Search

Objective To investigate the effects of naringin (Nar) on lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Methods Thirty C57BL/6 male mice (8 weeks old, SPF grade, weighting 20~23 g) were randomly divided into 3 groups (n=10): control group, saline (Sal)+LPS group, and Nar+LPS group. The mice of the last group were pretreated with Nar (80 mg/kg, i.p., once a day for 8 consecutive days). The exploratory behavior and anxiety-like behavior in mice were assessed by open field test, light and dark box experiment and elevated plus maze test. Sugar water preference test, hanging tail test and forced swimming test were used to evaluate the depression-like behaviors of the mice. Immunohistochemical assay for Iba1 was adopted to detect the effects of Nar and LPS treatments on the number of microglia in the hippocampus of mice. Western blotting and qRT-PCR were performed to determine the protein expression of NF-κB and the mRNA levels of IL-1β, TNF-α and NF-κB in mouse hippocampus, respectively. Results As compared with the control group, the mice in the Sal+LPS group showed decreased preference for sugar water (P < 0.05), and increased immobile time in the forced swimming test (P < 0.01) as well as in the hanging tail test (P < 0.05). The number of microglia in the hippocampus was elevated (P < 0.01), the protein level of NF-κB and the mRNA levels of IL-1β, TNF-α and NF-κB were also up-regulated (P < 0.05). When compared with the Sal+LPS group, the mice in the Nar+LPS group presented increased preference for sugar water (P < 0.01), and decreased immobility time in the forced swimming test (P < 0.01) and hanging tail test (P < 0.05), with higher number of microglia in the hippocampus (P < 0.01), and lower protein levels of NF-κB and mRNA levels of IL-1β, TNF-α and NF-κB (P < 0.01). Conclusion Nar may ameliorate LPS-induced depression-like behaviors in mice by inhibiting inflammation in the hippocampus.

Objective To investigate the effects of Chaihu Oral Liquid (CHOL) on the neurogenesis in hippocampal dentate gyrus (DG) and short-term memory defects in BTBR T+ Itpr3tf/J (BTBR) autism model mice. Methods Healthy adult male C57BL/6J(C57) mice (7~8 weeks old, 24.72±1.35 g) and BTBR mice (7~ 8 weeks old, 27.7±1.42 g) were randomly divided into groups as follows (n=4 in each group): C57 control, C57 drug treatment, BTBR control, and BTBR drug treatment. Mice in the treatment groups were given CHOL solution gavage (10 μL/g) once a day for 7 consecutive days, while those of the control group received equal volume of normal saline. Daily changes of body weight were recorded. After the last administration, hair grooming, bead embedding, new object recognition and open field experiments were conducted on the next day and lasted for 4 d. Finally, the samples of mice brain tissue were harvested, and immunofluorescence staining was performed to detect the NeuN, DCX, SOX2/GFAP labeled nerve cells in hippocampal DG. Results Behavioral results suggested that mice in the BTBR control group showed a more obvious preference for old objects in the new object recognition experiment (P < 0.01), as compared with the C57 control group, while the new object recognition index was significantly improved in the BTBR drug treatment group (P < 0.05). Moreover, the BTBR control group presented more repetitive behavior and longer movement distance than the C57 control during the hair grooming, bead embedding and open field experiments, as well as higher body weight (P < 0.05), whereas the BTBR treatment group had no significant changes in comparison with the BTBR control regarding these aspects. There were no notable differences between the C57 control and C57 treatment groups in terms of new object recognition index, repetitive behavior, motor ability and body weight. Immunofluorescence staining results indicated that the numbers of NeuN labeled mature neurons and DCX labeled newborn neurons in hippocampal DG were greatly decreased in the BTBR control group, so as the number of SOX/GFAP labeled neural progenitor cells (P < 0.01), while the number of neurocytes was remarkably increased in the BTBR drug treatment group (P < 0.05). There were no significant differences in the numbers of NeuN, DCX and SOX2/GFAP labeled neurocytes between the C57 control and the C57 treatment groups. Conclusion CHOL promotes the generation of hippocampal DG nerve progenitor cells, new and mature neurons in adult BTBR mice, and improves the short-term learning and memory dysfunction.

