Altered sleep behavior in a genetic mouse model of impaired fear extinction

Eva Maria Fritz,Matthias Kreuzer,Thomas Fenzl,Alp Altunkaya,Nicolas Singewald

doi:10.1038/s41598-021-88475-2

Abstract

Sleep disturbances are a common complaint of anxiety patients and constitute a hallmark feature of post-traumatic stress disorder (PTSD). Emerging evidence suggests that poor sleep is not only a secondary symptom of anxiety- and trauma-related disorders but represents a risk factor in their development, for example by interfering with emotional memory processing. Fear extinction is a critical mechanism for the attenuation of fearful and traumatic memories and multiple studies suggest that healthy sleep is crucial for the formation of extinction memories. However, fear extinction is often impaired in anxiety- and trauma-related disorders—an endophenotype that is perfectly modelled in the 129S1/SvImJ inbred mouse strain. To investigate whether these mice exhibit altered sleep at baseline that could predispose them towards maladaptive fear processing, we compared their circadian sleep/wake patterns to those of typically extinction-competent C57BL/6 mice. We found significant differences regarding diurnal distribution of sleep and wakefulness, but also sleep architecture, spectral features and sleep spindle events. With regard to sleep disturbances reported by anxiety- and PTSD patients, our findings strengthen the 129S1/SvImJ mouse models’ face validity and highlight it as a platform to investigate novel, sleep-focused diagnostic and therapeutic strategies. Whether the identified alterations causally contribute to its pathological anxiety/PTSD-like phenotype will, however, have to be addressed in future studies.

Highlights

‘Sleeping your worries away’ is not just a hollow phrase: an abundance of evidence approves that healthy sleep is crucial for emotional c oping[1,2]
S1 as well as BL6 mice showed circadian changes in sleep/wake activity that are typical for nocturnal animals, with higher amounts of sleep (NREMS, rapid-eye movement sleep (REMS)) and less wakefulness (WAKE) during the light period (Zeitgeber time: h0–h12) and vice versa during the dark period (Zeitgeber time: h12–h23)
To investigate whether the S1 mouse strain, for which a severe impairment of fear extinction learning has been previously described by different g roups[34,36,37,41,42,43,56], shows aberrant sleep patterns at baseline, we examined circadian sleep/wake behaviors of S1 mice in comparison to those of typically extinction-competent BL6 mice

Summary

Introduction

‘Sleeping your worries away’ is not just a hollow phrase: an abundance of evidence approves that healthy sleep is crucial for emotional c oping[1,2]. Aberrant neuronal activation patterns of fear- and extinction-relevant brain regions in S1 mice reported in immediate early gene m appings[33,41] as well as ex-vivo and in-vivo electrophysiological recordings[42,43] suggest a failure to properly engage the corticolimbic extinction circuitry: while activity in pro-extinction areas like infralimbic cortex and basolateral amygdala is typically reduced, increased activity is detectable in pro-fear regions like prelimbic cortex and the central medial nucleus of the amygdala This corresponds very well to imaging data from PTSD patients which typically show a hypoactivation of the ventromedial prefrontal cortex, the human equivalent to the infralimbic cortex, and an exaggerated amygdala reactivity during extinction r etrieval[44,45]. Our findings strengthen the face validity of the S1 mouse model and substantiate its relevance as a platform for future research on prognostic and diagnostic sleep biomarkers as well as sleep-targeted interventions in anxiety- and trauma-related disorders

Methods

Results

Discussion

Conclusion