Memory reactivation underlies experience-dependent adaptive regulation of sleep.
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| Title: | Memory reactivation underlies experience-dependent adaptive regulation of sleep. |
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| Authors: | Yu, Menghan (AUTHOR), Wang, Junjie (AUTHOR), Zhai, Zihan (AUTHOR), Huang, Ruoyi (AUTHOR), Fan, Guofan (AUTHOR), Su, Xiaoya (AUTHOR), Niu, Yijun (AUTHOR), Zhu, Haochen (AUTHOR), Chen, Jiayi (AUTHOR), Jiang, Grace (AUTHOR), Zhang, Tian (AUTHOR), Zhong, Yi (AUTHOR), Lei, Bo (AUTHOR) |
| Source: | Science. 6/4/2026, Vol. 392 Issue 6802, p1-18. 18p. |
| Subjects: | Sleep, Memory, Sleep interruptions, Neural circuitry, Episodic memory, Neurons, Psychological stress |
| Abstract: | Recent memories are consolidated during sleep by spontaneous reactivation. However, whether and how memory reactivation affects sleep dynamics remain unclear. By tracking and modulating memory activity during sleep in mice, we revealed that negative memory reactivation promoted arousal, whereas positive memory supported sleep stability. This regulation was mediated by the reactivation of experience-specific hippocampus-amygdala engram circuits during sleep. In chronic stress models, negative memory reactivation promoted sleep disturbance, and targeted suppression of memory reactivation restored normal sleep. Our findings establish a memory-dependent sleep regulation in which memory reactivation engages downstream circuits responsive to specific memory content. Editor's summary: Sleep has been shown to affect memory consolidation, and several studies have investigated the underlying mechanisms. However, how positive or negative memories affect sleep architecture remains to be elucidated. Working with mice, Yu et al. found that fear memory acquisition increased transitions from non–rapid eye movement sleep to wakefulness, whereas positive social memory reduced these transitions, promoting sleep (see the Perspective by Inokuchi). Mapping engram ensembles in the amygdala and hippocampus showed that negative engram reactivation activated wake-promoting brain regions. Suppressing negative memory engrams restored normal sleep. These results fill a critical gap in our understanding of the memory-sleep relationship. —Mattia Maroso INTRODUCTION: Sleep is not a static state but a dynamic process regulated by prior waking experiences. Memory replay or reactivation during sleep plays a main role in memory consolidation and forgetting. However, whether memory activity itself shapes sleep physiology remains poorly understood. RATIONALE: The influences of daily experience on subsequent sleep have been widely observed across species. Given that sleep is a state relatively isolated from exogenous stimuli, how experience-dependent regulation initiates and functions endogenously remains unclear. Because memory engrams encode experience to guide behaviors and exhibit spontaneous reactivation during sleep, we hypothesized that memory might also function as an endogenous regulator of adaptive sleep behaviors. To test this, we combined behavioral paradigms with targeted engram labeling and neuronal activity manipulation in mice. We used two-photon in vivo calcium imaging to track spontaneous engram activity during sleep as well as deep learning–based causal analysis. Moreover, by applying this mechanistic framework to a chronic stress model, we investigated the pathological origins of stress-associated sleep fragmentation. RESULTS: We found that after negative experiences, sleep becomes fragmented and revealed that such regulation is dependent on memory functions. By recording and manipulating memory engram cells during sleep, we show that these cells in the hippocampus-amygdala circuit serve as substrates for endogenously regulating sleep behaviors according to recent experiences. Furthermore, the reactivation of positive memory engrams stabilizes sleep by promoting non–rapid eye movement (NREM) continuity. Whole-brain projection mapping and functional c-Fos tracing revealed that such divergent functions of positive and negative memories derive from their distinct downstream networks. Positive engram cells preferentially project to and activate NREM-promoting regions, whereas negative engram cells predominantly project to wake-promoting centers. Applying these findings to a chronic stress model with sleep disturbances, we found that sleep fragmentation was induced by spontaneous reactivation of stressful memory engram cells. Targeted chemogenetic inhibition of these specific stress-associated engram cells during sleep rescued normal sleep continuity, reversing the pathological hyperactivation of the wake-promoting network. CONCLUSION: We have demonstrated that memory reactivation during sleep serves as the endogenous and active bridge linking daily experience to sleep regulation. As an endogenous trigger, memory reactivation actively sculpts sleep architecture based on the specific emotional content of recent waking experiences, allowing animals to flexibly deploy restorative or vigilant sleep strategies by linking the hippocampus-amygdala memory axis to downstream sleep-wake regulatory circuits. Pathologically, the reactivation of stressful memories acts as the fundamental driver of sleep fragmentation in a chronic stress model in mice. Our findings have identified an interaction between memory and sleep that could be leveraged for treating sleep disturbances. Experience-dependent adaptive regulation of sleep by memory reactivation.: (A) Reactivation of negative memory engrams within the basolateral amygdala (BLA) drives NREM-to-arousal transitions and increases arousability through preferential functional connection to wake-promoting networks. Conversely, positive memory reactivation improves sleep continuity and stability by engaging sleep-promoting networks. (B) In a chronic stress mouse model, the reactivation of stressful memory is involved in stress-induced sleep fragmentation, which can be therapeutically rescued by targeted engram inhibition during sleep. LC, locus ceruleus; LH, lateral hypothalamic area; MA, magnocellular nucleus; SNr, substantia nigra; VLPO, ventrolateral preoptic nucleus; W, wakefulness; R, REM; NR, NREM. