Melatonin attenuates intermittent hypoxia-induced cognitive impairment in aged mice: The role of inflammation and synaptic plasticity.

Intermittent hypoxia (IH), a major pathophysiologic alteration in obstructive sleep apnea syndrome (OSAS), is an important contributor to cognitive impairment. Increasing research suggests that melatonin has anti-inflammatory properties and improves functions related to synaptic plasticity. However, it is unclear whether melatonin has a protective effect against OSAS-induced cognitive dysfunction in aged individuals and the involved mechanisms are also unclear. Therefore, in the study, the effects of exposure to IH alone and IH in combination with daily melatonin treatment were investigated in C57BL/6 J mice aged 18 months. Assessment of the cognitive ability of mice in a Morris water maze showed that melatonin attenuated IH-induced impairment of learning and memory in aged mice. Enzyme-linked immunosorbent assay, polymerase chain reaction, and western blotting molecular techniques showed that melatonin treatment reduced the levels of the proinflammatory cytokines, interleukin-1ß, interleukin-6, and tumor necrosis factor-α, decreased the levels of NOD-like receptor thermal protein domain associated protein 3 and nuclear factor kappa-B, lowered the levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and increased the levels of the synaptic proteins, activity-regulated cytoskeleton-associated protein, growth-associated protein-43, postsynaptic density protein 95, and synaptophysin in IH-exposed mice. Moreover, electrophysiological results showed that melatonin ameliorated the decline in long-term potentiation induced by IH. The results suggest that melatonin can ameliorate IH-induced cognitive deficits by inhibiting neuroinflammation and improving synaptic plasticity in aged mice.

Subsequent maternal sleep deprivation aggravates cognitive impairment by modulating hippocampal neuroinflammatory responses and synaptic function in maternal isoflurane-exposed offspring mice.

INTRODUCTION: Pregnant women may need to undergo non-obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances during late gestation. Preclinical studies demonstrated that maternal isoflurane exposure (MISO) or maternal sleep deprivation (MSD) contributed to cognitive impairments in offspring. Research studies in mice have revealed that SD can aggravate isoflurane-induced cognitive deficits. However, it remains unclear whether MSD aggravates MISO-induced cognitive deficits in offspring. The purpose of this research was to explore the combined effects of MSD and MISO on offspring cognitive function and the role of neuroinflammation and synaptic function in the process of MSD + MISO. METHODS: Pregnant mice were exposed to 1.4% isoflurane by inhalation for 4 h on gestational day (GD) 14. Dams were then subjected to SD for 6 h (12:00-18:00 h) during GD15-21. At 3 months of age, the offspring mice were subjected to the Morris water maze test to assess cognitive function. Then the levels of inflammatory and anti-inflammatory markers and synaptic function-related proteins were assessed using molecular biology methods. RESULTS: The results of this study demonstrated that MISO led to cognitive dysfunction, an effect that was aggravated by MSD. In addition, MSD exacerbated the maternal isoflurane inhalation, leading to an enhancement in the expression levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha and a reduction in the hippocampal levels of IL-10, synaptophysin, post-synaptic density-95, growth-associated protein-43, and brain-derived neurotrophic factor. CONCLUSION: Our findings revealed that MSD aggravated the cognitive deficits induced by MISO in male offspring mice, and these results were associated with neuroinflammation and alternations in synaptic function.

Melatonin improves maternal sleep deprivation-induced learning and memory impairment, inflammation, and synaptic dysfunction in murine male adult offspring.

INTRODUCTION: Maternal sleep deprivation (MSD), which induces inflammation and synaptic dysfunction in the hippocampus, has been associated with learning and memory impairment in offspring. Melatonin (Mel) has been shown to have anti-inflammatory, antioxidant, and neuroprotective function. However, the beneficial effect of Mel on MSD-induced cognitive impairment and its mechanisms are unknown. METHODS: In the present study, adult offspring suffered from MSD were injected with Mel (20 mg/kg) once a day during postnatal days 61-88. The cognitive function was evaluated by the Morris water maze test. Levels of proinflammatory cytokines were examined by enzyme-linked immunosorbent assay. The mRNA and protein levels of synaptic plasticity associated proteins were examined using reverse transcription-polymerase chain reaction and western blotting. RESULTS: The results showed that MSD impaired learning and memory in the offspring mice. MSD increased the levels of interleukin (IL)-1creIL-6, and tumor necrosis factor-α and decreased the expression levels of brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density protein-95, and synaptophysin in the hippocampus. Furthermore, Mel attenuated cognitive impairment and restored markers of inflammation and synaptic plasticity to control levels. CONCLUSIONS: These findings indicated that Mel could ameliorate learning and memory impairment induced by MSD, and these beneficial effects were related to improvement in inflammation and synaptic dysfunction.

