Increased Lactobacillus Abundance Contributes to Stress Resilience in Mice Exposed to Chronic Social Defeat Stress.

INTRODUCTION: Accumulating evidence indicates that abnormalities in the composition of gastrointestinal (GI) microbiota play a vital role in stress-related disorders. Both human beings and animals perceive stressful events differently, i.e., resilience or susceptibility. However, the role of GI microbiota in stress resilience/susceptibility and the underlying mechanisms remain largely unknown. METHODS AND RESULTS: Sixty male C57BL/6J mice were exposed to 10-day chronic social defeat stress (CSDS), and 28 were found to be resilient to CSDS. We next analyzed microbiota compositions in the cecum using 16S rDNA gene sequencing, which revealed a significant increase in the relative abundance of Lactobacillus at the genus level in the resilient mice. In subsequent experiments, we found that oral administration of a strain of Lactobacillus (Lactobacillus murinus) for 2 weeks attenuated the increased levels of stress-induced corticosterone and anxiety-like behavior in stress-susceptible mice. The mRNA expression of tryptophan hydroxylase 2 (a rate-limiting enzyme in serotonin [5-HT] synthesis) was also significantly increased in the dorsal raphe nucleus (DR) of stress-susceptible mice. CONCLUSIONS: Lactobacillus contributes to stress resilience, and the DR 5-HT system may play an important role during this process. The above results suggest that certain organisms in the GI tract may play an essential role in stress response and be useful in the prevention and treatment of some stress-related psychiatric disorders, such as depression.

Endoplasmic reticulum stress and autophagy are involved in adipocyte-induced fibrosis in hepatic stellate cells.

Liver fibrosis, with the characterization of progressive accumulation of extracellular matrix (ECM), is the common pathologic feature in the process of chronic liver disease. Hepatic stellate cells (HSCs) which are activated and differentiate into proliferative and contractile myofibroblasts are recognized as the main drivers of fibrosis. Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression, but the direct fibrogenic effect of mature adipocytes on HSCs has been rarely reported. Therefore, the purpose of this study was to explore the fibrogenic effect of adipocyte 3T3-L1 cells on hepatic stellate LX-2 cells. The results showed that incubating LX-2 cells with the supernatant of 3T3-L1 adipocytes triggered the expression of ECM related proteins, such as α-smooth muscle actin (α-SMA), type I collagen (CO-I), and activated TGF ß/Smad2/3 signaling pathway in LX-2 cells. In addition, 3T3-L1 cells inhibited insulin sensitivity, activated endoplasmic reticulum stress and autophagy to promote the development of fibrosis. These results supported the notion that mature adipocytes can directly activate hepatic stellate cells, and the establishment of an in vitro model of adipocytes on HSCs provides an insight into screening of drugs for liver diseases, such as nonalcoholic fatty liver disease.

Glucuronomannan GM2 from Saccharina japonica Enhanced Mitochondrial Function and Autophagy in a Parkinson's Model.

Parkinson's disease (PD), one of the most common neurodegenerative disorders, is caused by dopamine depletion in the striatum and dopaminergic neuron degeneration in the substantia nigra. In our previous study, we hydrolyzed the fucoidan from Saccharina japonica, obtaining three glucuronomannan oligosaccharides (GMn; GM1, GM2, and GM3) and found that GMn ameliorated behavioral deficits in Parkinsonism mice and downregulated the apoptotic signaling pathway, especially with GM2 showing a more effective role in neuroprotection. However, the neuroprotective mechanism is unclear. Therefore, in this study, we aimed to assess the neuroprotective effects of GM2 in vivo and in vitro. We applied GM2 in 1-methyl-4-phenylpyridinium (MPP+)-treated PC12 cells, and the results showed that GM2 markedly improved the cell viability and mitochondrial membrane potential, inhibited MPP+-induced apoptosis, and enhanced autophagy. Furthermore, GM2 contributed to reducing the loss of dopaminergic neurons in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice through enhancing autophagy. These data indicate that a possible protection of mitochondria and upregulation of autophagy might underlie the observed neuroprotective effects, suggesting that GM2 has potential as a promising multifunctional lead disease-modifying therapy for PD. These findings might pave the way for additional treatment strategies utilizing carbohydrate drugs in PD.

