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

基本信息

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
项目类别：
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

项目摘要

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).

项目摘要 - 病理动画通常在儿童时期出现，是一个明显的风险后来焦虑和抑郁症的因素。为了深入了解该机制发展与压力相关的心理病理学的风险，我们开发了一种非人类灵长类动物（NHP）模型，称为焦虑温度（AT）。该模型允许基于机制的研究集中于发达的 NHP和人类共享的前额叶皮层（PFC）。在这方面，我们证明了PFC的参与病理动画中的背景PFC（DLPFC）等区域以及杏仁核和其他区域皮层下相关区域。神经影像学研究表明在动画和沮丧。 DLPFC参与情绪调节，工作记忆和认知控制，以及调节边缘区域的活性，例如基础杏仁核（BLA）。重要的是，DLPFC作为神经调节策略（例如重复经颅磁刺激（RTMS））的治疗目标并被认为参与介导各种认知疗法的影响。因为 NHP和人类之间的进化相关性，尤其是在PFC发展中，NHP是非常适合投资PFC在心理病理学中的作用。作为转化桥，我们的实验室员工方法，提供对相关大脑改变的深入机理理解具有极端动画，包括行为表型，功能和结构神经影像，RNA 测序和病毒载体介导的基因递送。该提议的重点是表征分子 DLPFC与AT相关的底物了解其自上而下的监管影响如何影响BLA， AT的介体，并探索DLPFC作为治疗目标。我们的实验室非常适合此当我们在NHP中使用具有行为表型，多模式成像的NHP的集成策略时，化学遗传学，电子显微镜和单核RNA测序（SNRNA-SEQ）。