Long-term discrimination and generalization of fear and extinction memories during sleep

学会什么时候害怕，也就是说，什么时候刺激预示着危险，什么时候不是，这对一个人的生存至关重要。在预测线索不太可能以完全相同的方式出现的不断变化的环境中，为了适应，学习到的联想需要推广到未来类似的情况。越来越多的证据表明，睡眠支持中性信息的概括，但对睡眠在概括危险和安全信息方面的作用知之甚少。我们假设睡眠本质上参与了危险和安全图式的逐渐形成，这是一个重要的先决条件，使人们能够对新情况进行概括。在平行的小鼠和人类研究中，我们将确定睡眠对条件恐惧和灭绝记忆的长期辨别和概括的影响（目的1）。我们将利用靶向记忆再激活来描述小鼠睡眠期间恐惧记忆加工的机制和神经相关因素（目的2）。最后，我们的目标是通过有针对性的记忆再激活来调节健康人类睡眠依赖的长期恐惧歧视和概括（目的3）。该项目将增加我们对睡眠在恐惧和灭绝记忆的区分和概括中的作用的机制理解，并指导下一个资助期的临床研究问题的转化。103

Learning when to fear, i.e., when a stimulus signals danger and when not, is essential to an individual’s survival. To behave adaptively in a changing environment where predictive cues are unlikely to occur in exactly the same way, learnt associations need to be generalized to future similar situations. Accumulating evidence indicates that sleep supports generalization of neutral information, but less is known about sleep’s role in generalizing danger and safety information. We hypothesize that sleep is essentially involved in the gradual formation of danger and safety schemas as an important prerequisite that enables the generalization to novel situations. In parallel mice and human studies, we will determine the impact of sleep on long-term discrimination and generalization of conditioned fear and extinction memories (Aim 1). We will characterize mechanisms and neural correlates of fear memory processing during sleep in mice using targeted memory reactivation (Aim 2). Finally, we aim to modulate sleep-dependent long-term fear discrimination and generalization in healthy humans using targeted memory reactivation (Aim 3). This project will increase our mechanistic understanding of sleep’s function in discrimination and generalization of fear and extinction memories, and also guide translation to clinical research questions in the next funding period. 103