Neurotrophic Pathways Research Articles

Elaphuri Davidiani Cornu Improves Depressive-Like Behavior in Mice and Increases Neurotrophic Factor Expression in Mouse Primary Astrocytes via cAMP and ERK-Dependent Pathways.

Elaphuri Davidiani Cornu (EDC) is the natural shedding horn of Elaphurus davidiauus Millne-Edwards that was used by people in ancient China for maintaining physical and mental health. We evaluated the antidepressant effect of EDC using depression-like animal models and explored possible mechanisms in mouse primary astrocyte cultures. We found that aqueous extracts of EDC significantly improved depression-like behavior in a mouse model of depression. The extracts enhanced expression of nerve growth factor and brain-derived neurotrophic factor neurotrophic factors in mouse prefrontal cortex and hippocampus tissues. In the mouse primary astrocyte cultures, the EDC aqueous extracts significantly increased the neurotrophic factor expression both at the transcriptional and protein levels. EDC extracts might exhibit these functions by regulating matrix metalloprotein-9 of the nerve growth factor and brain-derived neurotrophic factor metabolic pathways and might enhance expression of neurotrophic factors via the cAMP- and ERK-dependent pathways. We confirmed this possibility by showing the effects of related inhibitors, providing scientific evidence that supports the utility of EDC in the development of drugs to treat major depressive disorders.

Effect of desalted Salicornia europaea L. ethanol extract (PM-EE) on the subjects complaining memory dysfunction without dementia: a 12\xa0week, randomized, double-blind, placebo-controlled clinical trial

Desalted Salicornia europaea L. (SE) inhibits acetylcholine esterase, attenuates oxidative stress and inflammatory cytokines, and activates neurotrophic pathway. We performed 12-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy of PhytoMeal(a desalted SE)-ethanol extract (PM-EE), in improving the cognitive performance in patients with subjective memory impairment. 63 participants complaining memory dysfunction without dementia (Korean Mini-Mental State Examination [K-MMSE] score ≥ 23) were assigned to PM-EE 600 mg/day or placebo. The cognitive domain of the Alzheimer's disease assessment scale-Korean version (ADAS-K) was set as the primary outcome. After 12 weeks, there was no differences in the changes in the primary outcome or the frequency of adverse events between the groups. In the subgroup analysis for the 30 subjects with mild cognitive impairment (MCI, baseline K-MMSE scores ≤ 28), PM-EE significantly improved the color-reading score of the Korean color-word stroop test (8.2 ± 25.0 vs. − 4.7 ± 13.2, P = 0.018). Our findings suggest that PM-EE is safe but might not be effective in this setting of this study. However, PM-EE may improve the frontal executive function in the patients with MCI. Further large-sized studies with longer follow-up period is warranted (trial registration number KCT0003418).

Intermittent fasting promotes adult hippocampal neuronal differentiation by activating GSK-3β in 3xTg-AD mice.

Moderate dietary restriction can ameliorate age-related chronic diseases such as Alzheimer's disease (AD) by increasing the expression of neurotrophic factors and promoting neurogenesis in the brain. Glycogen synthase kinase-3β (GSK-3β) signaling is essential for the coordination of progenitor cell proliferation and differentiation during brain development. The mechanisms by which GSK-3β is involved in dietary restriction-induced neurogenesis and cognitive improvement remain unclear. Six-month-old male 3xTg-AD and wild-type mice were fed on alternate days (intermittent fasting, IF) or ad libitum (AL) for 3months. GSK-3β activity was regulated by bilaterally infusing lentiviral vectors carrying siRNA targeting GSK-3β into the dentate gyrus region of the hippocampus. Intermittent fasting promoted neuronal differentiation and maturation in the dentate gyrus and ameliorated recognized dysfunction in 3xTg-AD mice. These effects were reversed by siRNA targeting GSK-3β. After intermittent fasting, the insulin and protein kinase A signaling pathways were inhibited, while the adenosine monophosphate-activated protein kinase and brain-derived neurotrophic factor pathways were activated. These findings suggest that intermittent fasting can promote neuronal differentiation and maturation in the hippocampus by activating GSK-3β, thus improving learning and memory.