Objective To determine the effects of simulated altitude hypoxia conditions on anxiety- and depression-like behaviors in mice. Methods C57 adult male mice were divided into 3 groups (n=10): plain control group, 24 h plateau hypoxia group, and 7 d plateau hypoxia group. Behavioral observations were used to detect anxiety-like behaviors, short-term memory, and depression-like behaviors in the mice. Immunohistochemical assay was applied to measure the number of C-Fos, AVP and GR immunoreactive cells in the paraventricular nucleus of the hypothalamus. Enzyme linked immunosorbent assay (ELISA) was adopted to detect the concentrations of adrenocorticotropic hormone (ACTH) and corticosterone in the blood. Results The Results of the elevated plus maze test showed that the mice in the 7 d plateau hypoxia group had a lower percentage of open arm time and increased anxiety-like behavior than those of the control group. Tail suspension test indicated that the mice of the 7 d plateau hypoxia group had more immobile time and increased depression-like behavior than those of the control group (P < 0.01). In the forced swimming test, the 24 h hypoxia group had significantly longer immobility time and increased depression-like behavior than the control group (P < 0.05). Immunohistochemical assay showed that the C-Fos protein in the paraventricular nucleus of the hypothalamus was significantly activated in the 7-d plateau hypoxia group. The numbers of AVP and GR positive neurons were increased in the paraventricular nucleus of the hypothalamus in the 7 d plateau hypoxia group (P < 0.01). Compared with the control group, the ACTH concentration of mice was elevated in the 7 d plateau hypoxia group (P < 0.05), so was the corticosterone concentration in the mice in the 24 h plateau hypoxia group (P < 0.05). Conclusion Rapidly entering the high altitude can cause anxiety- and depression-like behaviors in mice, and the stress responses are regulated by the hypothalamic-pituitary-adrenal axis.

Objective To investigate the effects of metformin (MET) treatment during early postnatal period on hippocampal neurogenesis of neonatal BTBR T+Itpr3tf/J (BTBR) mouse model of autism. Methods Healthy C57BL/6J (C57) and BTBR male pups were randomly divided into C57 normal saline group (C57+NS), C57 MET treatment group (C57+MET), BTBR+NS, and BTBR+MET group, with 5 animals in each group. From postnatal day 7 (P7) to P14, MET (200 mg/kg) or normal saline (same volume of sterile saline solution) were intraperitoneally injected into the corresponding mice, once per day. In 2 h after the last injection on P14, all mice were sacrificed, and the brains were collected and sliced coronally. Fluorescent immunostaining was performed to detect the expression of 5-bromo-2'-deoxyuridine (BrdU), Ki67, Sox2/GFAP and Prox1 in the dentate gyrus (DG). Results On P14, the numbers of BrdU-labeled cells and Ki67-labeled cells were significantly less in the DG of BTBR+NS group than the C57+NS group (P < 0.05), while the numbers were obviously increased in BTBR+MET group than the C57+MET group (P < 0.05). Although there were remarkably less Sox2 and GFAP double-positive cells (neural stem cells) and Prox1-positive cells (newborn neurons) in BTBR+NS group than the C57+NS group (P < 0.05), the 2 kinds of cells were increased obviously in BTBR+MET group than the BTBR+NS group (P < 0.05). However, MET treatment showed no effect on the hippocampal neurons, and there were no significant differences in the numbers of BrdU-, Ki67-, Sox2/GFAP- and Prox1-labeled cells between the C57+MET and C57+NS groups. Conclusion MET treatment in early postnatal period significantly improves the defects of hippocampal neurogenesis, and promotes the proliferation of hippocampal DG neurons and neural stem cells in BTBR mice.

