Investigating the Recruitment of Lateral Hypothalamic Circuits for Encoding Fear Memories Following Experience with Reward Learning

奖励学习经验后调查下丘脑外侧回路编码恐惧记忆的情况

• 批准号: 10453103
• 负责人: Melissa Sharpe
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453103
• 关键词: Amygdaloid structure; Anxiety; Behavioral; Brain region; Calcium; Clinical; Complex; Correlative Study; Cues; Data; Development; Exhibits; Experimental Designs; Exploratory/Developmental Grant; Fiber; Fright; Home; Human; Hypothalamic structure; Lateral; Lead; Learning; Life; Longevity; Memory; Mental Health; Modeling; Nature; Neurons; Neurosciences; Pathologic; Photometry; Physiological; Population; Post-Traumatic Stress Disorders; Procedures; Rattus; Research; Rewards; Role; Site; Stimulus; Testing; Time; Translating; Work; cell type; conditioned fear; experience; fear memory; flexibility; glutamatergic signaling; hippocampal pyramidal neuron; insight; memory encoding; neural circuit; novel; optogenetics; recruit; relating to nervous system; resilience; sensor; traumatic event

PROJECT SUMMARY Decades of elegant research has led to development of rich models of how we encode fear memories. The fear circuit that has emerged from this research is complex. However, at the center of nearly all models of fear learning is the basolateral amygdala. Activity in basolateral amygdala neurons tracks fear learning, and glutamatergic signaling in this region is necessary for the acquisition and expression of conditioned fear. Indeed, it has been demonstrated that the “fear engram” in basolateral amygdala can be targeted and erased to reduce fear. This has led to efforts to develop treatments to erase problematic memories in a manner that may eventually translate to humans experiencing pathological fear as a result of maladaptive fear memories. However, we have recently shown that a neuronal population usually restricted to learning about rewards, can be recruited to encode fear memories as well (Sharpe et al., 2021, Nature Neuroscience). Specifically, GABAergic neurons in the lateral hypothalamus are not necessary to encode fear memories in experimentally- naïve rats. Yet if rats have had recent experience with reward learning, which is dependent on hypothalamic function, these neurons become critical to encode the fear memory. Importantly, this is in the context of an experimental design that controls for many experimental variables associated with experiencing fear and reward learning experiences. This suggests that reward learning primes the hypothalamus to encode fear memories. We will examine the impact that recruitment of the lateral hypothalamus has for the well-documented role of the basolateral amygdala in encoding fear memories. Our preliminary data suggest that reward learning shifts the fear circuit away from the basolateral amygdala and towards the lateral hypothalamus. We further hypothesize that there is a temporal gradient to the involvement of the lateral hypothalamus in fear, such that this role will decay with time from the reward learning experience. To formally test this, we will use cell-type specific optogenetics and fiber photometry of a genetically-encoded calcium sensor to manipulate and record basolateral amygdala pyramidal neurons and lateral hypothalamic GABAergic neurons. We will do this during fear learning in rats with or without reward learning experience, while varying the delay between reward and fear learning procedures. This will begin to characterize a novel fear circuit comprising lateral hypothalamus, expanding models of fear learning, and giving insight into how rewarding experience influences fear encoding. This work is important to human mental health. We know that enhancements in basolateral amygdala activity is produced by traumatic events, and correlated with subsequent enhancements in fear learning. Further, increased amygdala activity to fear cues is seen in humans with post-traumatic stress disorder (PTSD). Thus, a shift away from amygdala towards hypothalamic circuits to encode fear could confer resilience against problematic fear memories. This work will expand our understanding of where fear memories are acquired and stored, and will also reveal recruitment of a novel neural circuit that could confer resilience against problematic fear memories.

项目摘要 数十年的优雅研究导致了我们如何编码恐惧记忆的丰富模型的发展。恐惧 从这项研究中出现的电路很复杂。但是，几乎所有恐惧模式的中心 学习是基底外侧杏仁核。基底外侧杏仁核神经元的活动跟踪恐惧学习，并且 该区域中的谷氨酸能信号传导对于有条件恐惧的获取和表达是必要的。的确， 已经证明，基底外侧杏仁核中的“恐惧engram”可以被靶向并删除以减少 害怕。这导致努力以一种有时可能的方式开发治疗方法来消除有问题的记忆 转化为由于适应不良的恐惧记忆而经历病理恐惧的人类。 但是，我们最近表明，神经元的人群通常仅限于学习奖励，可以 也可以招募以编码恐惧记忆（Sharpe等，2021，自然神经科学）。具体来说， 下丘脑外侧的GABA能神经元无需在实验中编码恐惧记忆 但是，如果老鼠最近有奖励学习经验，这取决于下丘脑 功能，这些神经元对于编码恐惧记忆至关重要。重要的是，这是 实验设计控制与经验恐惧和奖励相关的许多实验变量 学习经验。这表明，下丘脑奖励学习素数以编码恐惧记忆。 我们将研究下丘脑外侧下丘脑对有据可查的作用的影响 基底外侧杏仁核编码恐惧记忆。我们的初步数据表明奖励学习转变 恐惧电路从基底外侧杏仁核和下丘脑侧偏离。我们进一步 假设有暂时的梯度涉及下丘脑的恐惧，这样 这个角色会随着奖励学习经验的时间而衰落。为了正式测试，我们将使用 遗传编码的钙传感器的细胞类型特异性光遗传学和光纤光度法，以操纵和 记录基底外侧杏仁核神经元和下丘脑GABA能神经元。我们会这样做 在有或没有奖励学习经验的老鼠学习期间，同时改变奖励之间的延迟 并害怕学习程序。这将开始表征一个新颖的恐惧回路，完成下丘脑的侧面， 扩大恐惧学习的模型，并深入了解奖励体验如何影响恐惧编码。 这项工作对人类心理健康很重要。我们知道大载杏仁核活性的增强是 由创伤事件产生，与后来的恐惧学习增强相关。此外，增加了 杏仁核活性在患有创伤后应激障碍（PTSD）的人类中可以看到恐惧提示。那，移开了 从杏仁核到下丘脑圈到编码恐惧，可以使韧性与有问题的恐惧相抗衡 回忆。这项工作将扩大我们对获得和存储恐惧记忆的理解，并将 还揭示了一种新型神经回路的招募，该神经电路可能会使有问题的恐惧记忆赋予韧性。