Pharmacogenomics of methadone: a narrative review of the literature.

Background: Methadone, a synthetic opioid with longer duration of action and lower abuse potential compared with morphine, is used to prevent opioid withdrawal, as well as to manage chronic and acute surgical pain. The variability in response to methadone has been widely recognized. The purpose of this article is to review the literature on the pharmacogenetic factors underlying this variability. Materials & methods: This is a narrative overview of the literature on the genetic variants affecting pharmacodynamics and pharmacokinetics of methadone, retrieved from searches of databases such as PubMed and google scholar. Discussion: Clinical responses to methadone may be affected by genetic variants in the opioidergic, dopaminergic and neurotrophic pathways. Polymorphisms in genes related to disposition and elimination of methadone alter the pharmacokinetics, and possibly pharmacodynamics of methadone. Cytochrome P450 enzymes and P-glycoprotein variants contribute to the interindividual variability in methadone pharmacokinetics. Evidence for single gene variants affecting methadone response remains weak. Multiple genetic variants must be considered in conjunction to improve predictive ability. Conclusion: Evidence remains scarce at this time, to recommend pharmacogenetic testing before methadone administration. Well-powered clinical studies are needed with population pharmacokinetic-pharmacodynamic modeling and multigenetic signature-based predictions to enable tailored use of methadone in clinical practice.

Erythropoietin shows gender dependent positive effects on social deficits, learning/memory impairments, neuronal loss and neuroinflammation in the lipopolysaccharide induced rat model of autism

We aimed to evaluate the effects of EPO in the lipopolysaccharide (LPS) induced rat model of autism in terms of social deficits, learning and memory impairments, as well as their neurochemical correlates.Sixteen female Sprague Dawley rats randomly distributed into two equel groups, then were caged with fertile males for mating. At the 10th day of pregnancy, 0.5 ml %0,9 NaCl saline was given to first group, 100 μg/kg LPS was given to second group to induce autism. On postnatal 21th day, forty-eight littermates were divided into four groups as; 8 male, 8 female controls, 16 male and 16 female LPS-exposed. Then, LPS groups were also divided in to two groups as saline (1 mg/kg/day) and EPO 600 U/kg/day groups, and animals were treated 45 days. At 50th day, after behavioral evaluations, brain levels of TNF-α, nerve growth factor (NGF) were measured. Histologically, hippocampal neuronal density and GFAP expression were assessed.Three-chamber sociability and social novelty test, passive avoidance learning test were revealed significant differences among the EPO and control groups. Histologically, hippocampal CA1 & CA3 regions displayed significant alterations regarding gliosis (GFAP-positive cells) and regarding frontal cortical thickness in EPO groups compare to controls. Biochemical measurements of the brain levels of TNF-α and NGF levels showed significant differences between controls and EPO groups.According to our findings EPO treatment has beneficial effects on ASD-like symptoms, learning and memory processes, neuronal loss and neuroinflammation in the LPS induced rat model of autism, with some gender differences through inflammatory and neurotrophic pathways.

Effects of Supervised Early Resistance Training versus standard care on cognitive recovery following cardiac surgery via median sternotomy (the SEcReT study): protocol for a randomised controlled pilot study

