Developmental Engagement of Neural Circuitry Underlying Safety Learning

安全学习背后的神经回路的发展参与

• 批准号: 10581708
• 负责人: Heidi Catherine Meyer
• 金额: $ 24.9万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581708
• 关键词: Address; Adolescence; Adolescent; Adolescent Development; Adult; Affective; Anatomy; Animals; Anxiety Disorders; Attenuated; Award; Basic Science; Behavior; Behavior Therapy; Behavioral; Behavioral Model; Behavioral inhibition; Biological; Brain; Buffers; Clinical; Code; Data; Development; Diagnosis; Economics; Effectiveness; Equilibrium; Exposure to; Extinction; Failure; Fiber; Foundations; Fright; Goals; Hippocampus; Human; Interneurons; Intervention; Knowledge; Learning; Link; Literature; Measures; Mediating; Mental disorders; Mentors; Methods; Modeling; Mus; Neurodevelopmental Disorder; Neurons; Outcome; Output; Parvalbumins; Phase; Photometry; Population; Positioning Attribute; Prefrontal Cortex; Process; Property; Protocols documentation; Regulation; Research; Rodent Model; Safety; Services; Severities; Signal Transduction; Somatostatin; Stimulus; Symptoms; System; Techniques; Testing; Time; Training; Viral Vector; anxiety-like behavior; career; cell type; cellular targeting; comorbidity; conditioned fear; excitatory neuron; in vivo calcium imaging; ineffective therapies; insight; neural; neural circuit; neurobiological mechanism; neuroimaging; novel; optogenetics; pharmacologic; psychologic; success; vulnerable adolescent

Project Summary 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. This project integrates adolescent behavioral models with cutting edge neural imaging and manipulation techniques to elucidate the yet unstudied mechanisms by which safety signals inhibit fear during adolescence. A ‘conditioned safety’ paradigm adapted for application during mouse adolescence is used 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. Research during the Mentored (K99) phase focused on the connection between the 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. In-vivo calcium imaging (fiber photometry) was used to record and optogenetics to manipulate activity in VH-PL neurons in adolescent mice, elucidating a link between real-time dynamics of safety and fear behavior to fluctuations VH-PL signaling. Drawing from the literature and integrating preliminary data collected during the K99 phase led to the advancement of the central 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. The goal of the Independent (R00) phase is to identify the PL interneuron targets of VH neurons and their relative activity during conditioned safety. Aim 1 will use a spectrally resolved fiber photometry system to record simultaneously from VH projections and select populations of PL interneurons. Aim 2 will use a Fos-activated (TRAP) viral-vector strategy to manipulate functional ensembles of PL interneurons to establish their contributions to the inhibition of fear. A foundation for accomplishing this research has been set through intensive training and discussion with an advisory panel of mentors, consultants, and collaborators with renowned expertise in adolescent development, fear learning, and circuit and cell-type specific neuronal modulation techniques. The candidate is well-positioned 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.

项目概要 焦虑症非常普遍，诊断在青春期达到顶峰，造成了巨大的心理和经济社会负担。此外，现有的减轻焦虑症中不当恐惧反应的行为疗法对于近一半的青少年群体来说效果有限或没有成功。开发更适合该群体的治疗方法的一个关键障碍是缺乏对与恐惧获得和抑制相关的关键神经回路如何成熟的了解。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。该项目将青少年行为模型与尖端神经成像和操作技术相结合，以阐明安全信号抑制青春期恐惧的尚未研究的机制。适合小鼠青春期应用的“条件安全”范式用于解决有关安全学习的关键基础科学问题，具有深远的转化和临床价值。通过这种范例，小鼠学会利用明确预测不存在厌恶结果（即“安全信号”）的刺激来减弱恐惧反应。指导（K99）阶段的研究重点是腹侧海马（VH）和前边缘皮层（PL）之间的联系，这些区域涉及情感行为的分配和调节，并且在整个青春期经历剧烈的变化。体内钙成像（光纤光度测定）用于记录和光遗传学来操纵青春期小鼠 VH-PL 神经元的活动，阐明安全和恐惧行为的实时动态与 VH-PL 信号波动之间的联系。借鉴文献并整合 K99 阶段收集的初步数据，提出了中心假设，即 VH 对 PL 中间神经元的投射通过产生对 PL 的净抑制来促进安全行为，这种净抑制在安全信号而非恐惧信号的整个过程中持续存在，并且青春期期间 VH 和 PL 内观察到的可塑性增强，为增强安全信号对恐惧条件性抑制的功效提供了一个“敏感窗口”。独立 (R00) 阶段的目标是识别 VH 神经元的 PL 中间神经元目标及其在条件安全期间的相对活动。目标 1 将使用光谱分辨光纤光度测量系统同时记录 VH 投影并选择 PL 中间神经元群体。目标 2 将使用 Fos 激活 (TRAP) 病毒载体策略来操纵 PL 中间神经元的功能整体，以确定它们对抑制恐惧的贡献。通过与导师、顾问和合作者组成的咨询小组的强化培训和讨论，为完成这项研究奠定了基础，他们在青少年发展、恐惧学习、回路和细胞类型特定神经元调制技术方面拥有著名的专业知识。该候选人非常适合从事独立研究职业，调查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水平目标。