Mitochondrial antioxidant elamipretide improves learning and memory impairment induced by chronic sleep deprivation in mice.

BACKGROUND: The inflammation and synaptic dysfunction induced by mitochondrial dysfunction play essential roles in the learning and memory impairment associated with sleep dysfunction. Elamipretide (SS-31), a novel mitochondrion-targeted antioxidant, was proven to improve mitochondrial dysfunction, the inflammatory response, synaptic dysfunction, and cognitive impairment in models of cerebral ischemia, sepsis, and type 2 diabetes. However, the potential for SS-31 to improve the cognitive impairment induced by chronic sleep deprivation (CSD) and its underlying mechanisms is unknown. METHODS: Adult c57BL/6J mice were subjected to CSD for 21 days using an activity wheel accompanied by daily intraperitoneal injection of SS-31 (5 mg/kg). The novel object recognition and Morris water maze test were used to evaluate hippocampus-dependent cognitive function. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to determine the effects of CSD and SS-31 on markers of mitochondria, inflammation response, and synaptic function. Enzyme-linked immunosorbent assays were used to examine the levels of proinflammatory cytokines. RESULTS: SS-31 could improve the cognitive impairment induced by CSD. In particular, SS-31 treatment restored the CSD-induced decrease in sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator alpha levels and the increase in levels nuclear factor kappa-B and inflammatory cytokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha. Furthermore, SS-31 significantly increased the levels of brain-derived neurotrophic factor, postsynaptic density protein-95, and synaptophysin in CSD mice. CONCLUSION: Taken together, these results suggest that SS-31 could improve CSD-induced mitochondrial biogenesis dysfunction, inflammatory response, synaptic dysfunction, and cognitive impairment by increasing SIRT1 expression levels.

Resveratrol prevents cognitive deficits induced by sleep deprivation via modulating sirtuin 1 associated pathways in the hippocampus.

Accumulating evidence confirms that sleep insufficiency is a high risk factor for cognitive impairment, which involves inflammation and synaptic dysfunction. Resveratrol, an agonist of the Sirt1, has demonstrated anti-inflammation and neuroprotective effects in models of Alzheimer's disease, Parkinson's disease, and schizophrenia. However, the beneficial effects of resveratrol on sleep deprivation-induced cognitive deficits and its underlying molecular mechanisms are unclear. In the present study, thirty-two male C57BL/6 J mice were randomly divided into a Control+DMSO group, Control+Resveratrol group, SD+DMSO group, and SD+Resveratrol group. The mice in the SD+Resveratrol group underwent 5 days of sleep deprivation after pretreatment with resveratrol (50 mg/kg) for 2 weeks, while the mice in the SD+DMSO group only underwent sleep deprivation. After sleep deprivation, we evaluated spatial learning and memory function using the Morris water maze test. We used general molecular biology techniques to detect changes in levels of pro-inflammatory cytokines and Sirt1/miR-134 pathway-related synaptic plasticity proteins. We found that resveratrol significantly reversed sleep deprivation-induced learning and memory impairment, elevated interleukin-1ß, interleukin-6, and tumor necrosis factor-α levels, and decreased brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density protein-95, and synaptophysin levels by activating the Sirt1/miR-134 pathway. In conclusion, resveratrol is a promising agent for preventing sleep deprivation-induced cognitive dysfunction by reducing pro-inflammatory cytokines and improving synaptic function via the Sirt1/miR-134 pathway.

An enriched environment ameliorates maternal sleep deprivation-induced cognitive impairment in aged mice by improving mitochondrial function via the Sirt1/PGC-1α pathway.

