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Maternal sleep deprivation at different stages of pregnancy impairs the emotional and cognitive functions,… Peng, Yan; Wang, Wei; Tan, Tao; He, Wenting; Dong, Zhifang; Wang, Yu T; Han, Huili Feb 15, 2016

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RESEARCH Open AccessMaternal sleep deprivation at differentstages of pregnancy impairs the emotionaland cognitive functions, and suppresseshippocampal long-term potentiation in theoffspring ratsYan Peng1,2†, Wei Wang1,2†, Tao Tan1,2, Wenting He1,2, Zhifang Dong1,2, Yu Tian Wang1,2,3 and Huili Han1,2*AbstractBackground: Sleep deprivation during pregnancy is a serious public health problem as it can affect the health ofpregnant women and newborns. However, it is not well studied whether sleep deprivation at different stages ofpregnancy has similar effects on emotional and cognitive functions of the offspring, and if so, the potential cellularmechanisms also remain poorly understood.Methods: In the present study, the pregnant rats were subjected to sleep deprivation for 6 h per day by gentlehandling during the first (gestational days 1–7), second (gestational days 8–14) and third trimester (gestational days15–21) of pregnancy, respectively. The emotional and cognitive functions as well as hippocampal long-termpotentiation (LTP) were tested in the offspring rats (postnatal days 42-56).Results: The offspring displayed impaired hippocampal-dependent spatial learning and memory, and increaseddepressive- and anxiety-like behaviors. Quantification of BrdU-positive cells revealed that adult hippocampalneurogenesis was significantly reduced compared to control. Electrophysiological recording showed that maternalsleep deprivation impaired hippocampal CA1 LTP and reduced basal synaptic transmission, as reflected by a decreasein the frequency and amplitude of miniature excitatory postsynaptic current in the hippocampal CA1 pyramidalneurons.Conclusions: Taken together, these results suggest that maternal sleep deprivation at different stages of pregnancydisrupts the emotional and cognitive functions of the offspring that might be attributable to the suppression ofhippocampal LTP and basal synaptic transmission.Keywords: Maternal sleep deprivation, Spatial learning and memory, Anxiety, Depression, Neurogenesis, Long-termpotentiation* Correspondence:†Equal contributors1Ministry of Education Key Laboratory of Child Development and Disorders,Children’s Hospital of Chongqing Medical University, Chongqing 400014, PRChina2Chongqing Key Laboratory of Translational Medical Research in CognitiveDevelopment and Learning and Memory Disorders, Children’s Hospital ofChongqing Medical University, Chongqing 400014, PR ChinaFull list of author information is available at the end of the article© 2016 Peng et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (, which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver( applies to the data made available in this article, unless otherwise stated.Peng et al. Molecular Brain  (2016) 9:17 DOI 10.1186/s13041-016-0197-3BackgroundSleep is a basic necessity for survival, since long-termsleep deprivation leads to severe physical and cognitiveimpairment, even death [1]. However, about 50 % peoplethroughout the world encounter one or more sleep dis-orders including insomnia, narcolepsy, somnambulismand the circadian rhythm sleep disorders [2]. Sleep dis-orders are especially prevalent in pregnancy due to aseries of obvious reasons including pregnancy-associatedhormonal, physical and behavioral changes [3, 4]. Accu-mulating evidence shows that sleep deprivation duringpregnancy not only increases the risk of maternal psy-chiatric disorders [5], but also leads to several harmfulconsequences to the offspring. For example, maternalsleep deprivation impairs adult neurogenesis andhippocampus-dependent spatial learning and memory inthe offspring rats [6, 7]. Furthermore, sleep deprivationduring pregnancy leads to the lower sexual behavior ofthe male offspring [8] and increased risk-taking behaviorin offspring [9, 10].Although maternal sleep deprivation has been shownto cause behavioral alterations in offspring [6–11], thereare few reports on the effects of sleep deprivation at dif-ferent stages of pregnancy on emotional and cognitivefunctions of the offspring. And potential mechanismsunderlying such effects also remain poorly understood.The hippocampal dentate