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.

项目概要 数十年的优雅研究已经开发出丰富的模型来解释我们如何编码恐惧记忆。 这项研究得出的电路很复杂，但它是几乎所有恐惧模型的核心。 学习是基底外侧杏仁核神经元的活动跟踪恐惧学习，并且 事实上，该区域的谷氨酸信号对于获得和表达条件性恐惧是必要的。 研究表明，基底外侧杏仁核中的“恐惧印迹”可以被针对性地消除，以减少 这导致人们努力开发治疗方法，以最终可能消除有问题的记忆。 转化为人类由于适应不良的恐惧记忆而经历病态恐惧。 然而，我们最近表明，通常仅限于学习奖励的神经元群体可以 也被招募来编码恐惧记忆（Sharpe et al., 2021, Nature Neuroscience）。 在实验中，下丘脑外侧的 GABA 能神经元不需要编码恐惧记忆。 然而，如果老鼠最近有过奖励学习的经验，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。 控制与体验恐惧和奖励相关的许多实验变量的实验设计 这表明奖励学习使下丘脑编码恐惧记忆。 我们将研究外侧下丘脑的募集对有据可查的下丘脑作用的影响。 我们的初步数据表明，奖励学习发生了变化。 我们进一步将恐惧回路从基底外侧杏仁核转向外侧下丘脑。 研究人员认为，下丘脑外侧参与恐惧存在时间梯度，例如 从奖励学习经验来看，这个角色会随着时间的推移而衰减。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类型特异性光遗传学和光纤光度测定，以操纵和 记录基底外侧杏仁核锥体神经元和外侧下丘脑 GABA 能神经元我们将这样做。 在有或没有奖励学习经历的老鼠的恐惧学习过程中，同时改变奖励之间的延迟 和恐惧学习程序，这将开始表征由外侧下丘脑组成的新型恐惧回路， 恐惧学习模型，并深入了解奖励性经历如何影响恐惧编码。 这项工作对人类心理健康很重要。我们知道基底外侧杏仁核活动的增强是重要的。 由创伤事件产生，并与随后的恐惧学习增强相关。 在患有创伤后应激障碍（PTSD）的人中，杏仁核对恐惧线索的活动发生了转变。 从杏仁核到下丘脑回路来编码恐惧可以赋予抵抗有问题的恐惧的能力 这项工作将扩大我们对恐惧记忆的获取和存储位置的理解。 还揭示了一种新的神经回路的招募，可以赋予人们抵抗有问题的恐惧记忆的能力。

项目成果

The cognitive (lateral) hypothalamus.

认知（外侧）下丘脑。

• 发表时间: 2024-01
• 影响因子: 19.9
• 作者: Sharpe; Melissa J
• 通讯作者: Melissa J

BehaviorDEPOT is a simple, flexible tool for automated behavioral detection based on markerless pose tracking.

BehaviourDEPOT 是一种简单、灵活的工具，用于基于无标记姿势跟踪的自动行为检测。

• 发表时间: 2022-08-23
• 影响因子: 7.7
• 作者: Gabriel, Christopher J;Zeidler, Zachary;Jin, Benita;Guo, Changliang;Goodpaster, Caitlin M;Kashay, Adrienne Q;Wu, Anna;Delaney, Molly;Cheung, Jovian;DiFazio, Lauren E;Sharpe, Melissa J;Aharoni, Daniel;Wilke, Scott A;DeNardo, Laura A
• 通讯作者: DeNardo, Laura A