Neurogenesis Research Articles

Outstanding partnership in neuroinflammation. Highlighting open‐angle glaucoma diagnosis and therapy

Aims/Purpose: Despite significant advances in neuroprotection strategies, patients are still at high risk for glaucoma neurodegeneration (GND), in which neuroinflammation (NINF) is exceedingly implicated. It has recently been shown that in the acute phase, NINF cascades lead to apoptosis, meanwhile in later stages a wide variety of signalling pathways act trying to repair existing damage. Also, NINF affects adult neurogenesis (NG), that, in turns, remains an unknown field to be explored in GND.Methods: A total of 135 participants of both sexes, aged 35–80 years, were selected and classified into: open‐angle glaucoma (OAG) patients (n = 70) and healthy controls (CG; n = 65). Demographics, clinical and molecular data were registered. Tears were collected from the inferior meniscus and frozen at −80°C until processing by the multiplex system (human cytokine panel) to determine the cytokine/chemokine levels. Data were processed by using the IBM SPSS 25.0 program.Results: Mean age of the participants was 62 ± 14 years (68% were aged over 60 years). Gender distribution was 38% males/62% females. Tears from patients with OAG showed differential expression profile of the assayed cytokines/chemokines, as compared to the CG. Specifically, the granulocyte‐macrophage colony stimulating factor (GM‐CSF; p < 0.001), interferon‐γ (IFN‐γ; p < 0.001), tumour necrosis factor alpha (TNFa); and interleukin (IL) ‐4 and − 10 (p < 0.05) revealed significantly higher levels in the OAG patients versus the CG.Conclusions: Liberation of anti‐ and pro‐inflammatory cytokines with a broad range of functions in adult NG, as the aforementioned factors: the GM‐CSF, INFg, TNFa, IL‐4 and IL‐10, can be fully considered when managing GND and visual outcomes.

Neuroregeneration and neuroprotection: prospects for growth factors and other bioactive substances clinical application

Traumatic injuries, as well as degenerative diseases of the nervous system, are extremely common nowadays, there- fore, in clinical practice the use new methods for their treatment, such as stimulation of reparative neurogene- sis by growth factors, is highly topical. Aim. To review the published results of the experimental use of various growth factors for reparative neurogenesis stimulation and neuroprotection and to evaluate the prospects for their clinical application. Methods. Publications’ search was carried out in open databases of scientific literature, such as PubMed, Cyberleninka and eLIBRARY.RU based on keywords and their combinations: «reparative neuro- genesis», «neuroprotection», «nervous tissue», «neurotro- phic factors», «growth factors», «implantation» (in Russian and English). The search depth is 20 years. Results. The sti mulating and depressing effects of the neurotrophins NGF, CNTF, NF3, NF4, BDNF, GDNF are analysed, as well as the Shh protein’s impact on the regeneration of neu- rons and glial cells of the central and peripheral nervous systems and the specificity of their action on specific cells. The influence of such nonspecific trophic factors as EGF, FGF, IGF-1, VEGF on the viability of cells of the nervous system is described, the results of the enhancement of neurogenesis by using stimulants of erythropoiesis and retinoic acid are given. The results of using various me- thods of growth factors implantation are demonstrated. Conclusions. In the course of the study, it was found that in recent studies, mainly preclinical, both positive and negative results of the neurotrophins and nonspe- cific growth factors application for stimulating reparative neurogenesis and neuroprotection have been experi- mentally achieved. The specificity of their action on vari- ous neurocytes and the dependence of the effect on the chosen route of administration during therapy are noted. It is concluded that additional research is needed to re- solve the issue of recommending these factors for clinical application.

Exercise-Induced Molecule Protects the Aging Brain

In both animals and humans, regular exercise improves neurogenesis and cognition. Transfer of blood from young mice to old mice also improves

Genome-Wide Analysis Identifies NURR1-Controlled Network of New Synapse Formation and Cell Cycle Arrest in Human Neural Stem Cells.