gyrus plays a critical role inlearning and memory throughout life, in part due tocontinuing neurogenesis occurrence in this area. Thereis a growing body of evidence showing that sleepdeprivation reduces dentate gyrus neurogenesis, whichmay contribute to the deficit of hippocampal-dependentcognitive function [12–14]. However, the effects of sleepdeprivation at different stages of pregnancy on adult hip-pocampal neurogenesis have not been extensively stud-ied, although a recent report has showed that maternalsleep deprivation inhibits hippocampal neurogenesis inthe young offspring rats [6]. In addition, several forms ofsynaptic plasticity in the CA1 area of the hippocampus,such as long-term potentiation (LTP) and long-term de-pression (LTD), have been proposed as the cellularmechanisms of information processing and memory for-mation [15–18]. Recent studies have demonstrated thatsleep deprivation impairs hippocampal LTP [19, 20],which may be attributed to the disruption of cyclic ad-enosine monophosphate signaling [20]. However, thereis no report about the influence of maternal sleepdeprivation on hippocampal CA1 LTP in offspring.Thus, the present study aimed to determine whethersleep deprivation at different stages of pregnancy affectsemotional and cognitive functions of the offspring, andif so, whether this influence is related to adult hippo-campal neurogenesis and hippocampal CA1 LTP in theoffspring.MethodsAnimalsFemale and male Sprague–Dawley rats were obtainedfrom Chongqing Medical University Animal Care Centre,and they mated in the laboratory colony of Children’sHospital of Chongqing Medical University. The offspringof these rats were used in the present study. Pregnant fe-males were housed individually in plastic cages in thetemperature-controlled (21 °C) colony room on a 12/12 hlight/dark cycle (8:00 a.m.–8:00 p.m.), and were free tofood and water. The pregnant rats were divided into 4groups: normal rearing (control), sleep deprivation at earlypregnancy stage (ESD, gestational days 1–7), sleepdeprivation at middle pregnancy stage (MSD, gestationaldays 8–14) and sleep deprivation at late pregnancy stage(LSD, gestational days 15–21). Within 24 h of birth, all lit-ters were culled to 10 pups with a goal of balancing thenumber of males and females equally. Young adult ratsfrom postnatal day (PND) 42–56 were used for behavioraland electrophysiological experiments. All experimentalprotocols were approved by Chongqing Medical Univer-sity Animal Care Committee.Sleep deprivationThe sleep deprivation was performed by gentle handlingfor 6 h per day (12:00–18:00) as previously described[10, 20]. Briefly, pregnant rats were kept awake by gentletapping or rattling of the cage and, if necessary, by gen-tly being touched with a soft brush if behavioral signs ofsleep were observed, such as closed eyes and immobility.Food and water were available ad libitum throughoutthe sleep deprivation period.Reagents and antibodiesAll drugs were purchased from Sigma-Aldrich. MouseAnti-BrdU monoclonal antibody was purchased fromSigma-Aldrich. Rabbit anti-NeuN monoclonal antibodywas purchased from Millipore. Rabbit anti-GFAP mono-clonal was purchased from Abcam. Complete proteaseinhibitor cocktail tablets and phosphatase inhibitor cock-tail tablets were purchased from Roche Applied Science.Morris water mazeSpatial learning and memory were examined with theMorris water maze using programs similar to those de-scribed previously [21, 22]. Briefly, rats were trained ina circular fiberglass pool (180-cm diameter) over 4 tri-als per day for 6 consecutive days to find a hidden plat-form. During each trial, the rats that cannot find thehidden platform within 60 s were guided to the plat-form where they remained for 20 s. A probe test wasperformed 24 h after the last learning trial. All trialswere recorded and analyzed by using an Any-mazetracking system (Stoelting, USA).Peng et al. Molecular Brain  (2016) 9:17 Page 2 of 10Elevated plus maze testThe plus maze apparatus consisted of two opposite openarms and two opposite closed arms (20-cm-tall walls onthe closed arms) arranged at right angles. At the begin-ning of the test, rats were put in the center of the appar-atus, which is elevated 1 m above the floor. The numberof entries and the time spent in each arm were recordedfor 10 min by ANY-maze video tracking system.Novelty-suppressed feeding testNovelty-suppressed feeding test was performed as