Objective To explore the therapeutic effect of estrogen receptor β agonist ly3201 on autism-like behaviors in BTBR mice. Methods Healthy neonatal (2 days old) C57BL/6J(C57) and BTBR littermate mice were both divided into 2 groups and subjected to intraperitoneal injections of estrogen receptor β agonist ly3201 at the dose of 1.6 mg/kg or normal saline of an equivalent volume. We measured the expression levels of estrogen receptor β in the cerebral cortex and hippocampus of the mice on day 14 after birth with immunohistochemistry and real-time PCR, and tested the mice for autism-like behaviors at 2 months of age. Results At 14 d after birth, the expression levels of estrogen receptor β in the cerebral cortex and hippocampus were significantly lower in BTBR mice than in C57 mice (P < 0.05), and treatment with ly3201 obviously enhanced estrogen receptor β expression in both BTBR and C57 mice (P < 0.01). In the three-chambered social test, BTBR mice with ly3201 treatment spent significantly longer time in the chamber with other mice than in the chamber with a new object (P < 0.05); they also spent significantly longer time for exploratory sniffing of other mice than of the new object (P < 0.05). In the male-female reciprocal social interaction test, compared with the saline-treated mice, BTBR mice with ly3201 treatment exhibited longer time of nose-to-nose sniffing (P < 0.05) and anogenital sniffing (P < 0.05) with a significantly reduced time for cage exploration (P < 0.05). Conclusion Estrogen receptor β agonist ly3201 activates the expression of endogenous estrogen receptor in the hippocampus and cortex to alleviate social deficits in BTBR mice.

Autism spectrum disorder (ASD) is considered a heterogeneous neurodevelopmental disorder characterized by significant social, communication, and behavioral impairments. The gut microbiota is increasingly considered a promising therapeutic target in ASD. Farnesoid X receptor (FXR) has recently been shown to modulate the gut microbiota. We hypothesized that FXR agonist GW4064 could ameliorate behavioral deficits in an animal model for autism: BTBR T+Itpr3tf/J (BTBR) mouse. As expected, administration of GW4064 rescued the sociability of BTBR mice in the three-chamber sociability test and male-female social reciprocal interaction test, while no effects were observed in C57BL/6J mice. We also found that GW4064 administration increased fecal microbial abundance and counteracted the common ASD phenotype of a high Firmicutes to Bacteroidetes ratio in BTBR mice. In addition, GW4064 administration reversed elevated Lactobacillus and decreased Allobaculum content in the fecal matter of BTBR animals. Our findings show that GW4064 administration alleviates social deficits in BTBR mice and modulates selective aspects of the composition of the gut microbiota, suggesting that GW4064 supplementation might prove a potential strategy for improving ASD symptoms. [ABSTRACT FROM AUTHOR]

