The effect of Banxia-houpo decoction on CUMS-induced depression by promoting M2 microglia polarization via TrkA/Akt signalling.

It has been reported that Banxia-houpo decoction (BXHPD) serves as the anti-depressant treatment for a mild and severe depressive disease with limited side effects. The present study was performed to evaluate the protective effect of BXHPD on chronic unpredicted mild stress (CUMS)-induced depression and explore its effect on TrkA/Akt-mediated microglia polarization. The CUMS procedure was carried out, and the mice were intragastrically treated with BXHPD once daily. The selective TrkA inhibitor GW441756 was applied to further investigate the role of TrkA in BXHPD-mediated microglia polarization. The behaviour test including open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), tail suspension test (TST) and forced swim test (FST) was performed. The concentrations of pro-inflammatory cytokines IL-6, TNF-α, IL-1ß, IL-12 and anti-inflammatory cytokines IL-4, IL-10 were determined using Enzyme-linked immunosorbent assay. The population of Iba1+ cells and the length of microglia processes were observed under the fluorescence microscope. The mRNA expressions of Arg1, Ym1 and Fizzl1 were measured by PCR. The protein expressions of TrkA, p-Tyr490-TrkA, p-Ser473-Akt, p-Ser473-Akt1, p-Ser474-Akt2, p-CREB and Jmjd3 were detected by western blot. Our results showed that BXHPD attenuated CUMS-induced depressive-like behaviour, promoted anti-inflammatory cytokines, inhibited pro-inflammatory cytokines, suppressed microglia activation, promoted M2 phenotype-specific indices and upregulated the expressions of TrkA, p-Tyr490-TrkA, p-Ser473-Akt, p-Ser473-Akt1, p-Ser474-Akt2, p-CREB and Jmjd3. The above beneficial effect of BXHPD can be blocked by TrkA inhibitor GW441756. This work demonstrated that BXHPD exerted an anti-depressant effect by promoting M2 phenotype microglia polarization via TrkA/Akt pathway.

Disrupted Maturation of Prefrontal Layer 5 Neuronal Circuits in an Alzheimer's Mouse Model of Amyloid Deposition.

Mutations in genes encoding amyloid precursor protein (APP) and presenilins (PSs) cause familial forms of Alzheimer's disease (AD), a neurodegenerative disorder strongly associated with aging. It is currently unknown whether and how AD risks affect early brain development, and to what extent subtle synaptic pathology may occur prior to overt hallmark AD pathology. Transgenic mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD pathogenesis. Among these lines, the 5XFAD mice rapidly develop key features of AD pathology and have proven utility in studying amyloid plaque formation and amyloid ß (Aß)-induced neurodegeneration. We reasoned that transgenic mutant APP/PS1 over-expression in 5XFAD mice may lead to neurodevelopmental defects in early cortical neurons, and performed detailed synaptic physiological characterization of layer 5 (L5) neurons from the prefrontal cortex (PFC) of 5XFAD and wild-type littermate controls. L5 PFC neurons from 5XFAD mice show early APP/Aß immunolabeling. Whole-cell patch-clamp recording at an early post-weaning age (P22-30) revealed functional impairments; although 5XFAD PFC-L5 neurons exhibited similar membrane properties, they were intrinsically less excitable. In addition, these neurons received smaller amplitude and frequency of miniature excitatory synaptic inputs. These functional disturbances were further corroborated by decreased dendritic spine density and spine head volumes that indicated impaired synapse maturation. Slice biotinylation followed by Western blot analysis of PFC-L5 tissue revealed that 5XFAD mice showed reduced synaptic AMPA receptor subunit GluA1 and decreased synaptic NMDA receptor subunit GluN2A. Consistent with this, patch-clamp recording of the evoked L23>L5 synaptic responses revealed a reduced AMPA/NMDA receptor current ratio, and an increased level of AMPAR-lacking silent synapses. These results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early developmental defects of cortical circuits, which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life.

Disrupted Timing of MET Signaling Derails the Developmental Maturation of Cortical Circuits and Leads to Altered Behavior in Mice.

