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

项目总结 经过几十年的优雅研究，我们开发出了丰富的模型，说明我们是如何编码恐惧记忆的。恐惧 从这项研究中发现的电路是复杂的。然而，在几乎所有恐惧模型的中心 学习是杏仁基底外侧核。杏仁核基底外侧神经元的活动跟踪恐惧学习，并且 这一区域的谷氨酸能信号对于条件性恐惧的获得和表达是必要的。的确， 已有研究表明，杏仁基底外侧核的“恐惧印记”可以被靶向并消除以减少 恐惧。这导致了人们努力开发治疗方法，以消除有问题的记忆，最终可能会 转化为人类由于不适应的恐惧记忆而经历病理性恐惧。 然而，我们最近的研究表明，通常仅限于学习奖赏的神经元群体可以 也被招募来编码恐惧记忆(Sharpe等人，2021年，自然神经科学)。具体来说， 在实验中，下丘脑外侧区的GABA能神经元并不是编码恐惧记忆所必需的。 天真的老鼠。然而，如果大鼠最近有奖赏学习的经历，这依赖于下丘脑 功能，这些神经元成为编码恐惧记忆的关键。重要的是，这是在一个 控制与体验恐惧和奖励相关的许多实验变量的实验设计 学习经历。这表明，奖赏学习启动了下丘脑来编码恐惧记忆。 我们将研究外侧下丘脑的招募对已有文献记载的 杏仁基底外侧核编码恐惧记忆。我们的初步数据表明，奖赏学习发生了转变 恐惧回路远离杏仁基底外侧核，流向下丘脑外侧。我们进一步 假设参与恐惧的外侧下丘脑存在时间梯度，例如 这一角色将随着时间的推移而从奖励学习经验中衰退。为了正式测试这一点，我们将使用 基因编码钙传感器的细胞型特定光遗传学和纤维光度学 记录基底外侧杏仁核锥体神经元和下丘脑外侧GABA能神经元。我们会这么做的 在有或没有奖赏学习经历的大鼠恐惧学习过程中，同时改变奖赏之间的延迟 害怕学习程序。这将开始描述一种新的恐惧回路，包括外侧下丘脑， 扩展恐惧学习的模型，并洞察奖励体验如何影响恐惧编码。 这项工作对人类的心理健康很重要。我们知道杏仁基底外侧核活动的增强 由创伤性事件产生，并与随后恐惧学习的增强相关。此外，增加了 在患有创伤后应激障碍(PTSD)的人类中，人们可以看到杏仁核对恐惧线索的活动。因此，一种转移 从杏仁核到下丘脑的环路编码恐惧可以增强对问题恐惧的韧性 回忆。这项工作将扩大我们对恐惧记忆是在哪里获得和存储的理解，并将 还揭示了一种新的神经回路的招募，这种回路可以赋予人们对有问题的恐惧记忆的韧性。

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.