de-scribed previously [23]. In brief, rats were deprived offood for 48 h prior to the test. During test, a single pelletof food was placed on a white filter paper located in thecenter of the arena (60 × 60 cm), and rat was placed in acorner of the arena to explore the arena for 12 min. Thelatency to begin eating food and the amount of foodconsumption were recorded. The rats were immediatelyreturned to their home cages after test, where food con-sumption was monitored for another 30 min.Forced swimming testRats were forced to swim in a cylinder filled with water(temperature 24–25 °C; 20 cm in diameter, 40 cm inheight) for 10 min. The latency to immobility and totalimmobility time were recorded and analyzed by usingANY-maze video tracking system.ImmunohistochemistryTo label newborn cells, rats were subjected to BrdU injec-tion (100 mg/kg, i.p.) at age of 2 weeks or 6 weeks, andwere sacrificed 4 weeks or 24 h after the last BrdU injec-tion, respectively. The animals were deeply anesthetizedand transcardially perfused with 4 % paraformaldehyde in100 mM phosphate buffer, pH 7.4. Immunohistochemistrywas performed on 30-μm coronal sections as previouslydescribed [23, 24]. Every sixth slice with the same refer-ence position was stained. Positive cells were quantitatedusing a 40× objective (Leica). Obtaining numbers weremultiplied by 6 to determine the estimated total numberof positive cells per dentate gyrus (DG) of rat.Electrophysiology in vivoRats were deeply anesthetized with sodium pentobarbitalat a dose of 60 mg/kg (i.p.) and then mounted to astereotaxic frame (Stoelting Co.). The core temperaturewas monitored and kept at 36.5 °C ± 0.5 °C. Stimulatingand recording electrodes (a pair of 100 μm outer diam-eter Teflon-coated wires; A-M Systems Inc.) were lo-cated at the Schaffer collaterals of dorsal hippocampusand ipsilateral striatum radiatum of hippocampal CA1area, respectively. Final positions of the electrodes weredetermined when an optimal response of field excitatorypost-synaptic potential (fEPSP) was obtained. Baselineresponses were recorded at 0.033 Hz for 30 min, with anintensity that evoked half of maximum amplitude. Oncethe stable baseline was obtained, a HFS consisted of 100pulses at 100 Hz was delivered to induce LTP.Electrophysiology in vitroRats were deeply anesthetized with 25 % urethane(1.5 g/kg, i.p.) and transcardially perfused with NMDGartificial cerebral spinal fluid (in mM: NMDG 93, HCl93, KCl 2.5, NaH2PO4 1.2, CaCl2 0.5, MgSO4 10,NaHCO3 30, HEPES 20, Na-ascorbate 5.0, Na-pyruvate3.0, Thiourea 2.0, NAC 12, and D-glucose 25, pH = 7.3.)prior to decapitation. The brain was rapidly dissectedand placed in ice-cold NMDG ACSF. Hippocampalslices (400 μm) were coronally sectioned with a vibra-tome (VT1200S, Leica Microsystems, Bannockburn, IL)and then were incubated in HEPES ACSF (in mM: NaCl92, KCl 2.5, NaH2PO4 1.2, CaCl2 0.5, MgSO4 10,NaHCO3 30, HEPES 20, Na-ascorbate 5.0, Na-pyruvate3.0, Thiourea 2.0, NAC 12, and 25 D-glucose, pH = 7.3.)for 1 h at 30 °C.Miniature excitatory postsynaptic currents (mEPSCs) ofhippocampal CA1 pyramidal neurons were recorded withpipette filled with internal solution (in mM: Cs-methanesulfonate 130, MgCl2 2.0, EGTA 0.5, HEPES 10,QX-314 5.0, K2ATP 5.0, and Na2GTP 0.3, pH = 7.3), resist-ance of which was 3–5 MΩ. Bicuculline methiodide(10 μM) and TTX (1 μM) were added in ACSF (in mM:NaCl 120, KCl 2.5, NaH2PO4 1.25, CaCl2 2.0, MgSO4 2.0,NaHCO3 26, glucose 10, pH = 7.3) to block GABA recep-tors and Na+ channels respectively. Data acquisition(filtered at 3 kHz and digitized at 10 kHz) was performedwith PatchMaster v2.73 (HEKA Electronic, Lambrecht/Pfalz, Germany) with holding potential at −70 mV. MiniAnalysis Program 6.0.3 (Synaptosoft Inc., Decatur, GA) wasused to automatically detected mEPSCs.Statistical analysisAll data are presented as mean ± SEM. Spatial learningdata were analyzed by a two-way ANOVA, with treat-ment (group) as the between-subjects factor and learn-ing day as the within-subjects factor. All the other datawere analyzed by a one-way ANOVA, with treatment(group) as the between-subjects factor. Significance levelwas set at p < 0.05.ResultsMaternal sleep deprivation impairs spatial learning andmemory in the offspring ratsWe first determined the influence of sleep deprivation atdifferent stages of pregnancy on spatial learning and mem-ory in the young adult offspring. The pregnant rats weresubjected to ESD, MSD and