The molecular regulation of the temporal dynamics of circuit maturation is a key contributor to the emergence of normal structure-function relations. Developmental control of cortical MET receptor tyrosine kinase, expressed early postnatally in subpopulations of excitatory neurons, has a pronounced impact on the timing of glutamatergic synapse maturation and critical period plasticity. Here, we show that using a controllable overexpression (cto-Met) transgenic mouse, extending the duration of MET signaling after endogenous Met is switched off leads to altered molecular constitution of synaptic proteins, persistent activation of small GTPases Cdc42 and Rac1, and sustained inhibitory phosphorylation of cofilin. These molecular changes are accompanied by an increase in the density of immature dendritic spines, impaired cortical circuit maturation of prefrontal cortex layer 5 projection neurons, and altered laminar excitatory connectivity. Two photon in vivo imaging of dendritic spines reveals that cto-Met enhances de novo spine formation while inhibiting spine elimination. Extending MET signaling for two weeks in developing cortical circuits leads to pronounced repetitive activity and impaired social interactions in adult mice. Collectively, our data revealed that temporally controlled MET signaling as a critical mechanism for controlling cortical circuit development and emergence of normal behavior.

Neuroplasticity: A Key Player in the Antidepressant Action of Chinese Herbal Medicine.

Traditional Chinese medicine (TCM) is a systematic medicine. It provides alternative strategies for the treatment of depression with its clinical experience, comprehensive diagnosis, and treatment theory. Chinese herbal medicine (CHM) is the major form of TCM prescription, and numerous CHMs have been demonstrated to possess remarkable antidepressant-like properties. A diversity of mechanisms have been implicated in CHM-associated antidepressant property. This paper reviewed the neuroplastic mechanisms underlying the antidepressant actions of CHM, finding that CHM repairs neuroplasticity by improving neurogenesis, neurotrophic factors, synaptic spine morphology, cell signaling, glutamatergic system, monoamine neurotransmitters, and neural apoptosis. CHM thereby exerts an antidepressant effect, attempting to offer a better understanding of the mechanisms implicated in TCM-related antidepressant-like efficacy and laying a foundation for the scientific evaluation and development of TCM in treating depression.

Conditional knockout of MET receptor tyrosine kinase in cortical excitatory neurons leads to enhanced learning and memory in young adult mice but early cognitive decline in older adult mice.

Human genetic studies established MET gene as a risk factor for autism spectrum disorders. We have previously shown that signaling mediated by MET receptor tyrosine kinase, expressed in early postnatal developing forebrain circuits, controls glutamatergic neuron morphological development, synapse maturation, and cortical critical period plasticity. Here we investigated how MET signaling affects synaptic plasticity, learning and memory behavior, and whether these effects are age-dependent. We found that in young adult (postnatal 2-3 months) Met conditional knockout (Metfx/fx:emx1cre, cKO) mice, the hippocampus exhibits elevated plasticity, measured by increased magnitude of long-term potentiation (LTP) and depression (LTD) in hippocampal slices. Surprisingly, in older adult cKO mice (10-12 months), LTP and LTD magnitudes were diminished. We further conducted a battery of behavioral tests to assess learning and memory function in cKO mice and littermate controls. Consistent with age-dependent LTP/LTD findings, we observed enhanced spatial memory learning in 2-3 months old young adult mice, assessed by hippocampus-dependent Morris water maze test, but impaired spatial learning in 10-12 months mice. Contextual and cued learning were further assessed using a Pavlovian fear conditioning test, which also revealed enhanced associative fear acquisition and extinction in young adult mice, but impaired fear learning in older adult mice. Lastly, young cKO mice also exhibited enhanced motor learning. Our results suggest that a shift in the window of synaptic plasticity and an age-dependent early cognitive decline may be novel circuit pathophysiology for a well-established autism genetic risk factor.

