Maternal sleep deprivation induces gut microbial dysbiosis and neuroinflammation in offspring rats.

Maternal sleep deprivation (MSD) is a global public health problem that affects the physical and mental development of pregnant women and their newborns. The latest research suggests that sleep deprivation (SD) disrupts the gut microbiota, leading to neuroinflammation and psychological disturbances. However, it is unclear whether MSD affects the establishment of gut microbiota and neuroinflammation in the newborns. In the present study, MSD was performed on pregnant Sprague-Dawley rats in the third trimester of pregnancy (gestational days 15-21), after which intestinal contents and brain tissues were collected from offspring at different postnatal days (P1, P7, P14, and P56). Based on microbial profiling, microbial diversity and richness increased in pregnant rats subjected to MSD, as reflected by the significant increase in the phylum Firmicutes. In addition, microbial dysbiosis marked by abundant Firmicutes bacteria was observed in the MSD offspring. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) showed that the expression levels of proinflammatory cytokines interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) were significantly higher in the MSD offspring at adulthood (P56) than in the control group. Through Spearman correlation analysis, IL-1ß and TNF-α were also shown to be positively correlated with Ruminococcus_1 and Ruminococcaceae_UCG-005 at P56, which may determine the microbiota-host interactions in MSD-related neuroinflammation. Collectively, these results indicate that MSD changes maternal gut microbiota and affects the establishment of neonatal gut microbiota, leading to neuroinflammation in MSD offspring. Therefore, understanding the role of gut microbiota during physiological development may provide potential interventions for cognitive dysfunction in MSD-impacted offspring.

Serum Folate Status Is Primarily Associated With Neurodevelopment in Children With Autism Spectrum Disorders Aged Three and Under-A Multi-Center Study in China.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Folate has been demonstrated to be associated with ASD. However, current studies on the correlation between folate and symptoms of children with ASD have inconsistent conclusions, use mainly small samples, and lack age-stratified analysis. This study aimed to explore the association between serum folate and symptoms of autistic children at different age groups from a multi-center perspective. Methods: We enrolled 1,300 children with ASD and 1,246 typically developing (TD) children under 7 years old from 13 cities in China. The Autism Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Childhood autism rating scale (CARS) were used to evaluate the symptoms of children with ASD. China neuropsychological and Behavior Scale-Revision 2016 (CNBS-R2016) scale was used to evaluate the neurodevelopment of children with ASD. Serum folate was measured by chemiluminescence assay in the two groups. Results: The serum folate levels of children with ASD were lower than that of TD children. In terms of core symptoms of ASD, we found that the serum folate levels were not associated with ABC, SRS, and CARS scores in ASD children of all ages but negatively associated with communication warning behavior scores of CNBS-R2016 in ASD children aged three and under. Concerning development quotients, it was at the age of three and under that serum folate levels were positively associated with gross motor, fine motor, language, and general quotient of ASD children. These ASD children aged three and under were further divided into two groups according to the median of serum folate (14.33 ng/mL); we found that compared to ASD children with folate ≤ 14.33 ng/mL, those with folate >14.33 ng/mL had lower communication warning behavior score and higher gross motor, fine motor, adaptive behavior, language, person-social, and general development quotients. Conclusion: We found that serum folate status was primarily associated with the neurodevelopment of children with ASD aged three and under. Furthermore, relatively higher serum folate levels may be more beneficial for children with ASD. Our results suggest that folate level should be paid more attention in ASD children, especially in early life, to better promote the intervention of ASD children.

Immunomodulatory role of mesenchymal stem cells in Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common causes of dementia and is characterized by gradual loss in memory, language, and cognitive function. The hallmarks of AD include extracellular amyloid deposition, intracellular neuronal fiber entanglement, and neuronal loss. Despite strenuous efforts toward improvement of AD, there remains a lack of effective treatment and current pharmaceutical therapies only alleviate the symptoms for a short period of time. Interestingly, some progress has been achieved in treatment of AD based on mesenchymal stem cell (MSC) transplantation in recent years. MSC transplantation, as a rising therapy, is used as an intervention in AD, because of the enormous potential of MSCs, including differentiation potency, immunoregulatory function, and no immunological rejection. Although numerous strategies have focused on the use of MSCs to replace apoptotic or degenerating neurons, recent studies have implied that MSC-immunoregulation, which modulates the activity state of microglia or astrocytes and mediates neuroinflammation via several transcription factors (NFs) signaling pathways, may act as a major mechanism for the therapeutic efficacy of MSC and be responsible for some of the satisfactory results. In this review, we will focus on the role of MSC-immunoregulation in MSC-based therapy for AD.

Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies.