LSD, respectively. SpatialPeng et al. Molecular Brain  (2016) 9:17 Page 3 of 10learning and memory was assessed using the Morris watermaze in the offspring on PND 42–56. The offspring ratsof all maternal sleep deprivation groups displayed a signifi-cant deficit in spatial learning, as reflected by taking muchlonger to find the hidden platform than control on day1–3 (day 1: F (3, 52) = 2.825, p = 0.048; day 2: F (3, 52) =4.370, p = 0.008; day 3: F (3, 52) = 7.320, p < 0.001;Fig. 1a). One day after the last training trial, a probetest with the platform removed was performed toexamine long-term spatial memory retrieval. The re-sults revealed that maternal sleep deprivation dramatic-ally impaired spatial memory retrieval in the offspringsince they spent much less time in the quadrant inwhich the platform was previously located (F (3, 52) =4.343, p = 0.008; Fig. 1b). These results suggest that ma-ternal sleep deprivation at different stages of pregnancydisplays similar deficits in spatial learning and memory.Maternal sleep deprivation increases anxiety anddepressive behaviors in the offspring ratsNext, we wanted to determine the influences of mater-nal sleep deprivation on emotional functions such asdepression and anxiety in the offspring. The resultsshowed that the latency to immobility was significantlyshorter in the offspring of ESD and LSD, but not MSD,compared to the control rats during forced swimmingtest (F (3, 64) = 5.578, p = 0.002; Fig. 2a). To furthercharacterize the increase in depression, we also exam-ined the total immobility time and found that the totalimmobility time was significantly longer in theFig. 1 Maternal sleep deprivation impaired spatial learning andmemory in the Morris water maze task. a The offspring of ESD(n = 16), MSD (n = 16) and LSD (n = 16) spent much longer time thancontrol (n = 8) in searching the hidden platform on training day 1–3.b A probe test was performed on day 7, the offspring of ESD, MSDand LSD spent much less time than control in the quadrant wherethe the hidden platform was located. *p < 0.05, **p < 0.01 vs. controlFig. 2 Maternal sleep deprivation increased depressive-like behaviorin the forced swimming task. a The offspring of ESD (n = 12) andLSD (n = 20), but not MSD (n = 18), showed significantly shorter latencyto immobility than control (n = 18) during forced swimming test. b Theduration of total immobility was much longer in the offspring of ESDand LSD, but not MSD, than control. *p < 0.05, **p < 0.01 vs. control;ns = no significant differencePeng et al. Molecular Brain  (2016) 9:17 Page 4 of 10offspring of ESD and LSD than other groups (F (3, 64) =15.669, p < 0.001; Fig. 2b).In Fig. 3, the results showed that both the time spentin the open arms (F (3, 81) = 9.990, p < 0.001; Fig. 3a) andthe number of entry into the open arms (F (3, 81) = 7.187,p < 0.001; Fig. 3b) were significantly reduced during ele-vated plus maze test in offspring rats of ESD, MSD andLSD compared with control. In order to further evaluatethe effect of maternal sleep deprivation on anxiety, weintroduced another behavioral model of anxiety, thenovelty-suppressed feeding test. The result showed thatthe latency to feeding was dramatically increased (F (3, 44) =5.534, p = 0.003; Fig. 4a), whereas the amount of foodconsumed was significantly reduced in the offspringrats of ESD, MSD and LSD during test (F (3, 44) = 6.544,p = 0.001; Fig. 4b). These differences were not attrib-uted to the influence of maternal sleep deprivation onthe appetite in the offspring as the total food consump-tion, including food intake during test and in theFig. 3 Maternal sleep deprivation increased anxiety-like behavior inthe elevated plus maze task. a The offspring of ESD (n = 22), MSD(n = 18) and LSD (n = 21) spent much less time than control (n = 24)in the open arms. b The number of entry into open arms wassignificantly reduced in the offspring of ESD, MSD and LSD comparedto control. *p < 0.05, **p < 0.01 vs. controlFig. 