Iridoids from Gardeniae fructus ameliorates depression by enhancing synaptic plasticity via AMPA receptor-mTOR signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Gardeniae fructus is a traditional Chinese herb which exerts antidepressant effect. However, its effective constituent and potential mechanism are still unknown. AIM OF THE STUDY: To examine whether iridoids, a type of monoterpenoids from Gardeniae fructus (IGF), exerts antidepressant effect by enhancing synaptic plasticity via AMPA receptor-mTOR signaling. MATERIALS AND METHODS: The antidepressant effect of IGF (15 mg/kg; 30 mg/kg; 45 mg/kg) was investigated in spatial restraint stress (SRS)-induced mice. The expression levels of AMPA receptor-mTOR signaling and synaptic proteins were measured by Western blot, dendritic spine density was observed in Golgi staining. AMPA receptor (AMPAR) inhibitor NBQX and mTOR inhibitor Rapamycin were employed to determine the roles of AMPAR and mTOR signaling in IGF-induced antidepressant effects. RESULTS: After IGF administration, the expression of the AMPA glutamate receptor Glutamate Receptor 1 (GluA1) was inhibited in SRS mice. We also observed a trend toward the up-regulation of the mammalian target of Rapamycin (mTOR) protein kinase, p70 ribosomal protein S6K (P70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). The protein levels of Synapsin-1 and PSD-95 were decreased after SRS challenge, along with declined dendritic spine density, which were all reversed with IGF treatment. Furthermore, the treatment efficacy of IGF were blocked with AMPA receptor inhibitor NBQX or mTOR inhibitor Rapamycin. CONCLUSION: IGF exerted antidepressive-like effects by stimulating AMPAR-mTOR signaling regulated synaptic plasticity enhancement. This work provided an important basis for developing IGF and Gardeniae fructus as potential anti-depressants.

α-Cyperone Confers Antidepressant-Like Effects in Mice via Neuroplasticity Enhancement by SIRT3/ROS Mediated NLRP3 Inflammasome Deactivation.

α-Cyperone (Cy) is a major active compound of Cyperus rotundus that has various pharmacological activities. But whether Cy possesses antidepressant effect is unknown. In this study, we exposed mice to chronic unpredictable mild stress (CUMS) with or without intervention with Cy. Our results showed that Cy significantly improved the depressive phenotypes in sucrose preference test, tail suspension test and forced swimming test. Meanwhile, increased SIRT3 expression, reduced ROS production and activated NF-κB signal were detected in the hippocampus of mice. NLRP3 inflammasome related proteins including NLRP3, ASC, Caspase-1, IL-1ß, IL-18 and GSDMD-N were downregulated after Cy administration. Synaptic proteins including Synapsin-1 and PSD-95 and dendritic spine density were improved after Cy treatment. Moreover, the protective effects of Cy in CUMS mice were compromised when co-administrated with SIRT3 inhibitor 3-TYP. Taken together, these findings suggested that Cy has therapeutic potential for treating depression and that this antidepressant effect may be attributed to SIRT3 stimulated neuroplasticity enhancement by suppressing NLRP3 inflammasome.

Effect of Wenshen-Yanggan Decoction on Movement Disorder and Substantia Nigra Dopaminergic Neurons in Mice with Chronic Parkinson's Disease.

