Developmental engagement of neural circuitry underlying safety learning

焦虑症非常普遍，诊断在青春期达到顶峰，造成了显著的 心理和经济社会负担。此外，现有的行为疗法可以减轻 焦虑障碍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的 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是如何成熟的。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。为此， 该项目将使用一种适用于青春期小鼠的新的“条件安全”范例来解决关键问题 关于安全学习的基础科学问题具有深远的翻译和临床价值。通过这件事 在范式中，小鼠学习利用刺激来明确预测不会出现令人厌恶的结果(即，安全 信号‘)服务于减弱恐惧反应。建议的研究集中在腹侧的海马体。 (VH)和前皮质(PL)，这两个区域参与情感行为的分配和调节， 在整个青春期经历强劲的变化。青少年行为模式将与尖端技术整合 神经成像和操作技术，以阐明尚未研究的安全信号 在青春期抑制恐惧。总之，拟议的实验旨在测试拱顶 假设VH投射到PL中间神经元通过产生对PL的净抑制来促进安全行为 这在安全的整个陈述中都是持续的，但不是恐惧的信号，而且增强的可塑性 青春期VH和PL内的观察为增强VH和PL的疗效提供了一个敏感窗口 通过安全信号对恐惧的条件性抑制。在指导(K99)阶段，光纤光度将用于 开发小鼠通过遗传编码将神经活动与安全和恐惧行为的实时动态联系起来 钙指示剂定位于VH-PL神经元。此外，将使用光遗传技术来确定 VH-PL神经元的活动是抑制恐惧的必要条件和充分条件。为了扩展这项工作，在《独立报》上 条件化过程中VH神经元下游PL中间神经元靶点的(R00)时相及其相对活动 将使用光谱分辨光纤光度测量系统同时从VH记录来识别安全性 PL中间神经元的投射和精选群体。最后，一种新的Fos激活(TRAP)病毒载体策略 将被用来操纵PL中间神经元的功能集合，以确定它们对抑制的贡献 恐惧。与指导团队进行密集培训，其中包括具有知名专业知识的合作者和顾问 在青春期发育中，恐惧学习和电路和细胞类型的特定神经元调制技术将 确保候选人的技术和专业发展，为她的独立研究生涯奠定基础 研究与精神疾病相关的发育期啮齿动物模型的行为规律并识别 电路级别的干预和治疗目标。

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.