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: 10581650
• 负责人: Melissa Sharpe
• 金额: $ 19.5万
• 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/10581650
• 关键词: Ablation; Amygdaloid structure; Behavioral; Brain region; Calcium; Clinical; Complex; Correlative Study; Cues; Data; Development; Exhibits; Experimental Designs; Exploratory/Developmental Grant; Fiber; Fright; Home; Human; Hypothalamic structure; Lateral; 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; anxiety reduction; cell type; conditioned fear; experience; fear memory; flexibility; glutamatergic signaling; hippocampal pyramidal neuron; insight; memory acquisition; memory encoding; neural; neural circuit; novel; optogenetics; recruit; resilience; sensor; success; 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 几十年来，我们对恐惧记忆的编码方式进行了大量的研究。的恐惧 从这项研究中出现的电路是复杂的。然而，在几乎所有恐惧模型的中心， 学习是基底外侧杏仁核。基底外侧杏仁核神经元的活动追踪恐惧学习， 这个区域的神经元能信号对于条件性恐惧的获得和表达是必要的。的确， 已经证明，基底外侧杏仁核中的“恐惧印记”可以被靶向和擦除， 恐惧这促使人们努力开发一种治疗方法，以消除有问题的记忆，最终可能 转化为人类由于适应不良的恐惧记忆而经历的病理性恐惧。 然而，我们最近的研究表明，一个通常只限于学习奖励的神经元群体， 也被招募来编码恐惧记忆（Sharpe等人，2021，Nature Neuroscience）。具体地说， 在实验中，外侧下丘脑中的GABA能神经元不是编码恐惧记忆所必需的- 幼稚的老鼠然而，如果老鼠最近有过奖励学习的经验，这是依赖于下丘脑的， 功能，这些神经元成为关键编码恐惧记忆。重要的是，这是在一个 一种控制许多与恐惧和奖励体验相关的实验变量的实验设计 学习经验。这表明，奖励学习使下丘脑准备好编码恐惧记忆。 我们将研究外侧下丘脑的募集对已被充分证明的下丘脑的作用的影响。 基底外侧杏仁核对恐惧记忆的编码我们的初步数据表明，奖励学习转移 恐惧回路从基底外侧杏仁核转移到外侧下丘脑。我们进一步 假设有一个时间梯度的参与外侧下丘脑的恐惧，如 这个角色会随着时间的推移而衰退。为了正式测试，我们将使用 基因编码钙传感器的细胞类型特异性光遗传学和光纤光度测定， 记录基底外侧杏仁核锥体神经元和外侧下丘脑GABA能神经元。我们会这样做 在有或没有奖励学习经验的大鼠的恐惧学习过程中， 害怕学习程序这将开始表征一种新的恐惧回路，包括外侧下丘脑， 扩展恐惧学习的模型，并深入了解奖励经验如何影响恐惧编码。 这项工作对人类的心理健康很重要。我们知道基底外侧杏仁核活动的增强 由创伤事件产生，并与随后的恐惧学习增强相关。此外，增加 在患有创伤后应激障碍（PTSD）的人中可以看到杏仁核对恐惧线索的活动。因此， 从杏仁核到下丘脑回路编码恐惧可以赋予对有问题的恐惧的恢复力 回忆这项工作将扩大我们对恐惧记忆是在哪里获得和储存的理解， 还揭示了一种新的神经回路的募集，这种回路可以赋予人们对有问题的恐惧记忆的恢复力。