This study aimed to explore the protective effects of Wenshen-Yanggan decoction on dopaminergic (DA) neuron injury in a rotenone-induced mouse model with chronic Parkinson's disease (PD) and explore its mechanism of action. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to measure the content of six main components in the Wenshen-Yanggan decoction. The chronic PD mouse model was established by treating 10-month-old healthy wild C57BL/6 male mice with rotenone 30 mg/kg/day for 28 days in succession. The pole test and rotarod test were applied to detect the rescue effect of Wenshen-Yanggan decoction in high, medium, and low dosages, respectively, on PD-like behaviors in mice with chronic PD. The protective effect of Wenshen-Yanggan decoction on the mesencephalic nigrostriatal DA neuron injury was determined employing tyrosine hydroxylase (TH) immunofluorescence staining. Enzyme-linked immunosorbent assay (ELISA) was adopted to measure the inflammatory cytokines in serum, including TNF-α (tumor necrosis factor-alpha), IFN-γ (interferon gamma), NF-κB (nuclear factor kappa-B), and IL-1ß (interleukin-1 beta). Western blotting was performed to quantify the expression of phosphorylated c-Jun N-terminal kinase (p-JNK), cleaved caspase-3, B-cell lymphoma-2 (Bcl-2), and NF-κB in the brain. Our results showed that the Wenshen-Yanggan decoction in high, medium, and low dosages reduced the turning time of mice (P < 0.01, P < 0.01, and P < 0.05). The high and medium dosages shortened the total climbing time of PD mice in the pole test (P < 0.01 and P < 0.05). Meanwhile, the high, medium, and low dosages increased the rod-standing time of PD mice in the rotarod test (P < 0.01, P < 0.05, and P < 0.05). Besides, the decoction reversed the decrease in TH-positive neurons induced by rotenone, upregulated TH protein expression, and downregulated the α-syn expression in the PD model. Moreover, the decoction in high dosage significantly inhibited the expression of p-JNK, cleaved caspase-3, and NF-κB in the midbrain of PD mice (P < 0.05, P < 0.05, and P < 0.01), upregulated the expression of Bcl-2 (P < 0.05), and decreased the content of TNF-α, IFN-γ, NF-κB, and IL-1ß in the serum (P < 0.001, P < 0.001, P < 0.001, and P < 0.001). Taken together, the Wenshen-Yanggan decoction could protect mice from rotenone-induced chronic PD, which might be related to the reduction of the DA neuron apoptosis via suppressing the inflammatory reaction and the neuronal apoptosis pathway.

Involvement of mTOR-related signaling in antidepressant effects of Sophoraflavanone G on chronically stressed mice.

SophoraflavanoneG (SG), an important prenylated flavonoid isolated from Sophoraalopecuroides.L, is effective for many illnesses. The present study was designed to investigate whether the compound could reverse depressive-like symptoms and investigate its possible mechanisms. Chronic Unpredictable Mild Stress (CUMS) mice were treated with fluoxetine and SG. The immobility time in forced swimming test (FST) and tail suspension test (TST) were recorded. The levels of pro-inflammatory cytokines and neurotransmitters in the hippocampus were evaluated. Furthermore, the protein expressions of PI3K, AKT, mTOR, p70S6K, BDNF, and Trkb in hippocampus were detected. Rapamycin, the selective mTOR inhibitor, was used to estimate the potential mechanism. As a result, after 7 days of SG treatment, the immobility time in FST and TST was declined obviously. The levels of IL-6, IL-1ß, and TNF-α in the hippocampus were significantly reduced, and the quantity of 5-HT and NE was raised considerably in SG-treated group compared with the CUMS-exposed group. Additionally, SG could up-regulate the expressions of PI3K, AKT, mTOR, 70S6K, BDNF, and Trkb. The blockade of mammalian target of rapamycin signaling blunted the antidepressant effect and reversed the up-regulation of BDNF expression caused by SG. These findings suggested that SG treatment alleviated depressive-like symptoms via mTOR-mediated BDNF/Trkb signaling.

Anti-depressant effects of oil from fructus gardeniae via PKA-CREB-BDNF signaling.

The dried ripe fruit of Gardenia jasminoides Ellis was usually applied as an herb medicine in Traditional Chinese Medicine. It was suggested that the Gardenia jasminoides oil extract (oil from Fructus Gardeniae [OFG]) might serve as a potential treatment for depression, whereas its pathogenesis still remained not fully understood. The present research was conducted to evaluate the anti-depressive effect of OFG in mice and explore its potential mechanism. The OFG and ketamine (KET) were intragastrically and intraperitoneally treated, respectively. Thereafter, the animals were subjected to the behavior tests. The expressions of protein kinase A (PKA), brain derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB) in hippocampus were detected by Western blot. The selective PKA inhibitor H-89 was also applied to confirm the mechanism. As a result, OFG and KET treatment improved the behavior performance. Furthermore, the administrations of OFG effectively enhanced the expressions of PKA, p-CREB, and BDNF. With the application of selective PKA inhibitor H-89, the ameliorated effects caused by OFG were blocked, but not by KET. In conclusion, the presented work indicated that OFG-exerted protective effect on depression through PKA-CREB-BDNF signaling.