Neuroprotective effects of salidroside on ageing hippocampal neurons and naturally ageing mice via the PI3K/Akt/TERT pathway.

Studies have found that salidroside, isolated from Rhodiola rosea L, has various pharmacological activities, but there have been no studies on the effects of salidroside on brain hippocampal senescence. The purpose of this study was to investigate the mechanistic role of salidroside in hippocampal neuron senescence and injury. In this study, long-term cultured primary rat hippocampal neurons and naturally aged C57 mice were treated with salidroside. The results showed that salidroside increased the viability and MAP2 expression, reduced ß-galactosidase (ß-gal) levels of rat primary hippocampal neurons. Salidroside also improved cognition dysfunction in ageing mice and alleviated neuronal degeneration in the ageing mice CA1 region. Moreover, salidroside decreased the levels of oxidative stress and p21, p16 protein expressions of hippocampal neurons and ageing mice. Salidroside promoted telomerase reverse transcriptase (TERT) protein expression via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway. In conclusion, our findings suggest that salidroside has the potential to be used as a therapeutic strategy for anti-ageing and ageing-related disease treatment.

Global prevalence of congenital heart disease in school-age children: a meta-analysis and systematic review.

BACKGROUND: Congenital heart disease (CHD) is the commonest birth defect. Studies estimating the prevalence of CHD in school-age children could therefore contribute to quantifying unmet health needs for diagnosis and treatment, particularly in lower-income countries. Data at school age are considerably sparser, and individual studies have generally been of small size. We conducted a literature-based meta-analysis to investigate global trends over a 40-year period. METHODS AND RESULTS: Studies reporting on CHD prevalence in school-age children (4-18 years old) from 1970 to 2017 were identified from PubMed, EMBASE, Web of Science and Google Scholar. According to the inclusion criteria, 42 studies including 2,638,475 children, reporting the prevalence of unrepaired CHDs (both pre-school diagnoses and first-time school-age diagnoses), and nine studies including 395,571 children, specifically reporting the prevalence of CHD first diagnosed at school ages, were included. Data were combined using random-effects models. The prevalence of unrepaired CHD in school children during the entire period of study was 3.809 (95% confidence intervals 3.075-4.621)/1000. A lower proportion of male than female school children had unrepaired CHD (OR = 0.84 [95% CI 0.74-0.95]; p = 0.001). Between 1970-1974 and 1995-1999, there was no significant change in the prevalence of unrepaired CHD at school age; subsequently there was an approximately 2.5-fold increase from 1.985 (95% CI 1.074-3.173)/1000 in 1995-1999 to 4.832 (95% CI 3.425-6.480)/1000 in 2010-2014, (p = 0.009). Among all CHD conditions, atrial septal defects and ventricular septal defects chiefly accounted for this increasing trend. The summarised prevalence (1970-2017) of CHD diagnoses first made in childhood was 1.384 (0.955, 1.891)/1000; during this time there was a fall from 2.050 [1.362, 2.877]/1000 pre-1995 to 0.848 [0.626, 1.104]/1000 in 1995-2014 (p = 0.04). CONCLUSIONS: Globally, these data show an increased prevalence of CHD (mainly mild CHD conditions) recognised at birth/infancy or early childhood, but remaining unrepaired at school-age. In parallel there has been a decrease of first-time CHD diagnoses in school-age children. These together imply a favourable shift of CHD recognition time to earlier in the life course. Despite this, substantial inequalities between higher and lower income countries remain. Increased healthcare resources for people born with CHD, particularly in poorer countries, are required.

Immunomodulatory Effects of a Low-Molecular Weight Polysaccharide from Enteromorpha prolifera on RAW 264.7 Macrophages and Cyclophosphamide- Induced Immunosuppression Mouse Models.