Rationale: Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders characterized by deficits in social communication and interaction, repetitive stereotyped behaviors, and cognitive impairments. Curcumin has been indicated to be neuroprotective against neurological and psychological disorders. However, the role of curcumin in autistic phenotypes remains unclear. Objectives: In the current study, we evaluated the effects of neonatal curcumin treatment on behavior and hippocampal neurogenesis in BTBRT+ltpr3tf/J (BTBR) mice, a model of autism. Methods: C57BL/6J (C57) and BTBR mouse pups were treated with 0.1% dimethyl sulfoxide (DMSO) or curcumin (20 mg/kg) from postnatal day 6 (P6) to P8. Neural progenitor cells (NPCs) in the hippocampal dentate gyrus (DG) were evaluated on P8, and neurogenesis was measured on P24 by immunofluorescence. A battery of behavioral tests was carried out when the mice were 8 weeks of age. Results: Neonatal curcumin treatment improved autism-related symptoms in BTBR mice, enhancing sociability, reducing repetitive behaviors, and ameliorating cognitive impairments. Furthermore, the suppression of hippocampal neurogenesis in BTBR mice was greatly rescued after neonatal curcumin treatment, leading to an increase in neurogenic processes and an increase in NPC proliferation concomitant with an expansion of the NPC pool on P8, and NPC differentiation towards the neuronal lineage was promoted in the DG of BTBR mice on P24. Conclusions: Our findings suggest that neonatal curcumin treatment elicits a therapeutic response through the restoration of hippocampal neurogenesis in BTBR mice and thus may represent a promising novel pharmacological strategy for ASD treatment. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) causes dysbiosis and intestinal barrier disruption, which further exacerbate brain damage via an inflammatory pathway. Gut microbiota remodeling by Lactobacillus acidophilus (LA) is a potential intervention.Objective: The aim of this study was to investigate the neuroprotective effects of LA in TBI and elucidated underlying mechanisms.Methods: C57BL/6 male mice (aged 8-9 wk) were subjected to weight-drop impact and gavaged with saline (TBI + vehicle) or LA (1 × 1010 CFU) (TBI + LA) on the day of injury and each day after for 1, 3, or 7 d. The sham + vehicle mice underwent craniotomy without brain injury and were gavaged with saline. Sensorimotor functions were determined pre-TBI and 1, 3, and 7 d postinjury. Indexes of neuroinflammation, peripheral inflammation, and intestinal barrier function were measured on days 3 and 7. Microbiota composition was measured 3 d postinjury. The data were mainly analyzed by 2-factor ANOVA.Results: Compared with sham + vehicle mice, the TBI + vehicle mice exhibited impairments in the neurological severity score (+692%, day 3; +600%, day 7) and rotarod test (-58%, day 3; -45%, day 7) (P < 0.05), which were rescued by LA. The numbers of microglia (total and activated) and astrocytes and concentrations of TNF-α and IL1-β in the perilesional cortex were elevated in the TBI + vehicle mice on day 3 or 7 compared with sham + vehicle mice (P < 0.05) and were normalized by LA. Compared with sham + vehicle mice, the TBI + vehicle mice exhibited increased serum concentrations of endotoxin and TNF-α, and intestinal barrier permeability (D-lactate) on days 3 and 7 (P < 0.05), and these changes were alleviated by LA. Three days postinjury, the microbiota composition was disrupted in the TBI + vehicle mice compared with sham + vehicle mice (P < 0.05), which was restored by LA.Conclusion: Our results demonstrate that LA exerts neuroprotective effects that may be associated with gut microbiota remodeling in TBI mice. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a developmental disability characterized by social deficits and repetitive stereotyped behaviors. There are currently no drugs available for the treatment of the core symptoms of ASD, suggesting an urgent need for new therapeutic strategies. The neurobiology of autism is complex, but emerging research indicates that defects in hippocampal neurogenesis are associated with ASD in both humans and mouse models of ASD, leading to the suggestion that restoring neurogenesis may be a novel therapeutic approach for ASD. Here, we found that postnatal treatment with TO901317 (TO), a potent liver X receptor (LXR) agonist, typically activated LXRβ and its target genes in the hippocampus, and alleviated the social deficits and stereotypical behaviors in BTBR T+ tf/J (BTBR) and valproic acid (VPA)-induced mouse models. In addition, we further confirmed that TO postnatal treatment also rescued the inhibition of adult hippocampal neurogenesis in these two models. In summary, our study suggests that LXR agonist targeting hippocampal neurogenesis may represent a novel potential therapy for ASD. [ABSTRACT FROM AUTHOR]