IntroductionMild cognitive impairment is considered a precursor to dementia and significantly impacts upon quality of life. The prevalence of mild cognitive impairment is higher in the post-surgical cardiac population than in the general population, with older age and comorbidities further increasing the risk of cognitive decline. Exercise improves neurogenesis, synaptic plasticity and inflammatory and neurotrophic factor pathways, which may help to augment the effects of cognitive decline. However, the effects of resistance training on cognitive, functional and overall patient-reported recovery have not been investigated in the surgical cardiac population. This study aims to determine the effect of early moderate-intensity resistance training, compared to standard care, on cognitive recovery following cardiac surgery via a median sternotomy. The safety, feasibility and effect on functional recovery will also be examined.MethodsThis study will be a prospective, pragmatic, pilot randomised controlled trial comparing a standard care group (low-intensity aerobic exercise) and a moderate-intensity resistance training group. Participants aged 18 years and older with coronary artery and/or valve disease requiring surgical intervention will be recruited pre-operatively and randomised 1:1 to either the resistance training or standard care group post-operatively. The primary outcome, cognitive function, will be assessed using the Alzheimer’s Disease Assessment Scale and cognitive subscale. Secondary measures include safety, feasibility, muscular strength, physical function, multiple-domain quality of recovery, dynamic balance and patient satisfaction. Assessments will be conducted at baseline (pre-operatively) and post-operatively at 2 weeks, 8 weeks, 14 weeks and 6 months.DiscussionThe results of this pilot study will be used to determine the feasibility of a future large-scale randomised controlled trial that promotes the integration of early resistance training into existing aerobic-based cardiac rehabilitation programs in Australia.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617001430325p. Registered on 9 October 2017. Universal Trial Number (UTN): U1111-1203-2131.

Integrative analysis of lithium treatment associated effects on brain structure and peripheral gene expression reveals novel molecular insights into mechanism of action

Lithium is a highly effective medication for bipolar disorder, but its mechanism of action remains unknown. In this study, brain MRI scans and blood samples for gene expression (total of 110 scans and 109 blood samples) were collected from 21 bipolar subjects before and after 2 and 8 weeks of lithium monotherapy and at the same time-points from untreated 16 healthy controls. We used linear mixed-effects models to identify brain structural features and genes with expression changed after lithium treatment, with correction for multiple testing, and correlated their concurrent changes to identify molecular pathways associated with lithium effects. There are significant increases in gray matter fraction, global cortical thickness, and the frontal and parietal cortices after 8 weeks of lithium treatment (corrected p < 0.05). Volume increases were also seen for putamen, hippocampus, thalamic nuclei, and thalamic substructures. Several genes showed significant expression changes, and 14 gene pathways were identified for the present integration analysis. Of these, nine pathways had significant correlations with structural changes (FDR < 0.05). Three neurotrophy-related pathways (GDNF family of ligands, NFAT immune-response, and p53-signaling pathway) correlated with structural changes in multiple regions. Mediation analysis showed that the sphingomyelin metabolism pathway is associated with HAM-D change (p < 0.01), and this effect is mediated via the volume of mediodorsal thalamus (p < 0.03). In summary, the integration of lithium effects on brain structural and peripheral gene expression changes revealed effects on several neurotrophic molecular pathways, which provides further insights into the mechanism of lithium action.

A peroxisome deficiency–induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.

Inhibition of Histone Deacetylase Reinstates Hippocampus-Dependent Long-Term Synaptic Plasticity and Associative Memory in Sleep-Deprived Mice

Sleep plays an important role in the establishment of long-term memory; as such, lack of sleep severely impacts domains of our health including cognitive function. Epigenetic mechanisms regulate gene transcription and protein synthesis, playing a critical role in the modulation of long-term synaptic plasticity and memory. Recent evidences indicate that transcriptional dysregulation as a result of sleep deprivation (SD) may contribute to deficits in plasticity and memory function. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as Vorinostat, a clinically approved drug for human use, has been shown to ameliorate cognitive deficits in several neurological disease models. To further explore the therapeutic effect of SAHA, we have examined its potential role in improving the SD-mediated impairments in long-term plasticity, associative plasticity, and associative memory. Here we show that SAHA preserves long-term plasticity, associative plasticity, and associative memory in SD hippocampus. Furthermore, we find that SAHA prevents SD-mediated epigenetic changes by upregulating histone acetylation, hence preserving the ERK-cAMP-responsive element-binding protein (CREB)/CREB-binding protein-brain-derived neurotrophic factor pathway in the hippocampus. These data demonstrate that modifying epigenetic mechanisms via SAHA can prevent or reverse impairments in long-term plasticity and memory that result from sleep loss. Thus, SAHA could be a potential therapeutic agent in improving SD-related memory deficits.