The water-soluble polysaccharide EP2, from Enteromorpha prolifera, belongs to the group of polysaccharides known as glucuronoxylorhamnan, which mainly contains glucuronic acid (GlcA), xylose (Xyl), and rhamnose (Rha). The aim of this study was to detect the immunomodulatory effects of EP2 on RAW 264.7 macrophages and cyclophosphamide (CYP)-induced immunosuppression mouse models. The cells were treated with EP2 for different time periods (0, 0.5, 1, 3, and 6 h). The results showed that EP2 promoted nitric oxide production and up-regulated the expression of pro-inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, in a time-dependent manner. Furthermore, we found that EP2-activated iNOS, COX2, and NLRP3 inflammasomes, and the TLR4/MAPK/NF-κB signaling pathway played an important role. Moreover, EP2 significantly increased the body weight, spleen index, thymus index, inflammatory cell counts, and the levels of IL-1ß, IL-6, and TNF-α in CYP-induced immunosuppression mouse models. These results indicate that EP2 might be a potential immunomodulatory drug and provide the scientific basis for the comprehensive utilization and evaluation of E. prolifera in future applications.

Preparation and Neuroprotective Activity of Glucuronomannan Oligosaccharides in an MPTP-Induced Parkinson's Model.

Parkinson's disease (PD), characterized by dopaminergic neuron degeneration in the substantia nigra and dopamine depletion in the striatum, affects up to 1% of the global population over 50 years of age. Our previous study found that a heteropolysaccharide from Saccharina japonica exhibits neuroprotective effects through antioxidative stress. In view of its high molecular weight and complex structure, we degraded the polysaccharide and subsequently obtained four oligosaccharides. In this study, we aimed to further detect the neuroprotective mechanism of the oligosaccharides. We applied MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to induce PD, and glucuronomannan oligosaccharides (GMn) was subsequently administered. Results showed that GMn ameliorated behavioral deficits in Parkinsonism mice. Furthermore, we observed that glucuronomannan oligosaccharides contributed to down-regulating the apoptotic signaling pathway through enhancing the expression of tyrosine hydroxylase (TH) in dopaminergic neurons. These results suggest that glucuronomannan oligosaccharides protect dopaminergic neurons from apoptosis in PD mice.

Oligo-Porphyran Ameliorates Neurobehavioral Deficits in Parkinsonian Mice by Regulating the PI3K/Akt/Bcl-2 Pathway.

Parkinson's disease (PD) is a neurodegenerative movement disorder that is caused by a selective loss of dopaminergic neurons. Current PD treatments provide symptomatic relief but do not prevent or decelerate disease progression. Previous studies have suggested that acetylated and phosphorylated porphyran, derived from Porphyra, produces a neuroprotective effect against 6-OHDA-induced damage. Due to its antioxidant and neuroprotective potential, this study evaluates whether oligo-porphyran (OP) could be beneficial in an experimental model of PD in mice. The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was intraperitoneally injected (20 mg/kg body weight) for seven days to simulate PD, followed by OP administration. We found that the behavioral deficits in spontaneous motor activity, latency to descend in a pole test, and suspension in a traction test were ameliorated, and excessive dopamine (DA) metabolism was suppressed after OP treatment. Additionally, we found that OP protected dopaminergic neurons by preventing MPTP-induced decreases in dopaminergic transporter and tyrosine hydroxylase protein levels. We speculated whether OP regulates a signaling pathway that affects the behavioral changes seen in PD mice. In this study, the PI3K/Akt/Bcl-2 pathway was detected. Our results demonstrate that OP increased the phosphorylation of PI3K/Akt/GSK-3ß and inhibited the activation of caspase-3 and poly (ADP-ribose) polymerase, with changes in the Bax/Bcl-2 ratio. These results showed that OP might promote DA neuron survival in vivo by regulating the PI3K/Akt/Bcl-2 pathway, thereby ameliorating the neurobehavioral deficits in a PD mouse model and suggesting OP as a neuroprotective treatment for PD.

Antihypertensive Effects of Two Novel Angiotensin I-Converting Enzyme (ACE) Inhibitory Peptides from Gracilariopsis lemaneiformis (Rhodophyta) in Spontaneously Hypertensive Rats (SHRs).