4 Maternal sleep deprivation increased anxiety-like behavior inthe novelty-suppressed feeding task. a The offspring of ESD (n = 12),MSD (n = 12) and LSD (n = 12) showed significantly longer latency tofeeding than control (n = 12) during the test. b The offspring of ESD,MSD and LSD consumed less food than control during the test.c No differences were observed in total food consumption includingduring test and in home cage among these groups. *p < 0.05,**p < 0.01 vs. control; ns = no significant differencePeng et al. Molecular Brain  (2016) 9:17 Page 5 of 10Fig. 5 Maternal sleep deprivation reduced adult hippocampal neuronal proliferation. a The offspring of ESD (n = 5), MSD (n = 5) and LSD (n = 5)showed significantly reduced the immunoreactivity (left panel) and number of newborn neuronal phenotype cells (right bar) compared tocontrol (n = 5), which were counted 24 h after last BrdU administration. b No differences were observed in the immunoreactivity (left panel) andnumber of newborn astrocytic phenotype cells (right bar) among these groups. *p < 0.05, **p < 0.01 vs. control; ns = no significant differenceFig. 6 Maternal sleep deprivation reduced adult hippocampal neuronal survival. a The offspring of ESD (n = 5), MSD (n = 5) and LSD (n = 5)showed significantly reduced the immunoreactivity (left panel) and number of newborn neuronal phenotype cells (right bar) compared tocontrol (n = 5), which were counted 4 weeks after last BrdU administration. b No differences were observed in the immunoreactivity (left panel)and number of newborn astrocytic phenotype cells (right bar) among these groups. **p < 0.01 vs. control; ns = no significant differencePeng et al. Molecular Brain  (2016) 9:17 Page 6 of 10homecage, remained unchanged among these groups(F (3, 44) = 0.403, p = 0.752; Fig. 4c).Taken together, these results indicate that maternalsleep deprivation increases anxiety and depression in theoffspring rats.Maternal sleep deprivation reduces adult hippocampalneurogenesis in the offspring ratsWe next tested the effects of sleep deprivation at differ-ent stages of pregnancy on hippocampal neurogenesis inthe offspring. To observe cell proliferation in the dentategyrus of the hippocampal formation, we treated animalswith BrdU daily from PND 42–44, and sacrificed themat PND 45. Since different phenotypes of the proliferatedcells can be labeled by BrdU, we used immunofluores-cent double-labelings of brain sections with BrdU andeither a neuronal (NeuN) or an astrocyte (GFAP)marker. We found that the number of BrdU-positivecells with neuronal phenotype (F (3, 16) = 6.620, p = 0.005;Fig. 5a) rather than astrocytic phenotype (F (3, 16) =2.976, p = 0.063; Fig. 5b) was significantly reduced in theoffspring of all maternal sleep deprivation groups com-pared to the control rats.In addition, to further determine the survival of newlygenerated cells and their commitment toward the neuronallineage, we treated animals with BrdU daily from PND 15–21, and sacrificed the rats 4 weeks after last BrdU adminis-tration. The results showed that the number of BrdU-positive cells with neuronal phenotype (F (3, 16) =16.271, p < 0.001; Fig. 6a) rather than astrocytic pheno-type (F (3, 16) = 1.833, p = 0.182; Fig. 6b) was signifi-cantly reduced in the offspring of maternal sleepdeprivation compared to the control rats.Thus, these results suggest that maternal sleepdeprivation leads to a significant reduction in adult hip-pocampal neurogenesis including neuronal proliferationand survival in the offspring rats.Maternal sleep deprivation impairs hippocampal LTP andbasal synaptic transmission in the offspring ratsAccumulating evidence supports that hippocampal LTPplays a critical role in learning and memory, and sleepdeprivation impairs hippocampal LTP [19, 20]. However,so far there is no study to examine the effect of maternalsleep deprivation on hippocampal LTP induction in theoffspring. Thus, we next examined the influence of ma-ternal sleep deprivation on offspring hippocampal LTP.The results showed that HFS induced a reliable LTP inthe control rats, whereas the LTP induced by HFS wassignificantly impaired in the offspring of ESD, MSDand LSD (F (3, 19) = 3.973, p = 0.024; Fig. 7a and b).Next, we further investigated the influence of maternalsleep deprivation on excitatory synaptic transmissionin the CA1 pyramidal neurons from hippocampalslices. The results showed that both amplitude (F (3, 55) =8.970, p < 0.001; Fig. 8a and b) and frequency (F (3, 55) =21.487, p < 0.001; Fig. 8a and c) of mEPSC were signifi-cantly reduced in the offspring of ESD, MSD and LSDcompared to the control rats. Altogether, these results in-dicate that maternal sleep deprivation disrupts hippocam-pal LTP and excitatory synaptic transmission, thereby maycontribute to memory deficits in the offspring rats.DiscussionThe physiological and biochemical changes of pregnancymay place women at risk for developing specific sleepdisorders [3, 4]. Indeed, recent report shows that abouttwo-thirds of the pregnant women are subjected to sleepdisorders [25]. Although it is widely accepted that mater-nal sleep restriction may lead to several harmful conse-quences to the offspring, human studies on sleepdeprivation during pregnancy and the child’s develop-ment are difficult and even impossible to be conductedFig. 