Developmental Engagement of Neural Circuitry Underlying Safety Learning

安全学习背后的神经回路的发展参与

基本信息

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
项目类别：
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

项目摘要

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治疗方法对近一半的青少年来说效果有限或没有成功。开发更适合这一群体的治疗方法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的知识。该项目的主要目标是确定青春期恐惧抑制的具体机制。行为模型利用尖端的神经成像和操作技术来阐明安全信号抑制青春期恐惧的尚未研究的机制，适用于小鼠青春期的“条件安全”范式用于解决有关影响深远的安全学习的关键基础科学问题。通过这种范例，小鼠学会利用刺激来明确预测厌恶结果（即“安全信号”），以减轻指导期间的恐惧反应。 (K99) 阶段重点关注腹侧海马 (VH) 和前边缘皮层 (PL) 之间的连接，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强烈的变化（纤维光度测定）。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，阐明安全的实时动态和恐惧行为与 VH-PL 信号波动之间的联系。结合 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 PL 的净抑制来促进安全行为，这种净抑制在整个安全呈现过程中持续存在，而不是恐惧信号，并且丰富的青春期期间观察到的 VH 和 PL 内的可塑性为增强安全信号条件性恐惧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 神经元和 PL 中间神经元的目标。目标 1 将使用光谱分辨光纤光度测定系统同时记录 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功能集合。 PL 中间神经元通过与具有青少年领域知名专业知识的导师、顾问和合作者组成的咨询小组进行强化培训和讨论，为完成这项研究奠定了基础。该候选人在研究与精神疾病相关的发育啮齿动物模型中的行为调节以及确定干预和治疗的回路水平目标方面具有良好的独立研究生涯。