Linking pathways and function in anxious adolescents

描述（由申请人提供）：焦虑症出现于青春期，以边缘区域功能障碍为特征，包括前额叶皮质、杏仁核和纹状体。在患有焦虑症的患者中，杏仁核一直表现出过度活跃，并且与前额叶皮层和纹状体有联系。前额叶皮层的投射抑制杏仁核，而杏仁核纹状体的投射检测显著性，并将积极的动机效价分配给复杂的刺激，以产生行为反应。前额叶皮层-杏仁核-纹状体回路的连通性尚未得到很好的表征，我们提出了旨在了解该回路如何被青少年焦虑症以及青少年行为抑制（焦虑的重要危险因素）所破坏的研究。为了更好地理解这些联系，我们首先提出在非人类灵长类动物中进行神经解剖学研究，利用双向束追踪技术绘制前额叶皮层亚区，通过单个杏仁核到纹状体区域。然后，我们将利用这些解剖学结果，在预测金钱奖励和惩罚的人类青少年的前额叶皮层、杏仁核和纹状体的连通性分析中，为感兴趣的区域创造种子。为了了解疾病和脆弱性的神经生物学变化，将在健康青少年群体以及患有焦虑症和行为抑制症的青少年群体中比较这种连通性。我们假设前额叶皮层的特定亚区对杏仁核纹状体通路的投射会有所不同，并且那些焦虑的人前额叶皮层与杏仁核之间的连接会减少，而杏仁核纹状体通路之间的连接会增加。目的1将绘制从前额皮质亚区通过杏仁核到纹状体区域的投影。Aim 1A将绘制前额叶皮层-杏仁核投影，而Aim 1B将绘制用于Aim 1A的同一动物的杏仁核纹状体投影。目的2将使用功能性磁共振成像（fMRI）和预期金钱奖励和损失的任务，比较患有焦虑症或行为抑制的青少年与正常健康青少年前额叶皮层-杏仁核-纹状体回路的功能连通性。

DESCRIPTION (provided by applicant): Anxiety disorders emerge in adolescence and are marked by dysfunction of limbic regions, including the pre- frontal cortex, amygdala and striatum. The amygdala has consistently been shown to be hyperactive among patients with anxiety disorders, and has connections with the pre-frontal cortex and the striatum. Projections from the pre-frontal cortex inhibit the amygdala, while amygdalostriatal projections detect salience and assign positive motivational valence to complex stimuli to create a behavioral response. The connectivity of the pre- frontal cortex-amygdala-striatum circuit has not been well characterized, and we propose studies aimed at understanding how this circuit is disrupted by anxiety disorders in adolescents, as well as adolescents with behavioral inhibition, a significant risk factor for anxiety. To better understand these connections, we first propose neuroanatomic studies in non-human primates that chart the subregions of the pre-frontal cortex through individual amygdalar nuclei to regions of the striatum using a bidirectional tract-tracing technique. We will then use these anatomic results to create seeds for regions of interest in a connectivity analysis of the pre- frontal cortex, amygdala and striatum in human adolescents anticipating monetary rewards and punishments. The connectivity will be compared in a healthy group of adolescents, as well as adolescents with anxiety disorders and behavioral inhibition, in order to understand neurobiologic changes of disease and vulnerability. We hypothesize that specific subregions of the pre-frontal cortex will project differentially to the amygdalostriatal pathways, and that those with anxiety will have decreased connectivity from their pre-frontal cortex to amygdala, with increased connectivity between their amygdalostriatal pathways. Aim 1 will map the projections from subregions of the pre-frontal cortex through amygdalar nuclei to regions of the striatum. Aim 1A will map the pre-frontal cortex-amygdala projections, while Aim 1B will map the amygdalostriatal projections within the same animal used for Aim 1A. Aim 2 will compare the functional connectivity of the pre-frontal cortex-amygdala-striatum circuit in human adolescents with anxiety disorders or behavioral inhibition with normal, healthy adolescents, using functional magnetic resonance imaging (fMRI) and a task of anticipation of monetary rewards and losses. PUBLIC HEALTH RELEVANCE: Anxiety disorders emerge during adolescence and are marked by dysfunction of the pre- frontal cortex, amygdala and striatum. We are researching how these regions are connected in adolescents with anxiety disorders and adolescents vulnerable to adolescent disorders, specifically those with behavioral inhibition.