Nuclear receptor-related 1 (Nurr1) protein has been identified as an obligatory transcription factor in midbrain dopaminergic neurogenesis, but the global set of human NURR1 target genes remains unexplored. Here, we identified direct gene targets of NURR1 by analyzing genome-wide differential expression of NURR1 together with NURR1 consensus sites in three human neural stem cell (hNSC) lines. Microarray data were validated by quantitative PCR in hNSCs and mouse embryonic brains and through comparison to published human data, including genome-wide association study hits and the BioGPS gene expression atlas. Our analysis identified ~40 NURR1 direct target genes, many of them involved in essential protein modules such as synapse formation, neuronal cell migration during brain development, and cell cycle progression and DNA replication. Specifically, expression of genes related to synapse formation and neuronal cell migration correlated tightly with NURR1 expression, whereas cell cycle progression correlated negatively with it, precisely recapitulating midbrain dopaminergic development. Overall, this systematic examination of NURR1-controlled regulatory networks provides important insights into this protein’s biological functions in dopamine-based neurogenesis.

Curcumin improves the behavior and memory in mice by modulating the core circadian genes and their associated micro-RNAs

Objective: To investigate the neuroprotective effects of curcumin in albino mice focusing on memory and behavior. Materials and Methods: Four groups of 7 mice each, different concentrations of curcumin were administered for 3 weeks in 3 groups and the remaining group was kept as control. The effect of curcumin on behavior and memory was studied using various tests. The expression of core circadian rhythm genes and micro RNAs were also studied. Results: Our results revealed that curcumin improves the mice's behavior by regulating oxidative stress, hippocampal neurogenesis, and modulation of core circadian genes and their associated micro-RNA. Conclusion: This study shows that curcumin has a potential neuroprotective effect.

Biological functions of growth factors in breast milk

Current studies have found that breast milk contains multiple growth factors with important biological functions, which play an important role in growth and immune regulation in early life.Epidermal growth factor(EGF)can promote the proliferation and differentiation of neonatal gastrointestinal mucosa epithelium, and can prevent the development of necrotizing colitis.Transforming growth factors(TGF)include transforming growth factor α and transforming growth factor β.Transforming growth factor α is related to gastrointestinal function, while transforming growth factor β promotes IgA production and has immunomodulatory effect.Hepatocyte growth factor(HGF)can not only promote gastrointestinal tract development as a nutritional factor, but also may work as an immune factor to enhance immunity.Neurotrophic factors promote early neurogenesis in the offspring of preeclampsia mothers.At the same time, the content of these growth factors in breast milk is related to the gestational age, region, diet and other factors.This article summarizes the research progress and clinical application value of these growth factors. Key words: Breast milk; Epidermal growth factor; Transforming growth factor; Hepatocyte growth factor; Neurotrophic factor

Effect of continuous environmental enrichment and aerobic exercise on rat plasma and hippocampal brain-derived neurotrophic factor

Objective: Environmental enrichment (EE) or exercise can positively affect memory function through increased long-term potentiation and neurogenesis, which is facilitated by brain-derived neurotrophic factor (BDNF). BDNF promotes blood vessel growth, angiogenesis linked to adult neurogenesis, and neuronal survival. Here, we investigated the effects of EE, aerobic exercise, and their combination on plasma and hippocampal BDNF levels. Materials and Methods: Twenty-four 7-month-old adult male Wistar rats weighing 300–400 g were randomly assigned to the following four groups: control (C), aerobic exercise (A), EE, and combined EE and aerobic exercise (EEA). Interventions were given for 8 weeks, and plasma and hippocampal BDNF levels were measured using enzyme-linked immunosorbent assay. Results: A combination of aerobic exercise and continuous EE produced the largest increase in hippocampal and plasma BDNF levels in adult rats. A positive correlation (r = 0.686, P = 0.002, n = 24) was observed between plasma and hippocampal BDNF levels in adult rats. Conclusion: We conclude that a combination of aerobic exercise and continuous EE increases plasma and hippocampal BDNF in adult rats.