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Recent memories are consolidated during sleep by spontaneous reactivation. However, whether and how memory reactivation affects sleep dynamics remain unclear. By tracking and modulating memory activity during sleep in mice, we revealed that negative memory reactivation promoted arousal, whereas positive memory supported sleep stability. This regulation was mediated by the reactivation of experience-specific hippocampus-amygdala engram circuits during sleep. In chronic stress models, negative memory reactivation promoted sleep disturbance, and targeted suppression of memory reactivation restored normal sleep. Our findings establish a memory-dependent sleep regulation in which memory reactivation engages downstream circuits responsive to specific memory content. Editor's summary: Sleep has been shown to affect memory consolidation, and several studies have investigated the underlying mechanisms. However, how positive or negative memories affect sleep architecture remains to be elucidated. Working with mice, Yu et al. found that fear memory acquisition increased transitions from non–rapid eye movement sleep to wakefulness, whereas positive social memory reduced these transitions, promoting sleep (see the Perspective by Inokuchi). Mapping engram ensembles in the amygdala and hippocampus showed that negative engram reactivation activated wake-promoting brain regions. Suppressing negative memory engrams restored normal sleep. These results fill a critical gap in our understanding of the memory-sleep relationship. —Mattia Maroso INTRODUCTION: Sleep is not a static state but a dynamic process regulated by prior waking experiences. Memory replay or reactivation during sleep plays a main role in memory consolidation and forgetting. However, whether memory activity itself shapes sleep physiology remains poorly understood. RATIONALE: The influences of daily experience on subsequent sleep have been widely observed across species. Given that sleep is a state relatively isolated from exogenous stimuli, how experience-dependent regulation initiates and functions endogenously remains unclear. Because memory engrams encode experience to guide behaviors and exhibit spontaneous reactivation during sleep, we hypothesized that memory might also function as an endogenous regulator of adaptive sleep behaviors. To test this, we combined behavioral paradigms with targeted engram labeling and neuronal activity manipulation in mice. We used two-photon in vivo calcium imaging to track spontaneous engram activity during sleep as well as deep learning–based causal analysis. Moreover, by applying this mechanistic framework to a chronic stress model, we investigated the pathological origins of stress-associated sleep fragmentation. RESULTS: We found that after negative experiences, sleep becomes fragmented and revealed that such regulation is dependent on memory functions. By recording and manipulating memory engram cells during sleep, we show that these cells in the hippocampus-amygdala circuit serve as substrates for endogenously regulating sleep behaviors according to recent experiences. Furthermore, the reactivation of positive memory engrams stabilizes sleep by promoting non–rapid eye movement (NREM) continuity. Whole-brain projection mapping and functional c-Fos tracing revealed that such divergent functions of positive and negative memories derive from their distinct downstream networks. Positive engram cells preferentially project to and activate NREM-promoting regions, whereas negative engram cells predominantly project to wake-promoting centers. Applying these findings to a chronic stress model with sleep disturbances, we found that sleep fragmentation was induced by spontaneous reactivation of stressful memory engram cells. Targeted chemogenetic inhibition of these specific stress-associated engram cells during sleep rescued normal sleep continuity, reversing the pathological hyperactivation of the wake-promoting network. CONCLUSION: We have demonstrated that memory reactivation during sleep serves as the endogenous and active bridge linking daily experience to sleep regulation. As an endogenous trigger, memory reactivation actively sculpts sleep architecture based on the specific emotional content of recent waking experiences, allowing animals to flexibly deploy restorative or vigilant sleep strategies by linking the hippocampus-amygdala memory axis to downstream sleep-wake regulatory circuits. Pathologically, the reactivation of stressful memories acts as the fundamental driver of sleep fragmentation in a chronic stress model in mice. Our findings have identified an interaction between memory and sleep that could be leveraged for treating sleep disturbances. Experience-dependent adaptive regulation of sleep by memory reactivation.: (A) Reactivation of negative memory engrams within the basolateral amygdala (BLA) drives NREM-to-arousal transitions and increases arousability through preferential functional connection to wake-promoting networks. Conversely, positive memory reactivation improves sleep continuity and stability by engaging sleep-promoting networks. (B) In a chronic stress mouse model, the reactivation of stressful memory is involved in stress-induced sleep fragmentation, which can be therapeutically rescued by targeted engram inhibition during sleep. LC, locus ceruleus; LH, lateral hypothalamic area; MA, magnocellular nucleus; SNr, substantia nigra; VLPO, ventrolateral preoptic nucleus; W, wakefulness; R, REM; NR, NREM. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.aed8630 |
