Developmental Engagement of Neural Circuitry Underlying Safety Learning

项目摘要 焦虑症非常普遍，诊断在青春期达到顶峰，造成巨大的心理和经济社会负担。此外，现有的减轻焦虑症不适当恐惧反应的行为疗法对近一半的青少年人口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的知识。这个项目的主要目标是确定恐惧抑制的潜在机制，特别是在青春期表现出来的机制。该项目将青少年行为模型与尖端的神经成像和操作技术相结合，以阐明尚未研究过的安全信号在青春期抑制恐惧的机制。适用于小鼠青春期应用的“条件性安全”范例被用来解决有关安全学习的关键基础科学问题，具有深远的翻译和临床价值。通过这个范例，小鼠学会了利用刺激来明确预测不存在令人厌恶的结果(即“安全信号”)，以减轻恐惧反应。导师(K99)阶段的研究重点是腹侧海马区(VH)和前部皮质(PL)之间的联系，这两个区域参与情感行为的分配和调节，并在青春期经历强劲的变化。体内钙成像(纤维光度法)被用来记录和控制青春期小鼠VH-PL神经元的活动，阐明了安全的实时动态和恐惧行为与VH-PL信号波动之间的联系。从文献中借鉴和整合在K99阶段收集的初步数据导致了中心假说的提出，即VH向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，这种抑制在整个安全信号的呈现过程中持续存在，而不是恐惧信号，并且在青春期观察到的VH和PL内的高度可塑性为安全信号对恐惧的条件性抑制的增强效果提供了一个“敏感窗口”。独立(R00)阶段的目标是确定VH神经元的PL中间神经元靶点及其在条件性安全期间的相对活动。AIM 1将使用一种光谱分辨纤维光度系统来同时记录VH投射和选定的PL中间神经元群体。目的2将使用Fos激活(TRAP)病毒载体策略来操纵PL中间神经元的功能集合，以确定它们对抑制恐惧的贡献。完成这项研究的基础已经通过密集的培训和与顾问、顾问和合作者组成的顾问小组进行了讨论，这些顾问、顾问和合作者在青少年发展、恐惧学习以及电路和细胞类型特定神经元调制技术方面具有著名的专业知识。候选人在独立的研究生涯中处于有利地位，研究与精神疾病相关的发育啮齿动物模型中的行为调节，并确定用于干预和治疗的电路水平目标。

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.