Developmental engagement of neural circuitry underlying safety learning

焦虑症非常普遍，诊断在青春期达到高峰， 心理和经济社会负担。此外，现有的行为治疗，以减轻 焦虑症中不适当的恐惧反应对近一半的青少年来说是有限的或没有成功 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以下方面的了解： 与恐惧获得和抑制相关的关键神经回路如何成熟。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。为此目的， 该项目将使用一种适用于青春期小鼠的新的“条件安全”范式来解决关键问题， 安全学习的基础科学问题具有深远的转化和临床价值。通过这个 在范例中，小鼠学会利用明确预测不存在令人厌恶的结果的刺激（即，的安全 信号），以减轻恐惧反应。拟议的研究集中在腹侧海马 (VH)和前边缘皮层（PL），参与情感行为的分配和调节的区域， 在整个青春期经历了巨大的变化。青少年行为模式将与尖端技术相结合 神经成像和操作技术，以阐明尚未研究的机制， 在青春期抑制恐惧。总之，拟议的实验旨在测试总体 假设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 在整个安全信号的呈现过程中，这种情绪是持续的，但不是恐惧信号， 在青春期期间在VH和PL内观察到的一个“敏感窗口”为增强的疗效提供了一个“敏感窗口”， 安全信号对恐惧的条件性抑制。在指导（K99）阶段，将使用光纤测光， 开发小鼠，通过基因编码将神经活动与安全和恐惧行为的实时动态联系起来， VH-PL神经元内有钙离子指示剂。此外，将使用光遗传学技术来确定是否 VH-PL神经元中的活性对于恐惧抑制是必要且充分的。为了扩展这项工作，在独立 (R00)使VH神经元的下游PL中间神经元靶标及其在条件性期间的相对活性相适应。 将使用光谱分辨光纤光度测定系统同时记录VH 预测和选择PL中间神经元的群体。最后，一种新的Fos激活（TRAP）病毒载体策略 将用于操纵PL中间神经元的功能集合，以确定它们对抑制的贡献。 恐惧与包括具有知名专业知识的合作者和顾问在内的辅导团队一起进行强化培训 在青少年发育中，恐惧学习以及电路和细胞类型特异性神经元调节技术将 确保候选人的技术和专业发展，定位她的独立研究生涯 研究与精神疾病相关的发育啮齿动物模型的行为调节， 回路级干预和治疗目标。

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. To this end, this project will use a novel ‘conditioned safety’ paradigm appropriate for use in adolescent mice 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. The proposed research focuses on 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. Adolescent behavioral models will be integrated with cutting edge neural imaging and manipulation techniques to elucidate the yet unstudied mechanisms by which safety signals inhibit fear during adolescence. Together, the proposed experiments are designed to test the overarching 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. In the Mentored (K99) phase, fiber photometry will be used in developing mice to link neural activity to real-time dynamics of safety and fear behavior via genetically encoded calcium indicators localized in VH-PL neurons. Further, optogenetic techniques will be used to establish whether activity in VH-PL neurons is necessary and sufficient for fear inhibition. To extend this work, in the Independent (R00) phase the downstream PL interneuron targets of VH neurons and their relative activity during conditioned safety will be identified using a spectrally resolved fiber photometry system to record simultaneously from VH projections and select populations of PL interneurons. Finally, a novel Fos-activated (TRAP) viral-vector strategy will be used to manipulate functional ensembles of PL interneurons to establish their contributions to the inhibition of fear. Intensive training with a mentoring team including collaborators and consultants with renowned expertise in adolescent development, fear learning, and circuit- and cell-type specific neuronal modulation techniques will ensure the candidate’s technical and professional development, situating her 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.