Accumulation of pathological tau is the hallmark of Alzheimer's disease and other tauopathies and is closely correlated with cognitive decline. Clearance of pathological tau from the brain is a major therapeutic strategy for tauopathies. The physiological capacity of the periphery to clear brain-derived tau and its therapeutic potential remain largely unknown. Here, we found that cisterna magna injected 131I-labelled synthetic tau dynamically effluxed from the brain and was mainly cleared from the kidney, blood, and liver in mice; we also found that plasma tau levels in inferior vena cava were lower than those in femoral artery in humans. These findings suggest that tau proteins can efflux out of the brain and be cleared in the periphery under physiological conditions. Next, we showed that lowering blood tau levels via peritoneal dialysis could reduce interstitial fluid (ISF) tau levels in the brain, and tau levels in the blood and ISF were dynamically correlated; furthermore, tau efflux from the brain was accelerated after the addition of another set of peripheral system in a parabiosis model. Finally, we established parabiosis mouse models using tau transgenic mice and their wild-type littermates and found that brain tau levels and related pathologies in parabiotic transgenic mice were significantly reduced after parabiosis, suggesting that chronic enhancement of peripheral tau clearance alleviates pathological tau accumulation and neurodegeneration in the brain. Our study provides the first evidence of physiological clearance of brain-derived pathological tau in the periphery, suggesting that enhancing peripheral tau clearance is a potential therapeutic strategy for tauopathies.

iTRAQ-Based Proteomics Suggests Ephb6 as a Potential Regulator of the ERK Pathway in the Prefrontal Cortex of Chronic Social Defeat Stress Model Mice.

PURPOSE: Major depressive disorder (MDD) is a worldwide concern and devastating psychiatric disease. The World Health Organization claims that MDD leads to at least 11.9% of the global burden of disease. However, the underlying pathophysiology mechanisms of MDD remain largely unknown. EXPERIMENTAL DESIGN: Herein, we proteomic-based strategy is used to compare the prefrontal cortex (PFC) in chronic social defeat stress (CSDS) model mice with a control group. Based on pooled samples, differential proteins are identified in the PFC proteome using iTRAQ coupled with LC-MS/MS. RESULTS: Ingenuity Pathway Analysis (IPA) is then followed to predict relevant pathways, with the ephrin receptor signaling pathway selected for further research. Additionally, as the selected key proteins of the ephrin receptor signaling pathway, ephrin type-B receptor 6 (EphB6) and the ERK pathway are validated by Western blotting. CONCLUSION AND CLINICAL RELEVANT: Altogether, increased understanding of the ephrin receptor signaling pathway in MDD is provided, which implicates further investigation of PFC dysfunction induced by CSDS treatment.

7,8-dihydroxyflavone Ameliorates Motor Deficits Via Suppressing α-synuclein Expression and Oxidative Stress in the MPTP-induced Mouse Model of Parkinson's Disease.

BACKGROUND: Parkinson disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and diminished dopamine content in the striatum, which is at least partly associated with α-synuclein protein overexpression in these neurons. Recent reports show that 7,8-dihydroxyflavone (DHF), a TrkB agonist, has beneficial effects in animal model of PD. However, it is unclear whether the therapeutic effects of DHF are associated with the expression of α-synuclein. AIMS: In this study, we investigated the protective effects of DHF on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced deficit of motor functions, the loss of dopaminergic neurons and the expression of α-synuclein as well as antioxidative activity in the C57BL/6 mice. RESULTS: Mice were treated with MPTP (30 mg/kg, i.p.) once a day for 5 days to induce dopaminergic neuron death in the SN. DHF (5 mg/kg, i.p.) was administrated once a day from the first day of MPTP injection until 9 days after the last injection of MPTP. Behavioral tests showed that DHF succeeded in ameliorating the impaired motor functions in the MPTP-treated mice. The immunohistochemical assay showed that the amelioration of motor function was accompanied by a reduction in the loss of dopaminergic neurons in the SN and striatum. Western blot analyses showed that DHF prevented the inactivation of TrkB and suppressed α-synuclein overexpression in the SN and striatum following MPTP treatment. Antioxidative activity detection revealed that DHF prevented MPTP-induced reduction in glutathione and total superoxide dismutase activity in the SN and striatum. CONCLUSION: Taken together, these results indicate that DHF treatment may suppress the accumulation of α-synuclein and oxidative stress via activating TrkB and subsequently block the loss of dopaminergic neurons in the SN and striatum, thereby ameliorating MPTP-induced motor deficits in the C57BL/6 mice.

Repeated morphine treatment influences operant and spatial learning differentially.

OBJECTIVE: To investigate whether repeated morphine exposure or prolonged withdrawal could influence operant and spatial learning differentially. METHODS: Animals were chronically treated with morphine or subjected to morphine withdrawal. Then, they were subjected to two kinds of learning: operant conditioning and spatial learning. RESULTS: The acquisition of both simple appetitive and cued operant learning was impaired after repeated morphine treatment. Withdrawal for 5 weeks alleviated the impairments. Single morphine exposure disrupted the retrieval of operant memory but had no effect on rats after 5-week withdrawal. Contrarily, neither chronic morphine exposure nor 5-week withdrawal influenced spatial learning task of the Morris water maze. Nevertheless, the retrieval of spatial memory was impaired by repeated morphine exposure but not by 5-week withdrawal. CONCLUSION: These observations suggest that repeated morphine exposure can influence different types of learning at different aspects, implicating that the formation of opiate addiction may usurp memory mechanisms differentially.