Research progress in the role of inflammation in regulating adult hippocampal neurogenesis in cognitive decline of elderly patients

The elderly patients often suffered from cognitive decline. Chronic inflammatory responses inhibit hippocampal neurogenesis, which is one of the important mechanisms of cognitive decline in the elderly patients. To provide insights for further study and new thoughts for prevention or treatment of cognitive decline in elderly patients, this article reviewed the research progresses on regulation of peripheral and central inflammation to hippocampal neurogenesis and their role in cognitive decline in elderly patients. Key words: Inflammation; Hippocampal; Neurogenesis; Aged; Cognition

Efficacy of Cell-Based Therapies for Traumatic Brain Injuries.

Traumatic brain injuries (TBIs) are a leading cause of death and disability. Additionally, growing evidence suggests a link between TBI-induced neuroinflammation and neurodegenerative disorders. Treatments for TBI patients are limited, largely focused on rehabilitation therapy, and ultimately, fail to provide long-term neuroprotective or neurorestorative benefits. Because of the prevalence of TBI and lack of viable treatments, new therapies are needed which can promote neurological recovery. Cell-based treatments are a promising avenue because of their potential to provide multiple therapeutic benefits. Cell-based therapies can promote neuroprotection via modulation of inflammation and promote neurorestoration via induction of angiogenesis and neurogenesis. Neural stem/progenitor cell transplantations have been investigated in preclinical TBI models for their ability to directly contribute to neuroregeneration, form neural-like cells, and improve recovery. Mesenchymal stem cells (MSCs) have been investigated in clinical trials through multiple different routes of administration. Intravenous administration of MSCs appears most promising, demonstrating a robust safety profile, correlation with neurological improvements, and reductions in systemic inflammation following TBI. While still preliminary, evidence suggests cell-based therapies may become a viable treatment for TBI based on their ability to promote neuroregeneration and reduce inflammation.

Recent advances in the effects and mechanism of repeated exposure to anesthetics on developing brain

Recent clinical studies report that children with multiple exposure to anesthesia are more likely to suffer from developing neurocognitive impairment, while single exposure to general anesthesia may not affect neurodevelopment. This article review clinical studies concerning repeated exposure to anesthetics on developing brain, which so far have not consistent results. Preclinical evidence indicates neurotoxicity due to repeated exposure to anesthetics, which may be related with neurogenesis, synaptic plasticity, and inflammatory reactions in the brain. The neurotoxicity of repeated exposure to anesthetics will become one of the hotspot in the research of anesthesia. Key words: Anesthetics; Developing brain; Repeated exposure

Proteome-wide detection of S-nitrosylation targets and motifs using bioorthogonal cleavable-linker-based enrichment and switch technique

Cysteine modifications emerge as important players in cellular signaling and homeostasis. Here, we present a chemical proteomics strategy for quantitative analysis of reversibly modified Cysteines using bioorthogonal cleavable-linker and switch technique (Cys-BOOST). Compared to iodoTMT for total Cysteine analysis, Cys-BOOST shows a threefold higher sensitivity and considerably higher specificity and precision. Analyzing S-nitrosylation (SNO) in S-nitrosoglutathione (GSNO)-treated and non-treated HeLa extracts Cys-BOOST identifies 8,304 SNO sites on 3,632 proteins covering a wide dynamic range of the proteome. Consensus motifs of SNO sites with differential GSNO reactivity confirm the relevance of both acid-base catalysis and local hydrophobicity for NO targeting to particular Cysteines. Applying Cys-BOOST to SH-SY5Y cells, we identify 2,151 SNO sites under basal conditions and reveal significantly changed SNO levels as response to early nitrosative stress, involving neuro(axono)genesis, glutamatergic synaptic transmission, protein folding/translation, and DNA replication. Our work suggests SNO as a global regulator of protein function akin to phosphorylation and ubiquitination.