Neuroprotective Effect of Echinacoside in Subacute Mouse Model of Parkinson's Disease.

OBJECTIVE: To study the protective effect of Echinacoside for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced dopaminergic (DA) neurons injury in the subacute mouse model of Parkinson's disease (PD) and to explore its mechanism of action. METHODS: We chose 10 weeks of healthy wild type C57BL/6 male mice, hypodermic MPTP 30 mg/kg/day, five days, to prepare PD subacute mouse model. Behavior indexes of open field test and pole test were applied to examine the function of ECH to PD subacute mice model of PD sample action. The effects of ECH on dopaminergic neurons and astrocyte were examined using Immunohistochemistry including tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) expression. The total numbers of TH-positive neurons and GFAP-positive cells in the substantia nigra pars compacts (SNpc) and ventral tegmental area (VTA) were obtained stereologically using the optical fractionator method. Enzyme-linked immunosorbent assay (ELISA) method was used to detect the inflammatory cytokines in the serum, including TNF-α (Ttumor necrosis factor alpha) and IFN-γ (interferon gamma). Protein expressions of ionized calcium binding adaptor molecule 1 (IBA-1), TNF-α, Cleaved caspase-3, glial derived neurotrophic factor (GDNF), and phosphorylated and total extracellular signal-regulated kinase (p-ERK and ERK) in the anatomical region of substantia nigra (SN) were tested by protein immunoblot method (i.e., Western blotting). RESULTS: ECH reversed the reduction of total distance in open field test in MPTP-induced PD model mice (P < 0.01), shortened the return time and total time of PD subacute model mice in pole test (P < 0.01, P < 0.05), significantly reversed the reduction of TH positive neurons induced by MPTP (P < 0.05), and reduced the activation of astrocytes (P < 0.05). Meanwhile, ECH significantly inhibited the expression of IBA-1, Cleaved caspase-3, and TNF-α in midbrain of MPTP model mice (P < 0.05, P < 0.05, and P < 0.05) and upregulated the expression of GDNF (P < 0.05). And ECH lowered the level of TNF-α and IFN-γ in serum (P < 0.05, P < 0.05). CONCLUSION: ECH has protective effects on the MPTP subacute model mice, its mechanism may be through inhibiting activation of microglia and astrocytes, reducing inflammatory reaction and promoting the secretion of neurotrophic factors, and eventually resulting in the reduction of the DA neurons apoptosis.

Anti-Depressive Effectiveness of Baicalin In Vitro and In Vivo.

Baicalin (BA), a major polyphenol compound isolated from the extracts of Scutellaria radix, has been previously reported to ameliorate depressive-like behaviors in mice with chronic unpredictable mild stress (CUMS). However, its underlying antidepressant mechanisms remain unclear. This study was designed to confirm the antidepressant-like effects of BA on CUMS induced behavioral abnormalities in mice, and sought to explore the pharmacological mechanisms in vivo and in vitro. The CUMS procedure was carried out to induce depression in mice. Afterwards, the tail suspension test (TST), forced swim test (FST), and open field test (OFT) were performed within 24 h, then sucrose preference test (SPT) was conducted. Additionally, PC12 cells were pretreated with BA for 2 h, then further stimulated with corticosterone for 24 h. The levels of Interleukin-1ß (IL-1ß), IL-6 and Tumor Necrosis Factor-α (TNF-α) in serum, hippocampus homogenate and cell culture medium were determined using the enzyme-linked immunosorbent assay (ELISA) method. The protein expressions of inhibition of high mobility group box 1 protein (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathways in hippocampus and PC12 cells were detected. Our results showed that CUMS-treated mice presented notable depressive-like symptoms, such as decreased sucrose consumption, increased FST and TST immobility time. While BA (25, 50 mg/kg) significantly attenuated these changes. Besides, BA treatment considerably inhibited inflammatory cytokinesl (IL-1ß, IL-6, TNF-α) levels in serum, hippocampus homogenate and cell culture medium. Western blot analysis indicated that BA inhibited the expressions of HMGB1, TLR4, and p-NF-κBp65 both in vivo and in vitro. In conclusion, the present study confirmed that BA possessed efficient antidepressant effects on depression, which was possibly related to the inhibition of HMGB1/TLR4/NF-κB pathways.

