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）：儿童期持续和高水平的持续焦虑是青春期焦虑和抑郁障碍发展的有力预测因素。这对女性尤其重要，因为青春期后，女孩患这些疾病的可能性是男性的两倍。这个建议的目的是了解高度焦虑的女孩持续焦虑的生物学机制，它如何随着时间的推移而变化，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方法来了解高度焦虑的女孩和年轻焦虑的雌性恒河猴中持续焦虑的神经生物学。神经影像学研究将集中在终纹床核（BST），因为它被认为是参与持续的焦虑和长期的威胁准备。将在人类和猴子中使用类似的范例以：1）表征高度焦虑女孩的脑功能的发育轨迹; 2）检查与焦虑和抑郁障碍的发作有关的改变的BST功能的相关性; 3）测试当年轻的焦虑雌性猴子成熟到青春期时BST在焦虑中的因果作用;和4）定义与改变的BST功能和持续焦虑相关的BST分子改变。虽然持续的焦虑反应可以是适应性的，但许多患有压力相关精神病理学的患者会经历极端的适应不良持续焦虑，特别是在不确定的条件下。为了了解焦虑女孩在向青春期过渡期间持续焦虑的神经基础，将对170名高度焦虑的女孩进行随访，从10/11岁到13/14岁，进行临床评估，多模式神经影像学以及持续焦虑的行为和激素测量。根据以前的工作，预计这些女孩中有40%将在青春期保持高水平的焦虑，这些稳定焦虑的女孩中有多达一半会发展出真正的焦虑和/或抑郁症。平行的功能性神经成像任务将用于焦虑的女孩和焦虑的雌性非人灵长类动物，以评估在暴露于长期和不确定的威胁期间与持续焦虑相关的大脑激活。在年轻的焦虑雌性猴子的机制研究将使用精确的MRI引导的BST神经元病变，以测试焦虑行为的BST的因果作用，并确定，首次在灵长类动物中，功能调制的BST输入的区域。最后，将使用激光捕获显微切割从猴脑中收获BST神经元，并使用RNA深度测序将基因表达的变化与焦虑严重程度和BST代谢联系起来。这些转化研究提供了机会，以测试有关BST功能的临床相关性和因果作用的假设。此外，研究BST神经元的分子组成提供了一个宝贵的机会，以确定新的分子机制，有助于在危险的儿童表型。这种模式和方法的组合具有开发新的，BST为重点的抗焦虑治疗的高转化潜力。

 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.