The neural function repair and mechanism of (-)-epicatechin on murine traumatic brain injury

Objective To investigate whether (-)-epicatechin plays a role in neurological repair on traumatic brain injury in mice. Methods The mice model of traumatic brain injury was established by modified weight drop method. Experimental mice were randomly (random number) divided into the injury+ (Veh) group and the injury + (-)-epicatechin (EC) group. At 3 days after operation, the expression of IL-1β and TNF-α were detected. The number of necrotic cells of the lesion area was detected by PI staining. At 28 days after SCI, Morris Water Maze test was performed to observe the ability of spatial learning and memory in mice. The expression of neurotrophic factors BDNF and NGF were examined by qRT-PCR. The expression of NeuN was detected by immunofluorescence staining. EdU staining was used to observe the neurogenesis in the SGZ region. Results Compared with the Veh group, EC treated group showed better spatial learning and memory ability in time spent in correct quadrant at day 27 and 28 [24 d: (26.333±5.037)% vs (26.583±5.802)%, P=0.938; 25 d (33.300±4.724)% vs (29.767±3.347)%. P=0.166; 26 d: (41.017±7.246)% vs (32.800±8.145)%, P=0.095; 27 d: (48.017±7.424)% vs (35.267±6.748)%, P=0.011; 28 d: (51.617±9.017)% vs (41.116±6.467)%, P=0.043] and in latency to platform at day 27 and 28 [24 d: (62.967±5.494) s vs (63.917±7.027) s, P=0.800; 25 d: (50.533±10.305) s vs (57.217±13.085) s, P=0.349; 26 d: (40.333±10.526) s vs (50.133±11.039) s, P=0.147; 27 d: (28.717±4.137) s vs (44.533±7.181) s, P=0.001; 28 d: (21.950±6.889) s vs (37.567±5.974) s, P=0.002]. There was a decreased expression of IL-1β and TNF-α and increased level of neurotrophic factor BDNF and NGF after EC treatment in EC treatment group, compared to the veh treatment group [IL-1β and TNF-α: (42.690±3.057) ng/mL and (750.167±51.941) ng/mL vs (71.670±4.996) ng/mL and (1 085.167±68.535) ng/mL, P=0.000 6 and 0.003; BDNF and NGF: 0.543±0.033 and 0.334±0.041 vs 0.756±0.088 and 0.514±0.047, P=0.048 and 0.017)]. EC decreased the cell death near injury area (54.833±5.486 vs 74.000±5.323, P=0.031), increased NeuN positive cells (76.667±6.386 vs 42.167±5.237, P=0.002), and increased neurogenesis in SGZ area (12.667±0.760 vs 7.500±1.258, P=0.031). Conclusions (-)-Epicatechin plays an important role in functional recovery after traumatic brain injury in mice. The underlying mechanisms are closely related to inhibited inflammation, enhanced neurotrophic factors and improved neurogenesis. Key words: Traumatic brain injury; (-)-epicatechin; Nerve repair; Brain derived neurotrophic factor; Inflammation factors

Research progress on fibroblast growth factor-2 in treatment of neurological diseases

The biological role of fibroblast growth factor-2 (FGF2) was extensive, previous researches confirmed FGF2 also effected on the neurogenesis and may be a new strategy for the treatment of neurological diseases. The study reviewed the research of FGF2 on the proliferation and differentiation of nervous system and treatment of neurological disease. Key words: Fibroblast growth factor-2; Neurogenesis; Neurological diseases

Effect of arsenic exposure on learning and memory in rat models and its underlying mechanisms