Echinacoside protects against MPTP/MPP+-induced neurotoxicity via regulating autophagy pathway mediated by Sirt1.

Parkinson's disease (PD) is a common chronic neurodegenerative disease and greatly affects the quality of PD patients' life. Current symptomatic treatment of PD is limited. There are no effective treatment and drugs that could radically cure PD. Increasing experimental evidence has proven a causal relationship between alpha-synuclein (α-synuclein, α-syn) and the neuropathology of Parkinson's diseases, although the exact pathophysiological role of α-synuclein is not fully clarified. Previous studies showed that monomers and polymers of α-synuclein were secreted from damaged nerve cells via exocytosis and occupied healthy nerve cells via endocytosis, which afford evidence for the prion-like role of α-synuclein. Autophagy is the known mechanism for eukaryotic cells to degrade protein polymers and damaged organelles that proteasome does not cope with. Therefore, promoting the clearance of α-synuclein by enhancing autophagy in neuronal cells could be a promising treatment in the early stage of PD. SIRT1 is a potent regulator of autophagy, because it deacetylates a mass of important transcription factors such as Forkhead Box subgroup O (FoxO) transcription factors family. SIRT1's action relates to FoxO, because FoxO transcription factors are involved in various molecular pathways underlying neuronal protection and autophagy. Moreover, Sirt1 deacetylates proautophagic proteins such as Atg5, Atg7, and Atg8. Echinacoside (ECH) is the main active ingredient of a widely used Chinese herb cistanche, which has been proven to elicit neuroprotective effects in models of neurodegenerative diseases. In this study, we found that ECH could improve PD-like symptoms in MPTP-lesioned mouse model. We further showed that the underlying mechanism of the action of ECH was associated with enhancing autophagy in neurons via bind to Sirt1 directly and affect FoxO expression. Our study demonstrated ECH as a potential therapeutic agent against PD.

Pilose antler peptide attenuates LPS-induced inflammatory reaction.

The present study was designed to study the effects of pilose antler peptide (PAP) on primary culture of nucleus pulposus cells in intervertebral disc. We demonstrated that PAP significantly inhibited lipopolysaccharides (LPS) induced over-production of inflammatory factors including interleukin-1ß (IL-1ß), tumor necrosis Factor-α (TNF-α) and interleukin-6 (IL-6) in nucleus pulposus cells. PAP also attenuated increase of malondialdehyde (MDA) and decrease of superoxide dismutase (SOD) induced by LPS challenge in a concentration-dependent manner. Moreover, the expression of the protein levels of mitogen-activated protein kinase (MAPK)/nuclear transcription factor-κB(NF-κB) were increased accompanying with the LPS challenge, which were significantly reversed after PAP treatment. Our results demonstrated the ability of PAP to antagonize LPS-mediated inflammation in primary culture of nucleus pulposus in intervertebral disc, suggesting a beneficial potential for its clinical application.

Expression of Disrupted-in-schizophrenia 1 in Hippocampus in Postpartum Depression Animal Models Induced by Pre-pregnancy Stress.

