Developmental engagement of neural circuitry underlying safety learning

安全学习背后神经回路的发展参与

• 批准号: 10018112
• 负责人: Heidi Catherine Meyer
• 金额: $ 8.71万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018112
• 关键词: Address; Adolescence; Adolescent; Adolescent Development; Adult; Affective; Age; Animals; Anxiety Disorders; Attenuated; Basic Science; Behavior; Behavior Therapy; Behavioral; Behavioral Assay; Behavioral Model; Biological; Brain; Clinical; Data; Development; Diagnosis; Economics; Effectiveness; Ensure; Exposure to; Extinction (Psychology); Failure; Fiber; Fright; Goals; Hippocampus (Brain); Human; Image; Interneurons; Intervention; Knowledge; Learning; Link; Measures; Mediating; Mental disorders; Mentors; Mus; Nature; Neurodevelopmental Disorder; Neurons; Outcome; Pharmacology; Phase; Photometry; Population; Process; Property; Protocols documentation; Regulation; Research; Rodent Model; Safety; Services; Severities; Signal Transduction; Stimulus; System; Techniques; Testing; Time; Training; Viral Vector; Work; anxiety-like behavior; associated symptom; calcium indicator; career; cell type; cellular targeting; conditioned fear; conditioning; design; experimental study; ineffective therapies; inhibitor/antagonist; insight; learned behavior; neural circuit; neurobiological mechanism; novel; optogenetics; psychologic; relating to nervous system; research and development; success; vulnerable adolescent

Anxiety disorders are highly prevalent, with diagnoses peaking during adolescence, creating a significant psychological and economic societal burden. Moreover, existing behavioral treatments to attenuate inappropriate fear responding in anxiety disorders have limited or no success for nearly half of the adolescent population. A critical barrier to developing treatments better suited for this group is a lack of knowledge about how key neural circuits related to fear acquisition and inhibition mature. The principal goal of this project is to identify the mechanisms underlying fear inhibition specifically as it manifests during adolescence. To this end, this project will use a novel ‘conditioned safety’ paradigm appropriate for use in adolescent mice to address key basic science questions about safety learning with far-reaching translational and clinical value. Through this paradigm, mice learn to utilize stimuli explicitly predicting the absence of an aversive outcome (i.e., ‘safety signals’) in service of attenuating fear responding. The proposed research focuses on the ventral hippocampus (VH) and prelimbic cortex (PL), regions involved in the allocation and regulation of affective behaviors, and that undergo robust changes across adolescence. Adolescent behavioral models will be integrated with cutting edge neural imaging and manipulation techniques to elucidate the yet unstudied mechanisms by which safety signals inhibit fear during adolescence. Together, the proposed experiments are designed to test the overarching hypothesis that VH projections to PL interneurons promote safety behavior by producing a net inhibition of PL that is sustained throughout presentations of safety, but not fear signals, and that the heightened plasticity observed within VH and PL during adolescence provides a ‘sensitive window’ for enhanced efficacy of the conditioned inhibition of fear by safety signals. In the Mentored (K99) phase, fiber photometry will be used in developing mice to link neural activity to real-time dynamics of safety and fear behavior via genetically encoded calcium indicators localized in VH-PL neurons. Further, optogenetic techniques will be used to establish whether activity in VH-PL neurons is necessary and sufficient for fear inhibition. To extend this work, in the Independent (R00) phase the downstream PL interneuron targets of VH neurons and their relative activity during conditioned safety will be identified using a spectrally resolved fiber photometry system to record simultaneously from VH projections and select populations of PL interneurons. Finally, a novel Fos-activated (TRAP) viral-vector strategy will be used to manipulate functional ensembles of PL interneurons to establish their contributions to the inhibition of fear. Intensive training with a mentoring team including collaborators and consultants with renowned expertise in adolescent development, fear learning, and circuit- and cell-type specific neuronal modulation techniques will ensure the candidate’s technical and professional development, situating her for an independent research career investigating behavioral regulation in developmental rodent models relevant to psychiatric illness and identifying circuit-level targets for intervention and treatment.

焦虑症非常普遍，诊断在青春期达到顶峰，造成了显着的 心理和经济社会负担。此外，现有的行为疗法可以减轻 对于近一半的青少年来说，对焦虑症的不适当的恐惧反应效果有限或没有成功 人口。开发更适合该群体的治疗方法的一个关键障碍是缺乏关于 与恐惧获得和抑制相关的关键神经回路如何成熟。该项目的主要目标是 确定恐惧抑制的机制，特别是在青春期表现出来的恐惧抑制机制。为此， 该项目将使用一种适合青春期小鼠的新型“条件安全”范例来解决关键问题 有关安全学习的基础科学问题具有深远的转化和临床价值。通过这个 在这种范例中，小鼠学会利用刺激来明确预测不存在令人厌恶的结果（即“安全性”） 信号”）以减轻恐惧反应。拟议的研究重点是腹侧海马 （VH）和前边缘皮层（PL），参与情感行为分配和调节的区域，并且 在整个青春期经历剧烈的变化。青少年行为模型将与尖端技术相结合 神经成像和操纵技术来阐明尚未研究的安全信号机制 抑制青春期的恐惧。总之，所提出的实验旨在测试总体 假设 VH 投射到 PL 中间神经元通过产生 PL 净抑制来促进安全行为 在整个安全演示过程中都持续存在这一点，但不是恐惧信号，并且增强的可塑性 在青春期期间观察到的 VH 和 PL 提供了一个“敏感窗口”，以增强 通过安全信号对恐惧进行条件性抑制。在指导（K99）阶段，光纤光度测定将用于 开发小鼠，通过基因编码将神经活动与安全和恐惧行为的实时动态联系起来 钙指示剂定位于 VH-PL 神经元。此外，光遗传学技术将用于确定是否 VH-PL 神经元的活动对于恐惧抑制来说是必要且充分的。为了扩展这项工作，《独立报》 (R00) 调节 VH 神经元的下游 PL 中间神经元靶标及其在条件反射期间的相对活动 将使用光谱分辨光纤光度测量系统从 VH 同步记录来确定安全性 PL 中间神经元的预测和选择群体。最后，一种新型 Fos 激活 (TRAP) 病毒载体策略 将用于操纵 PL 中间神经元的功能整体，以确定它们对抑制的贡献 的恐惧。由具有知名专业知识的合作者和顾问组成的指导团队进行强化培训 在青少年发展中，恐惧学习以及电路和细胞类型特定的神经元调节技术将 确保候选人的技术和专业发展，使她能够从事独立的研究职业 研究与精神疾病相关的发育啮齿动物模型的行为调节并确定 干预和治疗的回路级目标。