Objective To explore the effects of arsenic exposure on learning and memory and its potential mechanism in rats. Methods Water-based arsenic-exposed rat models were established on 4-10 postnatal days.The experimental animals were divided into 4 groups (10-12 cases in each group): the control group, the 15 μg/L As2O3 water group, the 30 μg/L As2O3 water group, and the 45 μg/L As2O3 water group.Cognitive functions were examined with the Morris water maze, exploratory behavior was detected by the exploratory behavior test.The hippocampus of pups from each experimental group was sectioned at various time points after arsenic exposure.The morphologies and neurogenesis of the neurons in the hippocampus CA1-CA3 region and dentate gyrus (DG) were observed by hematoxylin-eosin staining, Nissl staining, and doublecortin (DCX) immunostaining at different time points after arsenic exposure. Results Compared with the normal control group, the escape latency of the rats in the arsenic-exposed group was prolonged.The average escape latency of the rats in the normal control group, 15 μg/L As2O3 group, 30 μg/L As2O3 group and 45 μg/L As2O3 group were (17.00±9.53) s, (35.89±19.81) s, (26.60±18.84) s, and (33.79±18.08) s, respectively, and the difference among 4 groups was statistically significant (F=3.591, P<0.05), and the residence time in the original target quadrant was shortened, respectively, (38.93±8.33) s, (36.03±16.25) s, (29.85±9.27) s, and (29.84±10.16) s, respectively, and there was no significant difference among 4 groups (F=1.681, P=0.187). HE staining and Nissl staining showed that pathological changes such as edema, degeneration and necrosis were observed in the hippocampal CA1 area and CA2 area as well as dentate gyrus cells in rats exposed to arsenic in the acute phase.The higher the concentration of arsenic exposure, the more obvious the cell structure disorder was.However, 5 weeks after exposure, the pathological changes in hippocampal neurons in the arsenic-exposed group gradually returned to normal.Immunohistochemistry showed that the expressions of DCX in the CA1, CA2 and dentate gyrus of rats exposed to arsenic decreased significantly 24 h after arsenic exposure, especially in the 45 μg/L group.Five weeks after arsenic exposure, there was no expression in the hippocampal CA1-CA3 area, and there was still a small amount of expression in the dentate gyrus. Conclusions Postnatal low-concentration arsenic exposure may impair learning and abnormal germination of neurons in the hippocampal dentate gyrus may be the underlying mechanism. Key words: Arsenic exposure; Learning and memory; Hippocampus; Mechanism

Mechanism of mild hypothermia promoting nerve regeneration after traumatic brain injury in rats

Objective To investigate whether mild hypothermia can promote neurogenesis in the dentate gyrus of hippocampus and cognitive function recovery after traumatic brain injury (TBI) through inhibiting apoptosis of hippocampal neurons. Methods A total of 66 healthy adult Sprague-Dawley rats were randomly divided into sham group, TBI group and TBI+ hypothermia group, with 22 rats in each group. The rat TBI model was established using the fluid percussion device. The rats in TBI+ hypothermia group received 4-hour hypothermia therapy immediately after injury, with the target temperature of 33.5℃. Bromodeoxyuridine (BrdU) was injected into the rats' abdominal cavity to label the mitotic cells. The test of Morris water maze was used to evaluate the rats' spatial learning and memory capabilities. Immunofluorescence staining was used to observe the expression levels of BrdU, doublecortin (DCX), neuron specific nuclear protein (NeuN), cysteinyl aspartate specific proteinase 3 (caspase-3) and cleaved caspase-3 expressions in dentate gyrus of hippocampus at 7 days and 28 days after injury. Expressions apoptosis-related proteins including the factor associated suicide (FAS)/factor associated suicide ligand (FASL), B-cell lymphoma-2 (Bcl-2), caspase-3 and cleaved caspase-3 expressions were detected by Western blot assay. Results The water maze tests at 28 days after injury showed that compared with TBI group, the escape latency in TBI+ hypothermia group was significantly shorter [(24.2±5.9)s∶(18±4.1)s], and both the time in the target quadrant and the number of platform crossing were increased significantly [(24.9±6.5)s∶(31.7±5.2)s; (1.9±0.8) times∶(3.5±1.2)times](P<0.05). Compared with the sham group, in TBI group and TBI+ hypothermia group, the BrdU+ new-born cells in the dentate gyrus of hippocampus were significantly increased at 7 days after injury [(9.4±4.1)∶(33.4±3.8); (9.4±4.1)∶(45.8±5.6)], the BrdU+ /DCX+ new-born neurons were increased at 7 days after injury [(2.0±0.6)∶(9.6±1.6); (2.0±0.6)∶(19.2±3.7)], and the BrdU+ /NeuN+ mature neurons were increased at 28 days after injury [(2.6±1.0)∶(17.2±3.9); (2.6±1.0)∶(33.6±9.1)] (P<0.01). TBI group showed more obvious increase than the TBI+ hypothermia group (P<0.01). Moreover, compared with 7 days after injury, the number of BrdU+ cells at 28 days after injury was further increased in TBI+ hypothermia group but decreased in TBI group [(45.8±5.6)∶(58.8±9.2); (33.4±3.8)∶(22.0±3.5)](P<0.05 or <0.01). Compared with the sham group, the caspase-3+ NeuN+ and caspase-3+ NeuN+ apoptotic neurons were significantly increased at 7 days after injury in TBI group [(2.0±0.9)∶(11.6±2.6); (2.6±1.0)∶(10.2±2.9)] (P<0.05). Compared with the TBI group, the cleaved caspase-3+ NeuN+ apoptotic neurons were decreased in TBI+ hypothermia group [(6.6±2.0)∶(11.6±2.6)](P<0.05). Furthermore, compared with the TBI group, mild hypothermia might down-regulate the expression of FAS, FASL, cleaved caspase-3 and caspase-3 and up-regulate the expression of Bcl-2 in the hippocampus [(1.54±0.15) ∶(1.14±0.12); (1.06±0.04)∶(0.80±0.09); (0.84±0.03)∶(0.62±0.08); (0.93±0.06)∶(0.86±0.09); (0.71±0.01)∶(1.58±0.18)](P<0.05). Conclusions Mild hypothermia might inhibit apoptosis of hippocampal neurons through cleaved caspase-3, FAS/FASL and Bcl-2 pathways, thus improving the neurogenesis and maturation of neurons in the dentate gyrus of hippocampus and facilitating cognitive function recovery in rats. It indicates that the function of hypothermia in anti-apoptosis and neurogenesis and maturity of hippocampal neurons may have a potential role in predicting the prognosis of TBI patients. Key words: Hypothermia; Brain injuries; Hippocampus; Neuve regeneration; Apoptosis