A variety of biologically active products have been isolated from Gracilariopsis lemaneiformis. In the present study, two novel angiotensin-converting enzyme (ACE) inhibitory peptides, FQIN [M(O)] CILR, and TGAPCR, were screened and identified from G. lemaneiformis protein hydrolysates by LC-MS/MS. The IC50 values of FQIN [M(O)] CILR and TGAPCR were 9.64 ± 0.36 µM and 23.94 ± 0.82 µM, respectively. In the stability study, both peptides showed stabilities of pH, temperature, simulated gastrointestinal digestion, and ACE hydrolysis. The Lineweaver⁻Burk plot showed that the two peptides were noncompetitive inhibitors of ACE. Molecular docking simulated the intermolecular interactions of two peptides and ACE, and the two peptides formed hydrogen bonds with the active pockets of ACE. However, FQIN [M(O)] CILR was more closely linked to the active pockets of ACE, thereby exerting better ACE inhibition. Spontaneously hypertensive rats (SHRs) were studied with an oral dose of 10 mg/kg body weight. Both peptides reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP) in SHRs, of which FQIN [M(O)] CILR was able to reduce the systolic blood pressure by 34 mmHg (SBP) (p < 0.05). Therefore, FQIN [M(O)] CILR was an excellent ACE inhibitory peptide.

Chronic Co-species Housing Mice and Rats Increased the Competitiveness of Male Mice.

Rats are predators of mice in nature. Nevertheless, it is a common practice to house mice and rats in a same room in some laboratories. In this study, we investigated the behavioral and physiological responsively of mice in long-term co-species housing conditions. Twenty-four male mice were randomly assigned to their original raising room (control) or a rat room (co-species-housed) for more than 6 weeks. In the open-field and light-dark box tests, the behaviors of the co-species-housed mice and controls were not different. In a 2-choice test of paired urine odors [rabbit urine (as a novel odor) vs. rat urine, cat urine (as a natural predator-scent) vs. rabbit urine, and cat urine vs. rat urine], the co-species-housed mice were more ready to investigate the rat urine odor compared with the controls and may have adapted to it. In an encounter test, the rat-room-exposed mice exhibited increased aggression levels, and their urines were more attractive to females. Correspondingly, the levels of major urinary proteins were increased in the co-species-housed mouse urine, along with some volatile pheromones. The serum testosterone levels were also enhanced in the co-species-housed mice, whereas the corticosterone levels were not different. The norepinephrine, dopamine, and 5-HT levels in the right hippocampus and striatum were not different between the 2. Our findings indicate that chronic co-species housing results in adaptation in male mice; furthermore, it appears that long-term rat-odor stimuli enhance the competitiveness of mice, which suggests that appropriate predator-odor stimuli may be important to the fitness of prey animals.

Protective effect of Ganoderma lucidum polysaccharide against carbon tetrachloride-induced hepatic damage in precision-cut carp liver slices.

The aim of the present study was to investigate the protective effects of Ganoderma lucidum polysaccharide (GLPS) against carbon tetrachloride (CCl4)-induced hepatotoxicity in vitro in common carp. Precision-cut liver slices (PCLSs), which closely resemble the organ from which they are derived, were employed as an in vitro model system. GLPS (0.1, 0.3, and 0.6 mg/ml) was added to PCLS culture system before the exposure to 12 mM CCl4. The supernatants and slices were collected to detect molecular and biochemical responses to CCl4 and PCLS treatments. The levels of CYP1A, CYP3A, and CYP2E1 were measured by ELISA; the mRNA expressions of TNF-α, IL-1ß, IL-6, and iNOS were determined by RT-PCR; and the relative protein expressions of c-Rel and p65 were analyzed by western blotting. Results showed that GLPS inhibited the elevations of the marker enzymes (GOT, GPT, LDH) and MDA induced by CCl4; it also enhanced the suppressed activity of antioxidant enzymes (SOD, CAT, GSH-Px, T-AOC). The treatment with GLPS resulted in significant downregulation of NF-κB and inflammatory cytokine mRNA levels and significant decreases in the hepatic protein levels of CYP1A, CYP3A, and CYP2E1. These results suggest that GLPS can protect CCl4-induced PCLS injury through inhibiting lipid peroxidation, elevating antioxidant enzyme activity, and suppressing immune inflammatory response.

miR-376c inhibits cervical cancer cell proliferation and invasion by targeting BMI1.

