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.

项目摘要 焦虑症非常普遍，在青少年风景秀丽期间诊断峰值，造成了重大的心理和经济社会负担。此外，现有的行为治疗可减弱在焦虑症中反应不适当的恐惧，对于几乎一半的青少年人群而言，成功或没有成功。开发更适合该群体的治疗方法的关键障碍是缺乏有关关键神经回路如何与恐惧获取和抑制成熟有关的知识。该项目的主要目标是确定恐惧抑制的基本机制，特别是在青少年期间表现出来。该项目将青少年的行为模型与尖端神经成像和操纵技术相结合，以阐明安全信号在青少年期间抑制恐惧的尚未研究的机制。在小鼠青少年期间，适用于应用的“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，并具有深远的翻译和临床价值。通过这种范式，小鼠学会使用刺激明确预测缺乏厌恶结果（即“安全信号”）来减轻恐惧的反应。在指导阶段（K99）期间的研究重点是腹侧海马（VH）和前比皮层（PL）之间的联系，涉及情感行为分配和调节的区域，以及在青少年之间发生较大的变化。体内钙成像（纤维光度法）用于记录和光遗传学，以操纵青少年小鼠的VH-PL神经元的活性，从而阐明了安全性动力学和恐惧行为与波动VH-PL信号传导之间的联系。从文献中绘制并整合在K99阶段收集的初步数据，导致了中心假设的发展，即VH预测PL中间神经元通过产生对PL的净抑制促进安全行为，而PL的净抑制在整个安全性介绍中，但害怕信号却不害怕，但在VH和PL内观察到的可持续性在Asival seciality sigeptients in and Assipity sige signity seformitional sige and a insection signity sefiention''的良好效率上都提高了效率。独立（R00）阶段的目的是确定VH神经元的PL间神经元靶标及其在条件安全过程中的相对活性。 AIM 1将使用频谱分辨的光纤光度法系统仅从VH投影中记录并选择PL中间神经元的种群。 AIM 2将使用FOS激活（TRAP）病毒矢量策略来操纵PL中间神经元的功能集合，以确立其对抑制恐惧的贡献。通过与顾问，顾问和合作者的咨询小组进行了深入的培训和讨论，建立了实现这项研究的基础。该候选人对与精神病相关的发育啮齿动物模型中的行为调节进行了独立研究职业，并确定了用于干预和治疗的电路级目标。