BACKGROUND: Early life stress can cause cognitive impairment in aged offspring. Environmental enrichment (EE) is considered to be an effective non-pharmacological treatment for improving cognitive decline. The aim of this research was to evaluate the effect of EE, on cognitive impairment in aged offspring induced by maternal sleep deprivation (MSD) and the underlying mechanisms involved to investigate its potential value in clinical practice. METHODS: CD-1 damns were subjected or not to sleep deprivation during late gestation. Twenty-one days after birth, the offspring were assigned to standard or EE cages. At 18 months-old, the learning and memory function of the offspring mice was evaluated using Morris water maze. The hippocampal and prefrontal cortical levels of protein, gene, proinflammation cytokines, and oxidative stress indicators was examined by Western blot, real-time polymerase chain reaction, enzyme linked immunosorbent assay, and biochemical assays. RESULTS: Offspring in MSD group exhibited declined learning and memory abilities compared with control animals. Moreover, the hippocampal and prefrontal cortical levels of Sirtuin1 (Sirt1), peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), postsynaptic density protein-95, and synaptophysin were lower and those of proinflammation cytokines higher in the MSD group; meanwhile, the superoxide dismutase content was higher and the malondialdehyde and reactive oxygen species contents were lower. However, these deleterious changes were ameliorated by exposure to EE. CONCLUSIONS: EE attenuates MSD-induced cognitive impairment, oxidative stress, and neuroinflammation and reverses the reduction in synaptic protein levels in aged offspring mice via the Sirt1/PGC-1α pathway.

Sleep deprivation aggravates lipopolysaccharide-induced anxiety, depression and cognitive impairment: The role of pro-inflammatory cytokines and synaptic plasticity-associated proteins.

Growing evidence indicates that neuroinflammation plays a critical role in anxiety, depression, and cognitive impairment. Sleep loss disrupts the host's immune balance and increases neuroinflammation. This study explored whether chronic sleep deprivation aggravates lipopolysaccharide-induced anxiety, depression, and cognitive impairment and assessed the underlying mechanisms. Lipopolysaccharide (250 µg/kg) was administered to adult mice for 9 days, accompanied with daily intermittent sleep deprivation from 12:00 to 18:00 by using an activity wheel. Anxiety, depression, and cognitive function were evaluated using a task battery consisting of an open field, elevated plus maze, tail suspension, forced swimming, and Morris water maze tests. The levels of pro-inflammatory cytokines and synaptic plasticity-associated proteins were examined by enzyme-linked immunosorbent assay and western blot, respectively. The results showed that lipopolysaccharide increased anxiety- and depression-like behaviors, impaired cognitive function, uprelated interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and decreased brain-derived neurotrophic factor (BDNF), postsynaptic density-95 (PSD-95), and synaptophysin (SYN), which were aggravated by chronic sleep deprivation. These results suggest that chronic sleep deprivation exerted adverse effects on lipopolysaccharide-induced anxiety, depression, and cognitive impairment, which was associated with changes in pro-inflammatory cytokines and synaptic plasticity associated proteins.

Resveratrol ameliorates maternal immune activation-associated cognitive impairment in adult male offspring by relieving inflammation and improving synaptic dysfunction.

Maternal exposure to inflammation may represent a major risk factor for neuropsychiatric disorders with associated cognitive dysfunction in offspring in later life. Growing evidence has suggested that resveratrol exerts a beneficial effect on cognitive impairment via its anti-inflammatory and antioxidant properties and by ameliorating synaptic dysfunction. However, how resveratrol affects maternal immune activation-induced cognitive dysfunction and the underlying mechanisms are unclear. In the present study, pregnant dams were given an intraperitoneal injection of lipopolysaccharide (LPS; 50 µg/kg) on gestational day 15. Subsequently, the offspring mice were treated or not with resveratrol (40 mg/kg) from postnatal day (PND) 60 to PND 88. Male offspring were selected for the evaluation of cognitive function using the Morris water maze test. The hippocampal levels of pro-inflammatory cytokines were examined by ELISA. The mRNA and protein levels of sirtuin-1 (SIRT1), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95), and synaptophysin (SYP) were determined by RT-qPCR and western blot, respectively. The results showed that male offspring mice exposed to LPS in utero exhibited learning and memory impairment. Additionally, the levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) were increased while those of SIRT1, BDNF, PSD-95, and SYP were decreased in male offspring of LPS-treated mothers. Treatment with resveratrol reversed cognitive impairment and attenuated the increase in the levels of pro-inflammatory cytokines induced by maternal immune activation in the offspring mice. Furthermore, resveratrol reversed the deleterious effects of maternal immune activation on SIRT1, BDNF, PSD-95, and SYP levels in the hippocampus. Collectively, our results suggested that resveratrol can effectively improve learning and memory impairment induced by maternal immune activation via the modulation of inflammation and synaptic dysfunction.

