Extreme anxiety in females: The role of the bed nucleus of the stria terminalis (BST) during the transition to adolescence in human and nonhuman primates

 描述(由申请人提供)：儿童时期持续的和高水平的持续焦虑是青春期焦虑和抑郁障碍发展的强烈预测因素。这与女性尤其相关，因为在青春期过后，女孩患这些疾病的可能性是女性的两倍。这项建议的目标是了解高度焦虑的女孩持续焦虑的生物学机制，它是如何随着时间的推移而变化的，以及它如何转化为精神病理学。利用我们在人类和非人类灵长类动物中研究焦虑的独特经验，我们将使用翻译神经科学的方法来理解高度焦虑的女孩和年轻焦虑的雌性恒河猴持续焦虑的神经生物学。神经成像研究将集中在终纹床核(BST)，因为它被认为与持续的焦虑和长期的威胁准备有关。类似的范例将在人类和猴子身上使用：1)表征高度焦虑女孩的大脑功能发育轨迹；2)检查BST功能变化与焦虑和抑郁障碍发病的相关性；3)测试BST在焦虑中的因果作用；以及4)确定BST分子变化与BST功能变化和持续焦虑有关。虽然持续性焦虑反应可以是适应性的，但许多与应激相关的精神病理学患者经历了极端程度的适应性不良持续性焦虑，特别是在不确定的条件下。为了了解焦虑女孩在过渡到青春期期间持续焦虑的神经基础，170名高度焦虑的女孩将被跟踪调查，从10岁到13岁14岁，进行临床评估、多模式神经成像以及行为和荷尔蒙测量持续焦虑。根据以前的研究，预计这些女孩中有40%会在青春期保持高度焦虑，其中多达一半的稳定焦虑女孩会出现真正的焦虑和/或抑郁障碍。焦虑的女孩和焦虑的雌性非人类灵长类动物将使用平行的功能神经成像任务来评估在长期和不确定的威胁下与持续焦虑相关的大脑激活。对年轻焦虑雌性猴子的机制研究将使用精确的MRI引导的BST神经元损伤来测试BST在焦虑行为中的因果作用，并首次在灵长类动物中识别BST输入调节功能的区域。最后，将使用激光捕获显微解剖从猴子的大脑中获取BST神经元，并使用RNA深度测序将基因表达的变化与焦虑程度和BST新陈代谢联系起来。这些翻译研究提供了检验有关BST功能的临床相关性和因果作用的假设的机会。此外，检查BST神经元的分子组成为识别导致高危儿童表型的新的分子机制提供了宝贵的机会。这种模式和方法的组合对于开发新的、以BST为重点的抗焦虑治疗具有很高的翻译潜力。

 DESCRIPTION (provided by applicant): Persistent and high levels of sustained anxiety during childhood are a strong predictor of the development of anxiety and depressive disorders during adolescence. This is particularly relevant to females because after puberty girls are twice as likely to develop these disorders. The goal of this proposal is to understand the biological mechanisms of sustained anxiety in highly anxious girls, how it changes over time, and how it can transform into psychopathology. Capitalizing on our unique experience with studies of anxiety in both human and nonhuman primates, we will use a translational neuroscience approach to understand the neurobiology of sustained anxiety in highly anxious girls and young anxious female rhesus monkeys. Neuroimaging studies will focus on the bed nucleus of the stria terminalis (BST) because it is thought to be involved in sustained anxiety and prolonged threat preparedness. Similar paradigms will be used in humans and monkeys to: 1) characterize developmental trajectories of brain function in highly anxious girls; 2) examine the relevance of altered BST function in relation to the onset of anxiety and depressive disorders; 3) test the causal role of the BST in anxiety as young anxious female monkeys mature into adolescence; and 4) define BST molecular alterations that are linked to altered BST function and sustained anxiety. Although sustained anxiety responses can be adaptive, many patients with stress-related psychopathology experience extreme levels of maladaptive sustained anxiety, especially under conditions of uncertainty. To understand the neural underpinnings of sustained anxiety in anxious girls across the transition to adolescence, 170 highly anxious girls will be followed from age 10/11 to age 13/14 with clinical assessments, multimodal neuroimaging, and behavioral and hormonal measures of sustained anxiety. Based on previous work, it is expected that 40% of these girls will maintain high levels of anxiety into adolescence, with up to half of these stably anxious girls developing bona fide anxiety and/or depressive disorders. Parallel functional neuroimaging tasks will be used with anxious girls and anxious female nonhuman primates to assess brain activation associated with sustained anxiety during exposure to prolonged and uncertain threat. Mechanistic studies in young anxious female monkeys will use precise MRI-guided lesions of BST neurons to test the causal role of the BST in anxious behavioral and to identify, for the first time in primates, regions that are functionally modulated by BST input. Finally, BST neurons will be harvested from monkey brains using laser capture microdissection, and RNA deep sequencing will be used to link variations in gene expression to anxiety severity and BST metabolism. These translational studies provide the opportunity to test hypotheses about the clinical relevance and causal role of BST function. In addition, examining the molecular composition of BST neurons provides an invaluable opportunity to identify novel molecular mechanisms that contribute to the at-risk child phenotype. This combination of modalities and methods has high translational potential for developing novel, BST-focused, anti-anxiety treatments.