Objective To establish a postpartum depression animal model induced by pre-pregnancy stress,assess abnormal maternal depressive-like behavior,observe the expression of disrupted-in-schizophrenia 1 (DISC1) in the hippocampus,and detect serum estradiol and corticosterone.Methods A total of 32 female Balb/c were assigned to two groups using random number table:the control group and the pre-pregnancy stressed group(model group),and the model group was subjected to 3 weeks of chronic restraint stress. After the last stressor,the control group and the model group were housed with a male. About 4 weeks later,the mice gave birth to pups. Then at 3 weeks postpartum,open field test,tail suspension test,and sucrose preference test were carried out. The expressions of DISC1 mRNA and protein of hippocampus were detected by real-time quantitative polymerase chain reaction and Western blot,respectively. The serum levels of estradiol and corticosterone were detected with enzyme linked immunosorbent assay. Results After 3 weeks of postpartum,the model mice showed depression-like behaviors. In the open field test,there was no effect on the total distance moved or time spent in the center field (P>0.05). Immobility in tail suspension test was significantly increased (t=-4.950,P<0.001) and sucrose preference was significantly reduced in model group (t=2.475,P<0.05). There was significant statistical difference between control and model group on the expression of DISC1 mRNA (t=-8.915,P<0.001) and protein (t=-5.004,P<0.01) in hippocampus. There was no significant statistical difference on estradiol and corticosterone between two groups (P>0.05). Conclusion Chronic pre-pregnancy stress can induce dams into postpartum depression.The pathogenesis of postpartum depression may be related to the regulation of DISC1 in the hippocampus.

Transgenerational impairment of hippocampal Akt-mTOR signaling and behavioral deficits in the offspring of mice that experience postpartum depression-like illness.

Postpartum depression (PPD) has adverse effects on offspring and increases their vulnerability to psychiatric disorders such as depression. Akt-mTOR signaling in the hippocampus is implicated in depression but its role in the behavioral deficits in PPD offspring remains unknown. By using a prepregnancy stress model of PPD in which Balb/c females that experience chronic stress before pregnancy show long-lasting PPD-like behaviors, we tested depression-like behaviors in PPD offspring (PPD-F1) at juvenile and adult ages as well as in the second generation (PPD-F2) produced by cross of male PPD-F1 with naïve females. Hippocampal Akt-mTOR signaling was examined in the F1 and F2 generations of PPD, as well as in PPD-F1 mice treated with a single dose of the antidepressant ketamine. PPD-F1 showed depression-like behaviors at juvenile and adult stages, evidenced by reduced sucrose preference (SP), increased immobility time in the forced swim test (FST), and a longer latency to feed and reduced food consumption in the novelty suppressed feeding (NSF) test. PPD-F1 mice showed Akt-mTOR signaling deficiency in the hippocampus, with down-regulated expression of p-Akt, p-mTOR and p-p70S6K. A single dose of ketamine reversed the behavior deficits and the impairment in Akt-mTOR signaling in PPD-F1. Furthermore, the PPD-F2 mice remained deficient in the SP and NSF test and hippocampal Akt-mTOR signaling, although the performance in FST was normal. The present study demonstrated both long-term and transgenerational effects of PPD on the depression-like behaviors of offspring, and suggested impaired Akt-mTOR signaling may play a part.

Chronic stress prior to pregnancy potentiated long-lasting postpartum depressive-like behavior, regulated by Akt-mTOR signaling in the hippocampus.

Postpartum depression (PPD) affects over 10% of new mothers and adversely impacts the health of offspring. One of the greatest risk factors for PPD is prepregnancy stress but the underlying biological mechanism is unknown. Here we constructed an animal model which recapitulated prepregnancy stress induced PPD and tested the role of Akt-mTOR signaling in the hippocampus. Female virgin Balb/c mice received chronic restraint stress, followed by co-housing with a normal male mouse. We found that the chronic stress led to a transient depressive-like condition that disappeared within two weeks. However, prepregnantly stressed females developed long-term postpartum depressive-like (PPD-like) symptoms as indicated by deficient performance in tests of sucrose preference, forced swim, and novelty-suppressed feeding. Chronic stress induced transient decrease in Akt-mTOR signaling and altered expressions of glutamate receptor subunits NR1 and GluR1, in contrast to long-term deficits in Akt-mTOR signaling, GluR1/NR1 ratio, and hippocampal neurogenesis in PPD-like mice. Acute ketamine improved the molecular signaling abnormality, and reversed the behavioral deficits in PPD-like mice in a rapid and persistent manner, in contrast to ineffectiveness by chronic fluoxetine treatment. Taken together, we find that chronic prepregnancy stress potentiates a long-term PPD, in which Akt-mTOR signaling may play a crucial role.

