概况，以支持制定针对FASD的早期诊断和更有针对性的干预措施的具体战略。先前的临床前和临床研究表明，PAE影响大脑区域，改变支持社会行为的神经递质，包括前额叶皮质、杏仁核和下丘脑，以及催产素和加压素神经递质系统。因此，本提案将使用一个公认的中度PAE动物模型来表征社会行为及其潜在的神经关联。我们将检验这一假设，即PAE导致社会行为障碍(目标1)，这是由于OT/AVP系统的变化发展(目标2)。此外，由于临床和临床前文献支持催产素治疗在增强健康个体的社会行为方面以及在改善与自闭症、额颞痴呆和精神分裂症相关的社会行为缺陷方面的作用，我们还建议研究催产素治疗作为一种干预措施来挽救PAE后的社会行为缺陷(目标3)。拟议的研究将提供对PAE对社会行为影响的潜在机制的进一步洞察，并提出减轻此类缺陷的可能方法。

DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term that refers to the continuum of neurobehavioral and physiological impairments resulting from maternal alcohol consumption during pregnancy. Of the cognitive, physiological and behavioral impairments associated with prenatal alcohol exposure (PAE) documented in the clinical and pre-clinical literature, lifelong social behavior deficits serve as a unifying feaure across the entire continuum of Fetal Alcohol Spectrum Disorders (FASD). Impaired social behavior in individuals with FASD has widespread implications for other domains and may contribute to difficulties within the school environment, social rejection, trouble with the law, ad later mental health problems. PAE-related social behavior deficits emerge early in development and become more pronounced prior to and during adolescence, a critical period of development during which significant behavioral, cognitive, and physiological changes occur, including onset of puberty, making adolescence a unique period of increased vulnerability to social behavior dysfunction. However, because of the considerable overlap in the characteristics of FASD and other childhood disorders with social behavior impairments - including autism spectrum disorder (ASD) - reaching a definitive diagnosis presents a challenge for the clinical community. Indeed, it has been suggested that the difficulty in identifying individuals affected by FASD has led to an underestimation of its already high prevalence (2-5%) in the general population. The relevance of the current research proposal relies on the need for establishing a more specific social neurobehavioral profile that could support the development of specific strategies for earlier diagnoses and more targeted interventions for FASD. Previous pre-clinical and clinical research suggests that PAE affects brain areas and alters neurotransmitters shown to support social behavior, including the prefrontal cortex, amygdala, and hypothalamus, as well as the oxytocin and vasopressin neurotransmitter systems. Accordingly, the present proposal will characterize social behavior and its underlying neural correlates using a well-established animal model of moderate PAE. We will test the hypothesis that PAE results in social behavior impairments (Aim 1) that result from altered development of the OT/AVP systems (Aim 2). In addition, because the clinical and preclinical literature support a role for oxytocin treatment in enhancing aspects of social behavior in healthy individuals as well as in ameliorating social behavior deficits associated with ASD, frontotemporal dementia, and schizophrenia, we also propose to investigate oxytocin administration as an intervention for rescuing social behavior deficits following PAE (Aim 3). The proposed studies will provide further insight into mechanisms underlying the effects of PAE on social behavior, and suggest possible approaches for attenuation of such deficits.