Developmental Engagement of Neural Circuitry Underlying Safety Learning

项目摘要 焦虑症非常普遍，诊断在青春期达到高峰，造成了重大的心理和经济社会负担。此外，现有的行为治疗，以减轻不适当的恐惧反应的焦虑症有有限的或没有成功的近一半的青少年人口。开发更适合这一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。这个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。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，以阐明尚未研究的安全信号抑制青春期恐惧的机制。一个“条件安全”的范例适用于在小鼠青春期的应用程序是用来解决关键的基础科学问题的安全学习具有深远的转化和临床价值。通过这种模式，小鼠学会利用刺激明确预测不存在令人厌恶的结果（即，“安全信号”）以减弱恐惧反应。指导（K99）阶段的研究集中在腹侧海马（VH）和前边缘皮层（PL）之间的联系，这些区域参与情感行为的分配和调节，并在整个青春期发生强烈的变化。体内钙成像（纤维光度法）用于记录和光遗传学操纵青春期小鼠VH-PL神经元的活动，阐明了安全性和恐惧行为的实时动态与波动VH-PL信号传导之间的联系。从文献中提取并整合在K99阶段收集的初步数据导致了中心假设的进步，即VH投射到PL中间神经元通过产生PL的净抑制来促进安全行为，该PL的净抑制在整个安全信号的呈现过程中持续，而不是恐惧信号，在青少年时期观察到的VH和PL的可塑性增强为恐惧的条件抑制的增强功效提供了一个“敏感窗口”，安全信号。独立（R 00）阶段的目标是识别VH神经元的PL中间神经元靶标及其在条件安全期间的相对活性。目的1将使用光谱分辨光纤光度系统，同时记录从VH预测和选择PL中间神经元的群体。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，以建立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讨论与顾问小组的导师，顾问和合作者在青少年发展，恐惧学习，电路和细胞类型特定的神经元调制技术的知名专业知识。候选人是一个独立的研究生涯调查行为调节发育啮齿动物模型相关的精神疾病，并确定干预和治疗的回路水平的目标定位。

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.