[Effect of Postpartum Depression on Adolescent Depression of Mice Offspring].

OBJECTIVE: To study the effect of postpartum depression (PPD) on adolescent depression of mice offspring. METHODS: Totally 48 Balb/c female mice were equally randomized into control group and stress group. Control group was not given any stress, whereas stress group were given chronic stress: constraining (6 h/d) combined with light stimulation for 24 hours (twice a week). The stress group was divided into 3 groups to measue the animals' behaviors immediately after modeling, three weeks after modeling, and three weeks after delivery to test whether the PPD models were successfully constructed. The first generation (F1) of normal mothers and PPD-born F1 were as follows: control group (CTL-F1) and PPD offspring group (PPD-F1). The 3-4-week-old male CTL-F1 and PPD-F1 mice (n=8 each) were weighed, and received sucrose preference test, forced swimming test, and novelty-supressed feeding test to measure the depression-like behaviors. RESULTS: The 3-and 4-week-old PPD-F1 had significantly lower body mass than CTL-F1 (P=0.000, P=0.002). Also, the sucrose preference significantly decreased (P=0.000), the forced swimming immobility time significantly increased (P=0.001), the latency to feed significantly increased (P=0.000), while food intake significantly decreased (P=0.005). CONCLUSION: PPD offspring may be more susceptible to depression,with a possible eary onset in adolescence.

Paeonol attenuates lipopolysaccharide-induced depressive-like behavior in mice.

The present study was designed to detect the anti-depressant effects of paeonol and the possible mechanisms in the lipopolysaccharide-induced depressive-like behavior. Open-field test(OFT), tail suspension test(TST) and forced swimming test(FST) were used to evaluate the behavioral activity. The contents of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in mice hippocampus were determined by HPLC-ECD. Serum interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α levels were evaluated by enzyme-linked immunosorbent assay (ELISA). Our results showed that LPS significantly decreased the levels of 5-HT and NE in the hippocampus. LPS also reduced open-field activity, as well as increased immobility duration in FST and TST. Paeonol administration could effectively reverse the alterations in the concentrations of 5-HT, NE and reduce the IL-6 and TNF-α levels. Moreover, paeonol effectively downregulated brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and Nuclear factor-κB (NF-κB) in hippocampal. In conclusion, paeonol administration exhibited significant antidepressant-like effects in mice with LPS-induced depression.

Interaction between Wnt/ß-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review).

Gastric cancer (GC) is the third primary cause of cancer-related mortality and one of the most common type of malignant diseases worldwide. Despite remarkable progress in multimodality therapy, advanced GC with high aggressiveness always ends in treatment failure. Epithelial-mesenchymal transition (EMT) has been widely recognized to be a key process associating with GC evolution, during which cancer cells go through phenotypic variations and acquire the capability of migration and invasion. Wnt/ß-catenin pathway has established itself as an EMT regulative signaling due to its maintenance of epithelial integrity as well as tight adherens junctions while mutations of its components will lead to GC initiation and diffusion. The E-cadherin/ß-catenin complex plays an important role in stabilizing ß-catenin at cell membrane while disruption of this compound gives rise to nuclear translocation of ß-catenin, which accounts for upregulation of EMT biomarkers and unfavorable prognosis. Additionally, several microRNAs positively or negatively modify EMT by reciprocally acting with certain target genes of Wnt/ß-catenin pathway in GC. Thus, this review centers on the strong associations between Wnt/ß-catenin pathway and microRNAs during alteration of EMT in GC, which may induce advantageous therapeutic strategies for human gastric cancer.