The influence of sleep on fear extinction in trauma-related disorders

Pace‐Schott, Edward F.; Seo, Jakyeom; Bottary, Ryan

doi:10.1016/j.ynstr.2022.100500

Cited by 17 publications

(11 citation statements)

References 324 publications

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“…Fear is a kind of stress response when the body suffer from danger or traumatic events ( Fenster et al, 2018 ). Studies has shown that sleep impairments have significant effects on the generation and expression of fear, and fear also can cause sleep impairments, such as frequent nightmares, insomnia, and sleep fragmentation ( Pace-Schott et al, 2022 ), but the mechanism by which fear causes sleep impairments is still unclear. The present study demonstrated that the neural pathways from hypothalamic orexin neurons to the VLPO were activated in mice with conditioned fear and sleep-wake changes were observed when the pathways were artificially regulated.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, an increased number of researches have shown that amygdala, hippocampus, hypothalamus, locus coeruleus and medial prefrontal cortex are the main nucleus involved in regulating fear expression ( Burwell et al, 2004 ; Do-Monte et al, 2015 ; Soya et al, 2017 ). Fear often causes sleep impairments, such as insomnia, frequent nightmares, and sleep disruption ( Pace-Schott et al, 2022 ). The animal models of conditioned fear have been widely used to study fear-related diseases ( Soya et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Neural pathways from hypothalamic orexin neurons to the ventrolateral preoptic area mediate sleep impairments induced by conditioned fear

Zhou²,

Ma³

et al. 2023

Front. Neurosci.

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IntroductionFear and sleep impairments common co-exist, but the underlying mechanisms remain unclear. Hypothalamic orexinergic neurons are involved in the regulation of sleep-wake and fear expression. The ventrolateral preoptic area (VLPO) is an essential brain region to promote sleep, and orexinergic axonal fibers projecting to the VLPO are involved in the maintenance of sleep-wake. Neural pathways from hypothalamic orexin neurons to the VLPO might mediate sleep impairments induced by conditioned fear.MethodsTo verify above hypothesis, electroencephalogram (EEG) and electromyogram (EMG) were recorded for analysis of sleep-wake states before and 24 h after conditioned fear training. The retrograde tracing technique and immunofluorescence staining was used to identify the projections from the hypothalamic orexin neurons to the VLPO and to observe their activation in mice with conditioned fear. Moreover, optogenetic activation or inhibition of hypothalamic orexin-VLPO pathways was performed to observe whether the sleep-wake can be regulated in mice with conditioned fear. Finally, orexin-A and orexin receptor antagonist was administered into the VLPO to certify the function of hypothalamic orexin-VLPO pathways on mediating sleep impairments induced by conditioned fear.ResultsIt was found that there was a significant decrease in the non-rapid eye movement (NREM) and rapid eye movement (REM) sleep time and a significant increase in the wakefulness time in mice with conditioned fear. The results of retrograde tracing technique and immunofluorescence staining showed that hypothalamic orexin neurons projected to the VLPO and observed the CTB labeled orexin neurons were significantly activated (c-Fos+) in the hypothalamus in mice with conditioned fear. Optogenetic activation of hypothalamic orexin to the VLPO neural pathways significantly decreased NREM and REM sleep time and increased wakefulness time in mice with conditioned fear. A significant decrease in NREM and REM sleep time and an increase in wakefulness time were observed after the injection of orexin-A into the VLPO, and the effects of orexin-A in the VLPO were blocked by a pre-administrated dual orexin antagonist (DORA).ConclusionThese findings suggest that the neural pathways from hypothalamic orexinergic neurons to the VLPO mediate sleep impairments induced by conditioned fear.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neural pathways from hypothalamic orexin neurons to the ventrolateral preoptic area mediate sleep impairments induced by conditioned fear

Zhou²,

Ma³

et al. 2023

Front. Neurosci.

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“…The mechanisms underlying REM alterations in PTSD and, by extension, how they might be associated with impaired extinction recall are not clear. However, it was proposed that hyperarousal, characterized by impairment in the inhibitory control of amygdala activity by the medial PFC (mPFC) with a concomitant increase in noradrenergic activity, contributes to REM dysregulation (Cabrera et al 2024; Germain et al 2008; Pace-Schott et al 2015b; Pace-Schott et al 2023). Indeed, increased REMD may be a direct manifestation of hyperarousal in PTSD (Barbato 2023).…”

Section: Discussionmentioning

confidence: 99%

“…Fear extinction is not simply an erasure of fear but relies on new learning and memory. While the preponderance of studies does not show impaired extinction learning in PTSD (reviewed in (Bottary et al 2023; Pace-Schott et al 2023), accumulating evidence suggests that impaired retention of extinction memory, acquired after trauma exposure (Milad et al 2008), may be a critical mechanism that leads to PTSD (Helpman et al 2016; Milad et al 2008; Milad et al 2009; Milad and Quirk 2012; Shvil et al 2014; Suarez-Jimenez et al 2020; Wicking et al 2016). Sleep supports the consolidation of different types of memories, which stabilizes and integrates them, and enhances their retrieval (Klinzing et al 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies and meta-analyses find REM abnormalities in PTSD (Kobayashi et al 2007; Richards et al 2020; Zhang et al 2019), which also have been shown to be associated with the risk of developing PTSD after trauma (Mellman et al 2002; Mellman et al 2004; Mellman et al 2007). Therefore, it is postulated that sleep disruption, specifically of REM, may predispose traumatized individuals to develop PTSD symptoms by interfering with extinction memory (Colvonen et al 2019; Pace-Schott et al 2023). Supporting this hypothesis, in a sample overlapping that of the current report, we showed that prefrontal activations during extinction recall were associated with REM density during the night before extinction recall (Seo et al 2022).…”

Section: Introductionmentioning

confidence: 99%

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REM disruption and REM Vagal Activity Predict Extinction Recall in Trauma-Exposed Individuals

Yuksel,

Watford,

Muranaka

et al. 2023

Preprint

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Accumulating evidence suggests that rapid eye movement sleep (REM) supports the consolidation of extinction memory. REM is disrupted in PTSD, and REM abnormalities after traumatic events increase the risk of developing PTSD. Therefore, it was hypothesized that abnormal REM in trauma-exposed individuals may pave the way for PTSD by interfering with the processing of extinction memory. In addition, PTSD patients display reduced vagal activity. Vagal activity contributes to the strengthening of memories, including fear extinction memory, and recent studies show that the role of vagus in memory processing extends to memory consolidation during sleep. Therefore, it is plausible that reduced vagal activity during sleep in trauma-exposed individuals may be an additional mechanism that impairs extinction memory consolidation. However, to date, the contribution of sleep vagal activity to the consolidation of extinction memory or any emotional memory has not been investigated. To test these hypotheses, we examined the association of extinction memory with REM characteristics and REM vagal activity (indexed as high-frequency heart rate variability; HF-HRV) in a large sample of trauma-exposed individuals (n=113). Consistent with our hypotheses, REM sleep characteristics (increased REM density and shortened REM latency) were associated with poorer physiological and explicit extinction memory. Furthermore, higher HF-HRV during REM was associated with better explicit extinction memory. These findings support the notion that disrupted REM may contribute to PTSD by impairing the consolidation of extinction memory and indicate the potential utility of interventions that target REM sleep characteristics and REM vagal activity in fear-related disorders.

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