7 Maternal sleep deprivation impaired hippocampal LTP in vivo.a The plots of normalized slopes of fEPSPs showed that HFS (100 Hzfor 1 s) induced a much smaller hippocampal LTP in the offspring ofESD (n = 6), MSD (n = 6) and LSD (n = 6) than control (n = 5). b Thebar graph summarized the average percentage change of fEPSPslope immediately before and 55 min after HFS. *p < 0.05 vs. controlPeng et al. Molecular Brain  (2016) 9:17 Page 7 of 10due to ethical and other issues. Therefore, the presentstudy was designed to investigate the effects of maternalsleep deprivation by gentle handling in the rat model oncognitive and emotional functions in the offspring. Gen-tle handling protocols for sleep deprivation in animalmodels are widely used in research under laboratoryconditions [10, 20], as it is a simple method for sleepdeprivation [26].Previous studies have shown that pregnancy-relatedhormones such as progesterone, estrogen, cortisol andoxytocin are gradually increased during pregnancy, espe-cially in the third trimester of gestation, which markedlyaffect sleep quality [27]. Thus, a large number of reportshave focused on the influence of sleep deprivation dur-ing the last trimester of pregnancy on the developmentof the offspring [7, 9, 10, 28, 29]. Recently, a reportshows that paradoxical sleep deprivation using the mul-tiple platform method at different pregnant period im-pairs hippocampus-dependent spatial learning andmemory in the young offspring rats [6]. In full agree-ment with this finding, we here reported that maternalsleep deprivation through the gentle handling method atthe different stages of pregnancy displayed a similar def-icit in spatial learning and memory, especially for thefirst 3 days of learning in the Morris water maze task(Fig. 1), suggesting a delayed acquisition of spatial mem-ory in the offspring rats. In addition, Gulia and col-leagues have recently reported that pups born to sleepdeprived mothers displayed a decrease in ultrasonicvocalizations [11], indicating a depressive-like symptom.Consistent with this result, we here found that rats bornto mothers undergoing sleep deprivation displayed ap-parently depression during forced-swimming test (Fig. 2).However, we also found that maternal sleep deprivationsignificantly induced anxiety-like behaviors in the off-spring in both elevated-plus maze and novelty-suppressed feeding tests (Fig. 3 and Fig. 4), which is notconsistent with a previous report that sleep deprivationduring late pregnancy produces a decrease in anxiety-related behavior, as reflected by hyperactivity and in-creased risk-taking behavior in the offspring [10]. Giventhis controversy, further studies are required to deter-mine the exact reason for the different results.Although our findings, along with evidence accumu-lated from previous studies [6, 7], reveal that sufficientsleep at any stage of pregnancy is critical for the devel-opment of cognitive and emotional functions in the off-spring, how maternal sleep deprivation disruptscognitive and emotional functions in the offspring re-mains poorly understood. Consistent with recent reports[6, 7], we here confirmed that maternal sleep deprivationresulted in a dramatic decrease in the number of new-born neurons in the DG of the hippocampal formation(Fig. 5 and Fig. 6). Although the function of adult neuro-genesis is still under debate, integration of newborn neu-rons into the existing neuronal circuits may be involvedin memory processing and emotional regulation in thehippocampus [30, 31]. Thus, the inhibition ofFig. 