MicroRNAs (miRNAs) play crucial roles in cancer development and progression. The purposes of this study were to explore the role of miR-376c in cervical cancer and to clarify the regulation of BMI1 by miR-376c. Quantitative RT-PCR was used to measure miR-376c expression in cervical cancer tissues and cell lines. The cell proliferation, cell cycle and Transwell invasion assays were performed. A luciferase reporter assay was conducted to confirm the target gene of miR-376c, and the results were validated in cervical cancer cell lines and tissues. MiR-376c was significantly downregulated in cervical cancer cell lines and clinical tissues. Upregulation of miR-376c impaired cell proliferation, blocked G1/S checkpoint of cell cycle and suppressed cell invasion in vitro. BMI1 was verified as a direct target of miR-376c, which was further confirmed by the inverse expression of miR-376c and BMI1 in patient specimens. The newly identified miR-376c/BMI1 pathway provides an insight into cervical cancer progression and may represent a novel therapeutic target.

A Study of 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induced Liver Injury in Jian Carp (Cyprinus carpio var. Jian) Using Precision-Cut Liver Slices.

The aim of this study was to establish a model for the study of liver injury induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Jian carp using precision-cut liver slices (PCLS). PCLS were treated with TCDD at concentrations of 0, 0.05, 0.1, 0.3, and 0.6 µg/L for 6 h, followed by collection of the culture supernatant and PCLS for analysis. Several biochemical indices were analyzed, including glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA). Expression of mRNA was also estimated for cytochrome P4501A (CYP1A), aryl hydrocarbon receptor2 (AhR2), and aryl hydrocarbon receptor nuclear translocator2 (ARNT2). Results showed that some significant effects (p < 0.05) in MDA, GSH-Px and PCLS viability were observed at a TCDD concentration as low as 0.05 µg/L, and the observed effects increased with exposure concentration. Following exposure to TCDD for 6 h at a concentration of 0.3 µg/L, significant increases (p < 0.01) in the content of GPT, GOT, MDA, and LDH were observed, while SOD activity, GSH-Px activity, and PCLS viability were decreased (p < 0.01 or p < 0.05). Exposure to 0.3 µg/L TCDD also resulted in increased expression of mRNA for CYP1A, AhR2, and ARNT2. Overall, these results provide evidence of TCDD-induced liver injury and oxidative stress in Jian carp. These results also support the use of PCLS as an in vitro model for the evaluation of hepatotoxicity in Jian carp.

Next generation digital PCR measurement of hepatitis B virus copy number in formalin-fixed paraffin-embedded hepatocellular carcinoma tissue.

BACKGROUND: Hepatocellular carcinoma (HCC) is strongly associated with hepatitis B virus (HBV) infection. False-negative results are common in routine serological tests and quantitative real-time PCR because of HBV surface antigen (HBsAg) variation and low HBV copy number. Droplet digital PCR (ddPCR), a next generation digital PCR, is a novel, sensitive, and specific platform that can be used to improve HBV detection. METHODS: A total of 131 HCC cases with different tumor stages and clinical features were initially classified with a serological test as HBsAg positive (n = 107) or negative (n = 24) for HBV infection. Next, DNA templates were prepared from the corresponding formalin-fixed paraffin-embedded (FFPE) tissues to determine HBV copy number by ddPCR. RESULTS: HBV copy numbers, successfully determined for all clinical FFPE tissues (n = 131), ranged from 1.1 to 175.5 copies/µL according to ddPCR. The copy numbers of HBV were positively correlated with tumor-nodes-metastasis (P = 0.008) and Barcelona-Clinic Liver Cancer (P = 0.045) classification. Moreover, serum cholinesterase correlated with hepatitis B viral load (P = 0.006). CONCLUSIONS: HBV infection is a key factor that influences tumorigenesis in HCC by regulating tumor occurrence and development. ddPCR improves the analytical sensitivity and specificity of measurements in nucleic acids at a single-molecule level and is suitable for HBV detection.

Effects of curcumin on antioxidative activities and cytokine production in Jian carp (Cyprinus carpio var. Jian) with CCl4-induced liver damage.