Subsequent maternal sleep deprivation aggravates neurobehavioral abnormalities, inflammation, and synaptic function in adult male mice exposed to prenatal inflammation.

Objective: Studies have suggested that prenatal exposure to inflammation increases the risk of neuropsychiatric disorders, including anxiety, depression, and cognitive dysfunction. Because of anatomical and hormonal alterations, pregnant women frequently experience sleep dysfunction, which can enhance the inflammatory response. The aim of this study was to explore the effects of maternal sleep deprivation on prenatal inflammation exposure-induced behavioral phenotypes in offspring and identify the associated mechanisms. Methods: Pregnant mice received an intraperitoneal injection of lipopolysaccharide (LPS) on gestational day 15 and were subsequently subjected to sleep deprivation during gestational days 15-21. Anxiety-like behavior was evaluated by the open field test and the elevated plus maze test. Depression-like behavior was assessed by the tail suspension test and the forced swimming test. Cognitive function was determined using the Morris water maze test. The levels of markers of inflammation and synaptic function were examined employing general molecular biological techniques. Results: The results showed that prenatal exposure to LPS resulted in anxiety- and depression-like symptoms and learning and memory deficits, and these effects were exacerbated by maternal sleep deprivation. Furthermore, maternal sleep deprivation aggravated the prenatal LPS exposure-induced increase in the expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α and decrease in the levels of postsynaptic density-95 and synaptophysin in the hippocampus. Discussion: Collectively, these results suggested that maternal sleep deprivation exacerbates anxiety, depression, and cognitive impairment induced by prenatal LPS exposure, effects that were associated with an inflammatory response and synaptic dysfunction.

Effects of Sleep Reactivity on Sleep Macro-Structure, Orderliness, and Cortisol After Stress: A Preliminary Study in Healthy Young Adults.

Purpose: To investigate changes and links of stress and high sleep reactivity (H-SR) on the macro-structure and orderliness of sleep and cortisol levels in good sleepers (GS). Patients and Methods: Sixty-two GS (18-40 years old) were recruited, with 32 in the stress group and 30 in the control group. Each group was further divided into H-SR and low SR subgroups based on the Ford Insomnia Response to Stress Test. All participants completed two nights of polysomnography in a sleep laboratory. Before conducting polysomnography on the second night, the stress group completed the Trier Social Stress Test and saliva was collected. Results: The duration of NREM sleep stages 1, 2 (N1, N2) and rapid eye movement sleep (REM) decreased, and the values of approximate entropy, sample entropy, fuzzy entropy, and multiscale entropy increased under stress and SR effects. Stress increased rapid eye movement density, and H-SR increased cortisol reactivity. Conclusion: Stress can damage the sleep and increase cortisol release in GS, especially those with H-SR. N1, N2 and REM sleep are more easily affected, while NREM sleep stage 3 sleep is relatively stable.

Resveratrol ameliorates maternal separation-induced anxiety- and depression-like behaviors and reduces Sirt1-NF-kB signaling-mediated neuroinflammation.