Neurometabolic effects of sweetened solution intake during adolescence related to depressive-like phenotype in rats.

Exposure to artificial sweeteners, such as aspartame, during childhood and adolescence has been increasing in recent years. However, the safe use of aspartame has been questioned owing to its potentially harmful effects on the developing brain. The aim of this study was to test whether the chronic consumption of aspartame during adolescence leads to a depressive-like phenotype and to investigate the possible mechanisms underlying these behavioral changes. Adolescent male and female rats were given unlimited access to either water, solutions of aspartame, or sucrose in their home cages from postnatal day 21 to 55. Forced swim test revealed that both chronic aspartame and sucrose intake induced depressive-like behaviord, which was more pronounced in males. Additionally, repeated aspartame intake was associated with increased cerebrospinal fluid (CSF) aspartate levels, decreased hippocampal neurogenesis, and reduced activation of the hippocampal leptin signaling pathways in males. In females, we observed a main effect of aspartame: reducing PI3K/AKT one of the brain-derived neurotrophic factor pathways; aspartame also increased CSF aspartate levels and decreased the immunocontent of the GluN2A subunit of the N-methyl-d-aspartic acid receptor. The findings revealed that repeated aspartame intake during adolescence is associated with a depressive-like phenotype and changes in brain plasticity. Interestingly, males appear to be more vulnerable to the adverse neurometabolic effects of aspartame than females, demonstrating a sexually dimorphic response. The present results highlighted the importance of understanding the effects caused by the constant use of this artificial sweetener in sensitive periods of development and contribute to regulation of its safe use.

Possible Involvement of Tissue Plasminogen Activator/Brain-Derived Neurotrophic Factor Pathway in Anti-Depressant Effects of Electroacupuncture in Chronic Unpredictable Mild Stress-Induced Depression in Rats.

ObjectiveUsing a rat model of chronic unpredictable mild stress (CUMS), to investigate the effects of electroacupuncture (EA) on the tissue plasminogen activator (tPA)/brain-derived neurotrophic factor (BDNF) pathway.MethodsSixty male Sprague–Dawley rats were randomly divided into four groups: normal, model, fluoxetine (fluox), or EA. Experimental groups were subjected to 28 d of CUMS modeling. One hour after CUMS, the fluox and EA groups were treated with fluox and a 20 min EA intervention, respectively. Depressive-like behaviors were assessed by open field and sucrose preference tests. After the rats were sacrificed, brains were dissected and processed using hematoxylin and eosin (HE) staining to observe changes in the morphology and quantity of neurons in the hippocampal cornu ammonis 3 area. Western blot and real-time polymerase chain reaction (PCR) demonstrated the effects of EA on the tPA/BDNF pathway-related molecules in the hippocampi and raphe nuclei.ResultsCompared to the model group, the number of horizontal and vertical movements and the percentage of sucrose consumption in the EA groups were significantly increased (P < 0.01). Compared to the model group, HE staining showed that the hippocampal neurons in the EA and fluox groups were arranged neatly, with rich layers and complete cell structures. The Western blot and real-time PCR showed that the levels of tPA, BDNF, tropomyosin receptor kinase B, and BDNF micro RNA (mRNA) in the hippocampi of the EA group were higher than in the model group (P < 0.01, P < 0.01, P < 0.05, P < 0.01, respectively). The content of p75NTR, proBDNF, and tPA mRNA in the hippocampi of the EA group displayed no significant differences compared to the model group. The tPA mRNA content in the raphe nuclei of the EA group was higher than in the model group (P < 0.01), and the BDNF content in the raphe nuclei was lower than in the model group (P < 0.05). There were no significant differences in tPA and BDNF mRNA between the EA and model groups.ConclusionEA may reverse depressive-like behaviors in CUMS, which may be related to the tPA/BDNF pathway in the hippocampus.