Basic studies on neurotoxicity of general anesthetics in the developing brain

Animal researches on the toxicity of general anesthetics, mainly include laboratory studies from the rodent and non-human primate species. Basic studies have confirmed that general anesthetics can cause widely apoptosis in vulnerable regions of brain, changes on neurogenesis, synaptic plasticity, development of glial cells, and a series of histopathological changes. However, it is still uncertain of the relationship between the histopathological changes and cognitive changes, as well as learning and memory. And basic studies have also confirmed that the outcome of cognition and learning memory disfunction is related to the species of anesthetics, the exposure period, the exposure frequency and other factors. To make a review of recent animal researches on the neurotoxicity of the general anesthetic in fields of histopathology and long-term behavior in the developing period, to further explore the neurotoxic effect of general anesthetics on the development of brain in the development of the brain through animal experiments, and provide a theoretical basis for clinical research. Key words: Anesthetics, general; Developing period; Neurotoxicity; Basic research

Alzheimer's Disease and Its Potential Alternative Therapeutics.

Alzheimer’s Disease (AD) is a chronic neurodegenerative disease that affects over 5 million individuals in the United States alone. Currently, there are only two kinds of pharmacological interventions available for symptomatic relief of AD; Acetyl Cholinesterase Inhibitors (AChEI) and N-methyl-D-aspartic Acid (NMDA) receptor antagonists and these drugs do not slow down or stop the progression of the disease. Several molecular targets have been implicated in the pathophysiology of AD, such as the tau (τ) protein, Amyloid-beta (Aβ), the Amyloid Precursor Protein (APP) and more and several responses have also been observed in the advancement of the disease, such as reduced neurogenesis, neuroinflammation, oxidative stress and iron overload. In this review, we discuss general features of AD and several small molecules across different experimental AD drug classes that have been studied for their effects in the context of the molecular targets and responses associated with the AD progression. These drugs include: Paroxetine, Desferrioxamine (DFO), N-acetylcysteine (NAC), Posiphen/-(−)Phenserine, JTR-009, Carvedilol, LY450139, Intravenous immunoglobulin G 10%, Indomethacin and Lithium Carbonate (Li2CO3).

