Brain Mechanisms Mediating Genetic Risk for Anxiety and Depression

介导焦虑和抑郁遗传风险的大脑机制

• 批准号: 10522657
• 负责人: Ned H Kalin
• 金额: $ 77.75万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522657
• 关键词: Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Behavior assessment; Brain; Cell Nucleus; Child; Childhood; Chronic; Cognitive Therapy; Confocal Microscopy; Control Animal; Coupling; Data; Development; Down-Regulation; Electron Microscopy; Equilibrium; Foundations; Gene Delivery; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Risk; Glucocorticoids; Glutamates; Human; Investigation; Laboratories; Lasers; Life; Mediating; Mediator; Mental Depression; Mental disorders; Metabolic; Metabolism; Methods; Modeling; Molecular; Multimodal Imaging; Neuronal Plasticity; Neurons; Nuclear RNA; Pathological anxiety; Pathway interactions; Phenotype; Prefrontal Cortex; Primates; Psychopathology; Refractory; Research; Risk; Risk Factors; Role; Short-Term Memory; Stress; System; Techniques; Testing; Tissues; Viral Vector; anxious temperament; behavioral phenotyping; cell type; cognitive control; designer receptors exclusively activated by designer drugs; effective therapy; emotion regulation; experimental study; genetic approach; improved; insight; multimodal neuroimaging; neural circuit; neuroimaging; neuroregulation; nonhuman primate; repetitive transcranial magnetic stimulation; therapy development; transcriptome sequencing; treatment of anxiety disorders

PROJECT SUMMARY – Pathological anxiety commonly emerges during childhood and is a prominent risk factor for the later development of anxiety and depression. To gain insights into mechanisms underlying the risk to develop stress-related psychopathology, we developed a non-human primate (NHP) model, termed anxious temperament (AT). This model allows for mechanism-based studies focused on the well-developed prefrontal cortex (PFC) shared by NHPs and humans. In this regard, we demonstrated involvement of PFC regions such as the dorsolateral PFC (dlPFC) in pathological anxiety, along with the amygdala and other subcortical AT-related regions. Neuroimaging research points to hypoactivation of the dlPFC in anxiety and depression. The dlPFC is involved in emotion regulation, working memory, and cognitive control, and modulates activity of limbic regions, such as the basolateral amygdala (BLA). Importantly, the dlPFC serves as a treatment target for neuromodulation strategies such as repetitive transcranial magnetic stimulation (rTMS) and is thought to be involved in mediating the effects of various cognitive therapies. Because of the evolutionary relatedness between NHPs and humans, especially manifested in PFC development, NHPs are ideally suited for investigations of the role of the PFC in psychopathology. As a translational bridge, our laboratory employs methods that provide an in-depth mechanistic understanding of brain alterations associated with extreme anxiety, including behavioral phenotyping, functional and structural neuroimaging, RNA sequencing and viral vector-mediated gene delivery. The focus of this proposal is to characterize the molecular substrates of the dlPFC in relation to AT, to understand how its top-down regulatory influences impact the BLA, a mediator of AT, and to explore the dlPFC as a treatment target. Our laboratory is uniquely suited for this endeavor as we use an integrative strategy in NHPs with behavioral phenotyping, multimodal imaging, chemogenetics, electron microscopy and single nuclear RNA sequencing (snRNA-Seq).

病理性焦虑通常出现在儿童时期，是一个突出的风险 焦虑和抑郁的后期发展的因素。为了深入了解 风险发展压力相关的精神病理学，我们开发了一种非人灵长类动物（NHP）模型，称为 焦虑气质（AT）。该模型允许基于机制的研究集中在发育良好的 NHP和人类共享的前额叶皮层（PFC）。在这方面，我们展示了PFC的参与 在病理性焦虑中，背外侧前额叶皮层（dlPFC）等区域，沿着杏仁核和其他区域， 皮层下AT相关区域。神经影像学研究指出，焦虑症患者的dlPFC功能低下， 萧条dlPFC参与情绪调节、工作记忆和认知控制， 调节边缘区域的活动，例如基底外侧杏仁核（BLA）。重要的是，dlPFC作为 重复经颅磁刺激（rTMS）等神经调节策略的治疗靶点 并被认为参与调节各种认知疗法的效果。因为 NHPs和人类之间的进化相关性，特别是在PFC发育中表现出来，NHPs是 非常适合研究PFC在精神病理学中的作用。作为一座桥梁，我们 实验室采用的方法，提供了一个深入的机制，了解大脑的变化相关的 包括行为表型，功能和结构神经成像，RNA 测序和病毒载体介导的基因递送。该提案的重点是表征分子 与AT相关的dlPFC的底物，以了解其自上而下的监管影响如何影响BLA， AT的介导者，并探索dlPFC作为治疗靶点。我们的实验室是唯一适合这一点 奋进我们在NHP中使用行为表型分析，多模式成像， 化学遗传学、电子显微镜和单核RNA测序（snRNA-Seq）。