We investigated the protective effects of curcumin on liver-damaged Cyprinus carpio var. Jian (Jian carp). The carp were fed 0.1%, 0.5%, or 1.0% curcumin for 60 days, then injected intraperitoneally with 30% carbon tetrachloride solution. Liver and blood samples were collected to measure the liver index, serum- and liver-associated enzymes, liver histology, nuclear factor-κB (NF-κB)/c-Rel, interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and IL-12 mRNA expression, and the level of NF-κB/c-Rel protein in the liver, and for a comet assay. We found that 0.5% and 1.0% curcumin significantly reduced the CCl(4)-induced increase in the liver index. The comet assay showed that the tail moment, olive tail moment, tail length, and tail DNA% improved in fish pretreated with 0.5 or 1.0% curcumin. CCl(4)-induced histological changes, including extensive hepatocyte degeneration, indistinct cell borders, nuclear condensation, and karyolysis were clearly reduced after treatment with 0.5% and 1.0% curcumin. Moreover, 0.5% and 1.0% curcumin significantly inhibited the CCl(4)-induced increase in serum glutamic oxaloacetic transaminase and promoted the restoration of superoxide dismutase in the liver; 1.0% curcumin significantly reduced serum glutamic pyruvic transaminase and lactate dehydrogenase and hepatic malondialdehyde, but significantly increased the total antioxidant capacity and glutathione levels in the liver. The CCl(4)-induced upregulation of NF-κB/c-Rel, IL-1ß, and TNF-α mRNAs and NF-κB/c-Rel protein levels was inhibited by 0.5% and 1.0% curcumin, and IL-12 mRNA was reduced by all three doses of curcumin. The effects of curcumin on the liver index, enzymes, histological changes, and cytokines were dose-dependent. Our results indicate that curcumin reduces CCl(4)-induced liver damage in Jian carp by upregulating antioxidative activities and inhibiting NF-κB, IL-1ß, TNF-α, and IL-12 expression.

The beneficial pharmacological effects of Uncaria rhynchophylla in neurodegenerative diseases: focus on alkaloids.

With the intensification of aging population, the prevention or treatment of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, has drawn more and more attention. As a long used traditional Chinese medicine, Uncaria rhynchophylla (Miq.) Jacks., named Gouteng in Chinese, has been reported to have an effective neuroprotective role in neurodegenerative diseases. In this review, the beneficial pharmacological effects and signaling pathways of herbal formulas containing U. rhynchophylla, especially major compounds identified from U. rhynchophylla, such as corynoxine B, corynoxine, rhynchophylline, and isorhynchophylline, in neurodegenerative diseases, were summarized, which not only provide an overview of U. rhynchophylla for the prevention or treatment of neurodegenerative diseases but also give some perspective to the development of new drugs from traditional Chinese medicine.

Unconscious Integration of Categorical Relationship of Two Subliminal Numbers in Comparison with "5".

Many studies have shown that the brain can process subliminal numerals, i.e., participants can categorize a subliminal number into two categories: greater than 5 or less than 5. In the context of many studies on the unconscious integration of multiple subliminal stimuli, the issue of whether multiple subliminal numbers can be integrated is contentious. The same-different task is regarded as a perfect tool to explore unconscious integration. In the two experiments reported, we used a same-different task in which a pair of masked prime numbers was followed by a pair of target numbers, and participants were asked to decide whether the two target numbers were on the same (both smaller or larger than 5) or different sides (one smaller, the other larger than 5) of 5 in magnitude. The results indicated that the prime numbers could be categorized unconsciously, which was reflected by the category priming effect, and that the unconscious category relationship of the two prime numbers could affect the judgment on the category relationship of the two target numbers, as reflected by the response priming effect. The duration of the prime-to-target interstimulus interval (ISI) was also manipulated, showing a positive compatibility effect (PCE) of category priming and a negative compatibility effect (NCE) of response priming no matter whether the ISI was short (50 ms) or long (150 ms). The NCE, which occurred when the prime-to-target ISI was relatively short in this study, contradicted the conventional view but was consistent with previous results of unconscious integration based on an attention modulation mechanism. Importantly, this study provided evidence for the still-under-debate issue of numerical information integration.