Maternal separation in early life has a detrimental effect on the physiological and biochemical functions of the brains of offspring and can lead to anxiety- and depression-like behaviors later in life. Resveratrol possesses a variety of pharmacological properties, including anti-inflammatory, anxiolytic, and anti-depressive effects. In rodents, resveratrol can attenuate anxiety- and depression-like behaviors induced by chronic unpredictable mild stress, estrogen deficiency, and lipopolysaccharide. However, whether resveratrol administration during adolescence can counteract these behaviors when they result from maternal separation is unknown. In this study, male C57BL/6J mice were separated from their mothers for 4 h per day from postnatal day 2 (PND 2) to PND 21; starting on PND 61, resveratrol was administered intraperitoneally at 40 mg/(kg/day-1) for 4 weeks. At 3 months of age, anxiety and depression-like behaviors were assessed in the male offspring using a series of tasks consisting of an open field test, an elevated plus maze test, a forced swimming test, and a tail suspension test. The hippocampal levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) were measured by ELISA, while those of sirtuin 1 (Sirt1) and nuclear factor kappa B (NF-κB) p65 were determined by western blotting and PCR. The results showed that maternal separation led to increased anxiety- and depression-like behaviors, enhanced the levels of pro-inflammatory cytokines, and downregulated the Sirt1/NF-κB signaling pathway in the male offspring; however, these effects could be reversed by treatment with resveratrol. Our findings suggested that resveratrol can ameliorate inflammation and anxiety- and depression-like behaviors induced by maternal separation via the activation of the Sirt1/NF-κB pathway.

Long-term environmental enrichment overcomes depression, learning, and memory impairment in elderly CD-1 mice with maternal sleep deprivation exposure.

Early-life stress disrupts central nervous system development and increases the risk of neuropsychiatric disorder in offspring based on rodent studies. Maternal sleep deprivation (MSD) in rodents has also been associated with depression and cognitive decline in adult offspring. However, it is not known whether these issues persist into old age. Environmental enrichment is a non-pharmacological intervention with proven benefits in improving depression and cognitive impairment; however, it is unclear whether these benefits hold for aging mice following MSD exposure. The aim of this study was to explore the effects of MSD on depression and cognition in elderly offspring CD-1 mice and to determine whether long-term environmental enrichment could alleviate these effects by improving neuroinflammation and synaptic plasticity. The offspring mice subjected to MSD were randomly assigned to either a standard environment or an enriched environment. At 18 months of age, the forced swimming and tail suspension tests were used to evaluated depression-like behaviors, and the Morris water maze test was used to evaluate cognitive function. The expression levels of hippocampal proinflammatory cytokines and synaptic plasticity-associated proteins were also measured. MSD increased depression-like behaviors and impaired cognition function in aging CD-1 offspring mice. These effects were accompanied by upregulated interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α expression, and downregulated brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density-95, and synaptophysin expression in the hippocampus. All of these changes were reversed by long-term exposure to an enriched environment. These findings suggest that MSD exerts long-term effects on the behaviors of offspring in mice, leading to depression and cognitive impairment in older age. Importantly, long-term environmental enrichment could counteract the behavior difficulties induced by MSD through improving hippocampal proinflammatory cytokines and synaptic plasticity-associated proteins.

An enriched environment improves maternal sleep deprivation-induced cognitive deficits and synaptic plasticity via hippocampal histone acetylation.

INTRODUCTION: Growing evidence clearly demonstrates that maternal rodents exposure to sleep deprivation (SD) during late pregnancy impairs learning and memory in their offspring. Epigenetic mechanisms, particularly histone acetylation, are known to be involved in synaptic plasticity, learning, and memory. We hypothesize that the cognitive decline induced by SD during late pregnancy is associated with histone acetylation dysfunction, and this effect could be reversed by an enriched environment (EE). METHODS: In the present study, pregnant CD-1 mice were exposed to SD during the third trimester of pregnancy. After weaning, all offspring were randomly assigned to two subgroups in either a standard environment or an EE. When offspring were 3 months old, the Morris water maze was used to evaluate hippocampal-dependent learning and memory ability. Molecular biological techniques, including western blot and real-time fluorescence quantitative polymerase chain reaction, were used to examine the histone acetylation pathway and synaptic plasticity markers in the hippocampus of offspring. RESULTS: The results showed that the following were all reversed by EE treatment: maternal SD (MSD)-induced cognitive deficits including spatial learning and memory; histone acetylation dysfunction including increased histone deacetylase 2 (HDAC2) and decreased histone acetyltransferase (CBP), and the acetylation levels of H3K9 and H4K12; synaptic plasticity dysfunction including decreased brain-derived neurotrophic factor; and postsynaptic density protein-95. CONCLUSIONS: Our findings suggested that MSD could damage learning ability and memory in offspring via the histone acetylation pathway. This effect could be reversed by EE treatment.

