Linking pathways and function in anxious adolescents

描述（由申请人提供）：焦虑症出现在青春期，以边缘系统区域功能障碍为特征，包括前额叶皮层、杏仁核和纹状体。杏仁核在焦虑症患者中一直被证明是过度活跃的，并且与前额叶皮层和纹状体有关。来自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青少年焦虑症以及行为抑制青少年（焦虑的一个重要风险因素）如何破坏该回路的研究。为了更好地理解这些联系，我们首先提出了非人类灵长类动物的神经解剖学研究，使用双向束追踪技术，通过单个杏仁核到纹状体区域绘制前额叶皮层的子区域。然后，我们将使用这些解剖结果为感兴趣的区域创建种子，用于对人类青少年的前额叶皮层，杏仁核和纹状体进行连接分析，以预测金钱奖励和惩罚。将在一组健康的青少年以及患有焦虑症和行为抑制的青少年中比较连接性，以了解疾病和脆弱性的神经生物学变化。我们假设，前额叶皮层的特定子区域将不同地投射到杏仁核纹状体通路，焦虑症患者的前额叶皮层到杏仁核的连接性降低，而杏仁核纹状体通路之间的连接性增加。目标1将绘制从前额皮质亚区域通过杏仁核到纹状体区域的投射。Aim 1A将绘制前额叶皮层-杏仁核投射，而Aim 1B将绘制Aim 1A所用同一动物的杏仁核纹状体投射。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的前额叶皮层-杏仁核-纹状体回路的功能连接。 公共卫生相关性：焦虑症出现在青春期，其特征是前额叶皮层、杏仁核和纹状体功能障碍。我们正在研究这些区域是如何连接在青少年焦虑症和青少年易受青春期障碍，特别是那些与行为抑制。

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.