A Time Window for Memory Consolidation During NREM Sleep Revealed by cAMP Oscillation

Neurology Life Sciences Medicine
memory consolidation NREM sleep cAMP oscillation hippocampus neural activity

Time Window for Memory Consolidation—cAMP Oscillations Reveal Key Mechanisms in NREM Sleep

Academic Background

Sleep plays a crucial role in memory formation, particularly non-rapid eye movement (NREM) sleep, which is considered a critical stage for memory consolidation. However, the specific mechanisms underlying memory consolidation, especially how intracellular signaling molecules coordinate with neural activity, remain a mystery. Cyclic adenosine monophosphate (cAMP), as an intracellular second messenger, plays an important role in learning and memory. Although the significance of the cAMP signaling pathway in memory formation has been extensively studied, its real-time dynamics during sleep and its coordination with neural activity remain unclear.

To address this issue, researchers explored the dynamic changes of cAMP during sleep, particularly its oscillatory patterns in NREM sleep, and sought to reveal how these oscillations influence interactions between the hippocampus and cortex, thereby promoting memory consolidation. This study not only fills the gap in understanding the dynamic changes of cAMP signaling during sleep but also provides new insights into the mechanisms of memory consolidation.

Source of the Paper

This research was conducted by Ziru Deng, Xiang Fei, Siyu Zhang, and Min Xu, among others, from multiple institutions including the Institute of Neuroscience at the Chinese Academy of Sciences, Songjiang Hospital, and Songjiang Research Institute at Shanghai Jiao Tong University School of Medicine. The paper was published on June 18, 2025, in the journal Neuron, titled “A Time Window for Memory Consolidation during NREM Sleep Revealed by cAMP Oscillation.”

Research Process and Results

1. Dynamic Changes of cAMP Signaling During Learning

The study first measured cAMP signals in the hippocampus of mice using fiber photometry. Researchers employed a highly sensitive green fluorescent cAMP sensor (GFLAMP) and simultaneously monitored neural activity using a genetically encoded calcium indicator (GCaMP). The experiments involved mice performing spatial exploration tasks and auditory fear conditioning (AFC) tasks to study the relationship between cAMP signals and neural activity.

The results showed that cAMP and calcium signals significantly increased when mice explored objects, and the two were positively correlated. This indicates that cAMP signaling is closely related to neural activity during learning. Additionally, in the auditory fear conditioning task, footshock also triggered a rapid rise in cAMP signals, further confirming the critical role of cAMP in memory formation.

2. Dynamic Changes of cAMP Signaling Across the Sleep-Wake Cycle

Next, researchers analyzed changes in cAMP signals across different sleep stages. By recording polysomnography (EEG and EMG) in mice and measuring cAMP signals using fiber photometry, the study examined the dynamics of cAMP during NREM sleep, REM sleep, and wakefulness.

The results revealed that cAMP signals exhibited prominent infra-slow oscillations (ISO) during NREM sleep, with a cycle of approximately 60 seconds. These oscillations were synchronized with neural activity in the hippocampus and cortex, and cAMP signals were negatively correlated with calcium signals during NREM sleep. Furthermore, cAMP signals reached their lowest levels during REM sleep, while they were positively correlated with calcium signals during wakefulness. These findings suggest that cAMP signals exhibit distinct dynamic patterns across different sleep stages.

3. The Role of cAMP Oscillations in Memory Consolidation

To further investigate the role of cAMP oscillations in memory consolidation, researchers designed a closed-loop optogenetics experiment. In this experiment, mice were first trained in a spatial memory task, and then during the 3-hour post-training sleep period, researchers selectively inhibited hippocampal CA1 activity during the peak phase of cAMP oscillations using optogenetics.

The results showed that inhibiting hippocampal activity during the cAMP peak phase significantly impaired the mice’s spatial memory performance, while inhibition during the trough phase had no significant effect on memory. This indicates that hippocampal activity during the cAMP oscillation peak is crucial for memory consolidation. Additionally, researchers found enhanced functional connectivity between the hippocampus and cortex during the cAMP peak, further supporting the role of cAMP oscillations in memory consolidation.

4. Noradrenergic Signaling Regulates cAMP Oscillations

Finally, researchers explored the role of norepinephrine (NE) signaling in cAMP oscillations. By simultaneously measuring cAMP and NE signals, they found that NE signals were highly correlated with cAMP signals during NREM sleep, and the peak of NE signals preceded cAMP signals by approximately 6 seconds. Further pharmacological experiments showed that blocking β1 adrenergic receptors significantly reduced the amplitude of cAMP oscillations without affecting their rhythm. This suggests that NE signaling regulates the amplitude of cAMP oscillations through β1 receptors, thereby influencing memory consolidation.

Conclusions and Significance

This study reveals the infra-slow oscillatory patterns of cAMP signals during NREM sleep and demonstrates that these oscillations synchronize with neural activity in the hippocampus and cortex, forming a critical time window for memory consolidation. The research also found that norepinephrine signaling regulates the amplitude of cAMP oscillations through β1 receptors, thereby influencing memory consolidation. These findings provide new insights into the mechanisms of memory consolidation and offer potential targets for future therapeutic strategies targeting memory disorders.

Research Highlights

  1. Infra-Slow Oscillations of cAMP Signals in NREM Sleep: The study is the first to reveal the infra-slow oscillatory patterns of cAMP signals during NREM sleep, filling the gap in understanding the dynamic changes of cAMP signaling during sleep.
  2. Closed-Loop Optogenetics Experiment: Using closed-loop optogenetics, the study demonstrated that hippocampal activity during the cAMP oscillation peak is crucial for memory consolidation.
  3. Role of Noradrenergic Signaling: The research found that norepinephrine signaling regulates the amplitude of cAMP oscillations through β1 receptors, providing new perspectives on the neural regulatory mechanisms of memory consolidation.

Other Valuable Information

The study also found that cAMP oscillations are closely related to memory-related electrophysiological events such as hippocampal ripples and cortical spindles. These findings further support the important role of cAMP oscillations in memory consolidation and provide new directions for future research into the neural mechanisms of memory consolidation.

Through innovative experimental design and in-depth data analysis, this study reveals the dynamic changes of cAMP signaling during NREM sleep and its critical role in memory consolidation. These findings not only deepen our understanding of the mechanisms of memory formation but also provide new ideas for developing therapeutic strategies for memory disorders.