8 Maternal sleep deprivation reduced excitatory synaptic acticity. The offspring of ESD (n = 20), MSD (n = 13) and LSD (n = 12) showedsignificantly reduced mEPSC amplitude (b) and frequency (c) than control (n = 14), and corresponding representative traces were shown in graph(a). *p < 0.05, **p < 0.01 vs. controlPeng et al. Molecular Brain  (2016) 9:17 Page 8 of 10hippocampal neurogenesis induced by maternal sleepdeprivation in the present study may contribute to the im-pairment of hippocampus-dependent spatial learning andmemory as well as the increase in depression and anxietyin the offspring. In addition, more recent study has pro-posed that maternal sleep deprivation may lead to dysreg-ulation in microglial pro- and anti-inflammatoryactivation, and consequently inhibit adult hippocampalneurogenesis and impair hippocampal-dependentspatial learning and memory, as anti-inflammatorytreatment can relief cognitive impairment caused bymaternal sleep deprivation in offspring. [7]. Further-more, activity-dependent hippocampal synaptic plasti-city such as LTP has been considered as a cellularmechanism underlying information processing andmemory formation [15–17]. We therefore speculatethat maternal sleep deprivation may impair hippocam-pal LTP induction, and subsequently leads to memorydeficit in the young offspring rats. Indeed, we herefound that both hippocampal LTP (Fig. 7) and basalsynaptic transmission (Fig. 8) were significantly sup-pressed in the young offspring rats born to mothersundergoing sleep deprivation during pregnancy, whichmay contribute, at least partially, to the disruption ofcognitive and emotional functions.Notably, although we used gentle handling that mini-mizes stress [32], to perform maternal sleep deprivation,it may still be a stressful procedure. It has been docu-mented that maternal stress produces memory deficitsand hippocampal synaptic plasticity impairment in theoffspring [33–36]. Thus, the effects of acute stress result-ing from sleep deprivation on cognitive and emotionalfunctions in the young offspring rats cannot be occludedin the present study. Additionally, maternal sleepdeprivation during their inactive phase may lead to sleepcompensation during their active phase. Previous studieshave shown that phase-shifting circadian rhythms mayinfluence hippocampus-dependent memory [37, 38].Thus, maternal sleep deprivation may result in the dis-ruption of circadian rhythms, and subsequently contrib-utes to memory deficits in the offspring.Although our results show that maternal sleepdeprivation suppresses hippocampal neurogenesis andsynaptic plasticity that may contribute to memory defi-cits in the young offspring rats, the exact mechanismstill remains unclear. Further research is needed to en-hance our understanding of the effect of maternal sleepdeprivation on offspring development and the physio-logical mechanisms underlying this influence.ConclusionOverall, our study shows that maternal sleep deprivationat different stages of pregnancy leads to a significant in-crease in depression and anxiety, and dramatic deficitsin spatial learning and memory. These behavioralchanges are associated with the impairments of excita-tory synaptic transmission and LTP in the hippocampus.Competing interestThe authors declared that no conflicts of interest exist.Authors’ contributionsYP carried out the behavioral studies. WW carried out the immunoassays. TTcarried out the in vitro electrophysiological studies. WH carried out the invivo electrophysiological studies. HH, ZD and YTW conceived of the studyand drafted the manuscript. All authors read and approved the finalmanuscript.AcknowledgmentsThis work was supported by the 973 Program of the Ministry of Science andTechnology of China (2014CB548100), the National Natural ScienceFoundation of China (81271221, 81400874, 81571042 and 81501143), theNatural Science Foundation of Chongqing (cstc2015jcyjA00037), the ChinaPostdoctoral Science Foundation (2014M562505XB) and the ChongqingPostdoctoral Foundation (xm2014051).Author details1Ministry of Education Key Laboratory of Child Development and Disorders,Children’s Hospital of Chongqing Medical University, Chongqing 400014, PRChina. 2Chongqing Key Laboratory of Translational Medical Research inCognitive Development and Learning and Memory Disorders, Children’sHospital of Chongqing Medical University, Chongqing 400014, PR China.3Brain Research Centre and Department of Medicine, University of BritishColumbia, Vancouver, BC V6T 2B5, Canada.Received: 17 December 2015 Accepted: 3 February 2016References1. 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Animal Learn Behav. 2001;29(2):133–42.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript your next manuscript to BioMed Central and we will help you at every step:Peng et al. Molecular Brain  (2016) 9:17 Page 10 of 10


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