Rationale: Resveratrol (RSV) has been indicated to exhibit beneficial effects on depression and anxiety treatment by suppression of inflammatory processes. Depression triggered by deficiency of estrogen and anxiety-like behaviors are associated with inflammation. The role of RSV in ovariectomized mice is unclear. Objectives: We examine whether the RSV, a Sirt1 activator, alleviates ovariectomy-induced anxiety- and depression-like behaviors through the inhibition of inflammatory processes. Methods: Female C57BL/6J mice (6–8 weeks of age, 17–20 g) were ovariectomized and treated with RSV at a dose of 20 mg/kg for 2 weeks. Depression- and anxiety-like behaviors were compared with vehicle-injected control animals. Immunohistochemistry and qPCR were used to detect inflammation in the hippocampal region. Results: Ovariectomized mice were observed to suffer from anxiety- and depression-like behaviors. These effects were attenuated by treatment with RSV. Immunohistochemical staining results showed that RSV could reverse the increase of microglial activation in the hippocampal dentate gyrus. At a molecular level, RSV inhibited the activation of NLRP3 and NF-κB in the hippocampal region caused by deficiency of estrogen. Conclusions: RSV suppressed the production of inflammatory cytokines by enhancing Sirt1 levels. Our findings indicated that RSV-induced Sirt1 activation counteracted estrogen deficiency-induced psychobehavioral changes via inhibition of inflammatory processes in the hippocampus. In anxiety and depression disorders, RSV is supposed to be an effective treatment for postmenopausal changes. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complicated, heterogeneous disorder characterized by social interaction deficits and repetitive stereotypical behaviors. Neuroinflammation and synaptic protein dysregulation have been implicated in ASD pathogenesis. Icariin (ICA) has proven to exert neuroprotective function through anti-inflammatory function. Therefore, this study aimed to clarify the effects of ICA treatment on autism-like behavioral deficits in BTBR mice and whether these changes were related to modifications in the hippocampal inflammation and the balance of excitatory/inhibitory synapses. ICA supplementation (80 mg/kg, once daily for ten days, i.g.) ameliorated social deficits, repetitive stereotypical behaviors, and short-term memory deficit without affecting locomotor activity or anxiety-like behaviors of BTBR mice. Furthermore, ICA treatment inhibited neuroinflammation via decreasing microglia number and the soma size in the CA1 region of the hippocampus, as well as the protein levels of proinflammatory cytokines in the hippocampus of BTBR mice. In addition, ICA treatment also rescued excitatory-inhibitory synaptic protein imbalance by inhibiting the increased vGlut1 level without affecting the vGAT level in the BTBR mouse hippocampus. Collectively, the observed results indicate that ICA treatment alleviates ASD-like features, mitigates disturbed balance of excitatory-inhibitory synaptic protein, and inhibits hippocampal inflammation in BTBR mice, and may represent a novel promising drug for ASD treatment. • Icariin treatment ameliorates social deficits and stereotypical behaviors in adult BTBR mice. • Icariin improves cognitive function in adult BTBR mice. • Icariin inhibits hippocampal neuroinflammation in BTBR mice. • Icariin decreases vGlut1 expression in the hippocampus of BTBR mice. [ABSTRACT FROM AUTHOR]

Ethanol (EtOH) exposure during a period comparable to the third trimester in human results in obvious neurotoxicity in the developing hippocampus and persistent deficits in hippocampal neurogenesis. Dexmedetomidine (DEX), a highly selective α-2-adrenergic agonist has been demonstrated to restore the impaired neurogenesis and neuronal plasticity in the dentate gyrus (DG) that follows neurological insult. However, the protective roles of DEX in the EtOH-induced deficits of postnatal neurogenesis in the hippocampus are still unknown. Mice were pretreated with DEX prior to EtOH exposure to determine its protective effects on impaired postnatal hippocampal neurogenesis. Six-day-old neonatal mice were treated with DEX (125 μg/kg) or saline, followed by EtOH at a total of 5 g/kg or an equivalent volume of saline on P7. Immunohistochemistry and immunofluorescence were used to evaluate the neurogenesis and activated microglia in the DG. Quantitative real time PCR (qRT-PCR) was utilized to assess the expression of inflammatory factors in the hippocampus. DEX pretreatment attenuated the inhibition of EtOH-mediated hippocampal neurogenesis and the reduction of hippocampal neural precursor cells (NPCs). We further confirmed that DEX pretreatment reversed the EtOH-induced microglia activation in the DG as well as the upregulation of the hippocampal TNFα, MCP-1, IL-6, and IL-1β mRNA levels. Our findings indicate that DEX pretreatment protects against EtOH-mediated inhibition of hippocampal neurogenesis in postnatal mice and reverses EtOH-induced neuroinflammation via repressing microglia activation and the expression of inflammatory cytokines. • DEX reverses the EtOH-induced microglia activation in the dentate gyrus. • DEX restores the up-regulated hippocampal inflammatory factors level. • DEX attenuates the reduction of hippocampal neural precursor cells. • DEX attenuates the inhibition of EtOH-mediated hippocampal neurogenesis. [ABSTRACT FROM AUTHOR]