Altered cognition and anxiety in adolescent offspring whose mothers underwent different-pattern maternal sleep deprivation, and cognition link to hippocampal expressions of Bdnf and Syt-1.

Background: Inadequate sleep during pregnancy negatively affects the neural development of offspring. Previous studies have focused on the continuous sleep deprivation (CSD) paradigm, but the sleep pattern during late pregnancy is usually fragmented. Objective: To compare the effects of CSD and fragmented sleep deprivation (FSD) in late pregnancy on emotion, cognition, and expression of synaptic plasticity-related proteins in offspring mice. Methods: Pregnant CD-1 mice were either subjected to 3/6 h of CSD/FSD during gestation days 15-21, while those in the control group were left untreated. After delivery, the offspring were divided into five groups, i.e., control (CON), short or long CSD (CSD3h, CSD6h), and short or long FSD (FSD3h, FSD6h). When the offspring were 2 months old, the anxiety-like behavior level was tested using the open field (OF) and elevated plus maze (EPM) test, and spatial learning and memory were evaluated using the Morris water maze (MWM) test. The expression of hippocampal of brain-derived neurotrophic factor (Bdnf) and synaptotagmin-1 (Syt-1) was determined using RT-PCR and western blotting. Results: The CSD6h, FSD3h, and FSD6h had longer latency, fewer center times in the OF test, less open arms time and fewer numbers of entries in the open arms of the EPM, longer learning distance swam and lower memory percentage of distance swam in the target quadrant in the MWM test, and decreased BDNF and increased Syt-1 mRNA and protein levels in the hippocampus. Compared to the CSD6h, the FSD3h and FSD6h had longer distance swam, a lower percentage of distance swam in the target quadrant, decreased BDNF, and increased Syt-1 mRNA and protein levels in the hippocampus. Conclusion: The results suggested that maternal sleep deprivation during late pregnancy impairs emotion and cognition in offspring, and FSD worsened the cognitive performance to a higher extent than CSD. The observed cognitive impairment could be associated with the expression of altered hippocampal of Bdnf and Syt-1 genes.

Environmental Enrichment Reverses Maternal Sleep Deprivation-Induced Anxiety-Like Behavior and Cognitive Impairment in CD-1 Mice.

Preclinical studies have clearly indicated that offspring of mothers who suffered sleep deprivation during pregnancy exhibit anxiety, depression-like behaviors, and cognitive deficits. The cognitive impairment induced by maternal sleep deprivation (MSD) is currently poorly treated. Growing evidence indicates that an enriched environment (EE) improves cognition function in models of Alzheimer's disease, schizophrenia, and lipopolysaccharide. However, the effects of EE on hippocampal-dependent learning and memory, as well as synaptic plasticity markers changes induced by MSD, are unclear. In the present study, pregnant CD-1 mice were randomly divided into a control group, MSD group, and MSD+EE group. Two different living environments, including standard environment and EE, were prepared. When male and female offspring were 2 months, the open field test and elevated plus maze were used to assess anxiety-like behavior, and the Morris water maze was used to evaluate hippocampal learning and memory. Western blotting and real-time fluorescence quantitative polymerase chain reaction were used to detect the expression of brain-derived neurotrophic factor and Synaptotagmin-1 in the hippocampus of offspring. The results revealed that MSD-induced offspring showed anxiety-like behaviors and cognitive impairment, while EE alleviated anxiety-like behavior and cognitive impairment in offspring of the MSD+EE group. The cognitive impairment induced by MSD was associated with a decreased brain-derived neurotrophic factor and an increased Synaptotagmin-1, while EE increased and decreased brain-derived neurotrophic factor and Synaptotagmin-1 in the hippocampus of mice from the MSD+EE group, respectively. Taken together, we can conclude that EE has beneficial effects on MSD-induced synaptic plasticity markers changes and can alleviate anxiety-like behaviors and cognitive impairment.