Fear Memory-Triggered Sleep Disruption: Insights from Ventral Hippocampus-Basolateral Amygdala Manipulation

Study Objectives A daytime fearful experience may cause sleep disturbances in the following nights, but the underlying neural circuits remain unclear. Here, we investigated how fear memory influences sleep and examined the contribution of the ventral CA1-basolateral amygdala (vCA1-BLA) pathway to fear-associated alterations in sleep. Methods All experiments were performed on adult male mice. To probe the effect of fear memory, we presented fear-conditioned auditory stimuli during sleep and quantified sleep-to-wake transitions, with particular attention to responses within the fear-associated context. We used calcium imaging, optogenetics, local field potential, chemogenetics, and activity-dependent genetic labeling tools (ADGLT) to assess the contribution of the vCA1-BLA pathway to sleep changes during re-exposure to fear-associated cues. Results The vCA1-BLA pathway showed stronger neuronal activity when the asleep mice were exposed to fear-conditioned auditory stimuli within the fear-associated context. Inhibiting this pathway reduced the increased transitions from sleep to wakefulness in response to re-exposure to combined contextual-auditory fear cues. Functional connectivity analysis between the vCA1 and BLA demonstrated enhanced information flow from vCA1 to BLA during tone-triggered sleep–wake transitions. Using ADGLT to re-stimulate the vCA1➔BLA neurons previously activated during fear conditioning increased stimulation-triggered sleep-to-wake transitions during sleep and elicited freezing responses during wakefulness. Conclusion Enhanced activity within the vCA1-BLA circuit is associated with increased sleep-to-wake transitions when animals are exposed to combined fear-conditioned environmental and auditory conditions. These findings provide evidence that fear-associated neural ensembles can be re-engaged during sleep and may interfere with sleep continuity, highlighting a potential neural mechanism underlying fear-related sleep disturbances.