Chronic Sleep Restriction in Developing Male Mice Results in Long Lasting Behavior Impairments

Abstract

Sleep abnormalities are prevalent in autism spectrum disorders (ASD). Moreover, the severity of ASD symptoms are correlated with the degree of disturbed sleep. We asked if disturbed sleep during brain development itself could lead to ASD-like symptoms, particularly behavioral manifestations. We reasoned that sleep is known to be important for normal brain development and plasticity, so disrupted sleep during development might result in changes that contribute to behavioral impairments associated with ASD. We sleep-restricted C57BL/6J male mice [beginning at postnatal day 5 (P5) and continuing through P52] 3 h per day by means of gentle handling and compared the data with a stress group (handled every 15 min during the 3-h period) and a control group (no additional handling). From P42–P52, we assessed the behavioral effects of sleep-restriction in this pre-recovery phase. Then, we allowed the mice to recover for 4 weeks and tested behavior once again. Compared to the control group, we found that sleep restricted-mice had long-lasting hypoactivity, and impaired social behavior; repetitive behavior was unaffected. These behavior changes were accompanied by an increase in the downstream signaling products of the mammalian target of rapamycin pathway. These data affirm the importance of undisturbed sleep during development and show that, at least in this model, sleep-restriction can play a causative role in the development of behavioral abnormalities. Assessing and treating sleep abnormalities in ASD may be important in alleviating some of the symptoms.

Association Between Sleep Deficiencies with Behavioral Problems in Autism Spectrum Disorder: Subtle Sex Differences

“…In experimental studies on wild‐type (WT) mice, we have tried to address this question by chronically sleep restricting developing male and female mice [Sare, Levine, Hildreth, Picchioni, & Smith, 2015; Sare et al, 2019]. Even after a period of recovery sleep, we found that chronic sleep restriction resulted in long‐lasting social behavior deficits in male mice [Sare et al, 2015; Sare et al, 2019]. In female mice, we found increased social interactions following chronic sleep restriction [Sare et al, 2015].…”

Adolescent sleep is critical for the developmental shaping of social novelty preference

“…2A and 2B), suggesting that distinct neural circuits underlie the shaping of these behavioral preferences and are vulnerable to sleep interventions at distinct developmental stages. More interestingly, both sleep manipulations, regardless in early childhood (Sare et al, 2016;Sare et al, 2019) or during adolescence (Fig. 3A and 3B), resulted to long-lasting behavioral changes in social interactions, highlighting the idea that sleep helps to shape the neural network underlying social behavior when it is still plastic during development, and the effects become "fixed" as the neural network matures in adulthood.…”

“…A study using chronic sleep restriction during the early postnatal stage in mice (P5 -P42) showed that it induced a series of longlasting behavioral changes 4 weeks after the completion of sleep restriction, including hypoactvity in both sexes, slightly increased sociality and social novelty preference in female mice but not in male mice, and female-specific decrease of marble burying behavior (Sare et al, 2016). However, a most recent follow-up study from the same lab showed that the same postnatal sleep restriction in male mice indeed led to changes of social interaction behaviors, with sociality increased but social novelty preference impaired (Sare et al, 2019). The sleep restriction method used in these studies could be potentially problematic because its effects on sleep cannot be validated by EEG in mouse pups and the influence of maternal separation at this young age cannot be excluded, however results from these studies somewhat echoes with ours showing impairment only in social novelty preference but not in sociality preference by SD at later adolescence ( Fig.…”

Effects of Treatment With Hypnotics on Reduced Sleep Duration and Behavior Abnormalities in a Mouse Model of Fragile X Syndrome

“…We chose to examine novelty-induced activity, anxiety-like behavior, and social behavior based on our prior experiments which showed that chronically disrupted sleep during development in WT mice had a long lasting effect on these behaviors ( Saré et al, 2015 , 2019 ). Interestingly, we noted that both caffeine and DORA-22 resulted in decreased activity in the open-field.…”

“…Additionally, chronic sleep restriction beginning early in postnatal development in wild-type (WT) mice resulted in behavioral changes, particularly in social behavior and activity levels. The behavioral changes persisted even after recovery sleep ( Saré et al, 2015 , 2019 ).…”