5-HT1A receptors within the intermediate lateral septum modulate stress vulnerability in male mice.

Chronic stress is a major risk factor for psychiatric disorders. However, certain individuals may be at higher risk due to greater stress susceptibility. Elucidating the neurobiology of stress resilience and susceptibility may facilitate the development of novel strategies to prevent and treat stress-related disorders such as depression. Mounting evidence suggests that the serotonin (5-HT) system is a major regulator of stress sensitivity. In this study, we assessed the functions of 5-HT1A and 5-HT2A receptors within the lateral septum (LS) in regulating stress vulnerability. Among a group of male mice exposed to chronic social defeat stress (CSDS), 47.2% were classified as stress-susceptible, and these mice employed more passive coping strategies during the defeat and exhibited more severe anxiety- and depression-like behaviors during the following behavioral tests. These stress-susceptible mice also exhibited elevated neuronal activity in the LS as evidenced by greater c-Fos expression, greater activity of 5-HT neurons in both the dorsal and median raphe nucleus, and downregulated expression of the 5-HT1A receptor in the intermediate LS (LSi). Finally, we found the stress-induced social withdrawal symptoms could be rapidly relieved by LSi administration of 8-OH-DPAT, a 5-HT1A receptor agonist. These results indicate that 5-HT1A receptors within the LSi play an important role in stress vulnerability in mice. Therefore, modulation of stress vulnerable via 5-HT1A receptor activation in the LSi is a potential strategy to treat stress-related psychiatric disorders.

GABAergic synapses from the ventral lateral septum to the paraventricular nucleus of hypothalamus modulate anxiety.

Emotional disorders, such as anxiety and depression, represent a major societal problem; however, the underlying neurological mechanism remains unknown. The ventral lateral septum (LSv) is implicated in regulating processes related to mood and motivation. In this study, we found that LSv GABAergic neurons were significantly activated in mice experiencing chronic social defeat stress (CSDS) after exposure to a social stressor. We then controlled LSv GABAergic neuron activity using a chemogenetic approach. The results showed that although manipulation of LSv GABAergic neurons had little effect on anxiety-like behavioral performances, the activation of LSv GABAergic neurons during CSDS worsened social anxiety during a social interaction (SI) test. Moreover, LSv GABAergic neurons showed strong projections to the paraventricular nucleus (PVN) of the hypothalamus, which is a central hub for stress reactions. Remarkably, while activation of GABAergic LSv-PVN projections induced social anxiety under basal conditions, activation of this pathway during CSDS alleviated social anxiety during the SI test. On the other hand, the chemogenetic manipulation of LSv GABAergic neurons or LSvGABA-PVN projections had no significant effect on despair-like behavioral performance in the tail suspension test. Overall, LS GABAergic neurons, particularly the LSv GABAergic-PVN circuit, has a regulatory role in pathological anxiety and is thus a potential therapeutic target for the treatment of emotional disorders.

Dopamine D2 receptor within the intermediate region of the lateral septum modulate social hierarchy in male mice.

The dopamine (DA) system has long been involved in social hierarchies; however, the specific mechanisms have not been elucidated. The lateral septum (LS) is a limbic brain structure that regulates various emotional, motivational, and social behaviors. DA receptors are abundantly expressed in the LS, modulating its functions. In this study, we evaluated the functions of DA receptors within different subregions of the LS in social dominance using a confrontation tube test in male mice. The results showed that mice living in social groups formed linear dominance hierarchies after a few days of cohousing, and the subordinates showed increased anxiety. Fos expressions was elevated in the entire LS after a confrontation tube test in the subordinates. However, DA neurons were more activated in the dominates within the ventral tegmental area and the dorsal raphe nucleus. Quantitative real-time polymerase chain reaction results showed that D2 receptor (D2R) within the intermediate region of the LS (LSi) were elevated in the subordinate. In the following pharmacological studies, we found simultaneous D2R activation in the dominants and D2R inhibition in the subordinates switched the original dominant-subordinate relationship. The aforementioned results suggested that D2R within the LSi plays an important role in social dominance in male mice. These findings improve our understanding of the neural mechanisms underlying the social hierarchy, which is closely related to our social life and happiness.