Role of C-X-C motif chemokine 13 in sepsis-associated encephalopathy in mice

Objective To evaluate the role of C-X-C motif chemokine 13(CXCL13)in sepsis-associated encephalopathy in mice. Methods A total of 64 healthy male C57BL/6J mice, aged 3-4 months, weighing 20-25 g, were divided into 4 groups(n=16 each)using a random number table method: sham operation group(Sham group), sepsis group(S group), CXCL13 siRNA group(si-CXCL13 group)and negative control siRNA group(si-control group).5-bromo-2-deoxyuridine(BrdU)50 mg/kg was intraperitoneally injected twice a day for 3 consecutive days in the four groups, and then lipopolysaccharide 500 μg/kg was intraperitoneally injected to establish the sepsis model in S, si-CXCL13 and si-control groups.CXCL13 siRNA 5 μl and siRNA 5 μl were injected into the left lateral cerebral ventricle in si-CXCL13 and si-control groups, respectively, at 3 days before establishing the model.Morris water maze test was performed at 5 days after establishing the model.The escape latency, time spent in the target quadrant, and the number of crossing the platform were recorded.Mice were sacrificed after the end of test, brains were removed and hippocampi were isolated for examination of the pathological changes of the dentate gyrus(with a light microscope)and for determination of the expression of CXCL13, C-X-C motif chemokine receptor 5(CXCR5)and brain-derived neurotrophic factor(BDNF), and the number of BrdU and BrdU/NeuroD positive cells(by immunofluorescence). Results Compared with sham group, the escape latency was significantly prolonged, the time spent in the target quadrant was shortened, and the number of crossing the platform was reduced on 2nd-4th days, the number of BrdU positive cells in the dentate gyrus was increased, and the number of BrdU/NeuroD positive cells in the dentate gyrus was decreased in S, si-CXCL13 and si-control groups, and the expression of CXCL13 and CXCR5 was up-regulated, and the expression of BDNF was down-regulated in LPS and si-control groups(P 0.05). Conclusion CXCL13 is involved in sepsis-associated encephalopathy through regulating hippocampal neurogenesis, and the mechanism may be related to down-regulating the expression of hippocampal BDNF in mice. Key words: Sepsis; Brain; Chemokine CXCL13

Erratum to: Metformin treatment ameliorates diabetes-associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1.

[This corrects the article DOI: 10.1002/2211-5463.12436.].

Influence of lithium in neuron-glia interaction in primary hippocampal cell culturing

Recently, special attention has been given to the possible neuroprotective effects of lithium, especially by the discovery of its regulatory effects on pro and anti-apoptotic proteins. Lithium substantially increases the cytoprotective proteins expression in the central nervous system, both in rat cortex and in human cells of neuronal origin. In addition to neuroprotective actions, it aids in the regeneration of axons in the central nervous system of mammals. Lithium negatively regulates the expression and activity of enzymes that exert important functions in cerebral homeostasis: synaptic plasticity, neurogenesis, andphosphorylation of tau protein. Microglia is known for its importance in neuropathologies. However, under physiological conditions, such immune cells interact actively with neurons, being able to modulate the fate and functions of the synapses. Such ability of microglial cells suggests the consequences of changes in microglial phenotype under pathological conditions, which makes it relevant to understand the interaction between microglial and other developing brain cells and their influence on the formation of neuronal and synaptic networks. The current work aims to identify the main pathway of neuronal-glia integration activated by chronic treatment with lithium (0.02mM; 0.2mM and 2mM) in hippocampal neurons, exploring the use of bioinformatics tools in microarray data. Treatment of primary hippocampal neurons with lithium changed the genes related to different neuroprotection pathwaysat the highest therapeutic dose (2mM). There was dissociation between the therapeutic and sub therapeutic dose of lithium in neuroprotection. Therefore, treatment at therapeutic doses (2mM) modified different signaling pathways when compared to the sub-therapeutic dose (0.02 and 0.2mM).