Abstract:

Sleep problems may induce fear-related mood disorders such as anxiety, post-traumatic stress disorder (PTSD), and phobias, among others. Studying the cognitive cognitive and neural mechanisms involved in the relationship between sleep problems and fear learning can help enhance the prediction, diagnosis, and treatment of fear-related mood disorders. Previous studies have shown that sleep deprivation affects fear acquisition mainly by inhibiting the activity of the ventral medial prefrontal cortex (vmPFC) and blocking its functional connections with the amygdala, resulting in impaired safe learning that fails to inhibit fear of threatening stimuli, thus enhancing fear acquisition. In contrast, sleep deprivation during the fear memory consolidation phase impairs the activity of the amygdala and hippocampus, thereby impairing fear memory. On the other hand, sleep deprivation during the extinction learning phase results in delayed activation of brain regions associated with extinction learning, which in turn impairs fear extinction memory. Further studies have reported that different stages of sleep have distinct effects on brain regions associated with fear learning; in particular, rapid eye movement (REM) sleep deprivation (insufficient) and complete sleep deprivation have similar effects on the cognitive and neural mechanisms of fear learning. Deprivation of REM sleep suppresses vmPFC activity, enhances amygdala activation, and thus enhances fear acquisition. In addition, reduced functional connectivity in the limbic cortex disrupts fear memory consolidation. Deprivation of REM sleep after extinction learning phase increases amygdala, insula, and dorsal anterior cingulate cortex (dACC) activity and diminishes mPFC, thereby impairing extinction memory. Therefore, after clinical treatment, quality of sleep, particularly REM sleep, should be ensured at night. In addition to reinforcing recently acquired memories, REM sleep is involved in integrating new information into existing knowledge structures, reorganizing these structures, and generalizing recently acquired memories; therefore, improving REM sleep can promote fading retention and generalization. In contrast, the slow-wave sleep (SWS) stage facilitates fear extinction learning through target memory reactivation, which allows the hippocampus to re-code threatening stimuli and accelerate the consolidation of new safety information in the amygdala. During the SWS stage, participants are not conscious and therefore do not have to directly face the threatening stimulus, thus avoiding some of the drawbacks of traditional extinction therapy applied during wakefulness for patients with fear-related mood disorders, such as anxiety disorders and (PTSD). Clinically relevant studies have found that individuals with insomnia also exhibit delayed activation of the fear extinction brain regions, with related activation occurring only during extinction recall. At the same time, individuals with insomnia have stronger learned fear which causes their insomnia and can easily develop into pathological anxiety or PTSD. Furthermore, sleep immediately following exposure therapy can optimize the therapeutic effect and may even promote extinction generalization; therefore, sleep should be used in combination with traditional exposure therapy. Future research should be conducted to further the study of the neural mechanisms by which sleep affects fear generalization and the effect of circadian rhythm disruption on fear extinction, as well as clarifying the problems in the translation of animal sleep studies to human sleep studies.

Key words: fear acquisition, fear generalization, fear extinction, REM, SWS, sleep deprivation, insomnia disorder