Dl-3n-butylphthalide improves spatial learning and memory in rats with vascular dementia by reducing autophagy via regulation of the mTOR signaling pathway.

Dl-3n-butylphthalide (NBP) has been reported to be a beneficial and promising drug for the treatment and prevention of vascular dementia (VD). NBP has been demonstrated to improve learning and memory in rats with vascular cognitive impairment by activating the silent information regulator 1/brain-derived neurotrophic factor pathway. However, NBP is a multi-target drug. Therefore, the present study aimed to determine whether the protective effects of NBP on learning deficits in a rat model of VD were due to the inhibition of autophagy via the phosphorylated mammalian target of rapamycin (p-mTOR) pathway. NBP treatment attenuated memory damage in rats with VD, as demonstrated by T-maze and Morris water maze tests. NBP administration also significantly reduced the levels of the characteristic autophagic proteins Beclin 1 and LC3II and upregulated phosphorylation levels of mTOR at Ser-2448 compared with the VD group. However, treatment of rats with VD with NBP plus the mTOR inhibitor rapamycin failed to significantly suppress Beclin 1 and LC3II expression. These results suggested that the beneficial effects of NBP on learning deficits in a rat model of VD were due to the suppression of ischemia-induced autophagy via the p-mTOR signaling pathway.

Ellagic acid supports neuron by regulating astroglia Nrf2.

Astroglia support neuron by providing substrates for neuronal metabolism, glutamate clearance, and antioxidative protection. Nuclear factor erythroid 2-related factor 2 (Nrf2) participates in the antioxidative defense response. Also, Nrf2 signaling is recognized to activate the neurotrophic pathway to replace/protect damaged organelles. Ellagic acid (EA), an extraction component of fruits and nuts, presents many pharmacological activities such as anti-inflammation, antioxidation, and neuroprotection. However, few studies have been focused on the neurotrophic properties of EA. Our study investigated whether EA could increase neuronal survival and the target cells. Thus, primary neuron-enriched cultures and primary astroglia-enriched cultures were applied to detect whether EA-elicited neurotrophic effects were mediated by astroglia Nrf2. This study indicated that EA promoted neuronal survival. Further, astroglia Nrf2 participate in EA-elicited neuronal survival with the following scenarios. First, EA elicited astroglia proliferation, glial cell line-derived neurotrophic factor (GDNF) release, and Nrf2 activation. Second, after silencing astroglia Nrf2, EA-induced astrogliosis, GDNF release, and neuronal survival disappeared. Thus, EA-mediated astroglia Nrf2 activation is important to enhance neurotrophic effects on neurons, which might provide new insights for neurodegenerative disease.

The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration.

We recently demonstrated that NLY01, a novel glucagon-like peptide-1 receptor agonist, exerts neuroprotective effects in two mouse models of PD in a glia-dependent manner. NLY01 prevented microglia from releasing inflammatory mediators known to convert astrocytes into a neurotoxic A1 reactive subtype. Importantly, we provided evidence that this neuroprotection was not mediated by a direct action of NLY01 on neurons or astrocytes (e.g., by activating neurotrophic pathways or modulating astrocyte reactivity per se). In the present article, we provide a generalist review of microglia and astrocytes in neurodegeneration and discuss the emerging paradigm of A1 astrocyte neurotoxicity in more detail. We comment on specific inferences that are naturally suggested by our work in this area and the differential level of support it offers to each. Finally, we discuss implications for the overall goal of creating disease-modifying therapies for PD, survey emerging methodologies for accelerating translational research on glia in neurodegeneration, and describe expected challenges for developing glia-directed therapies that do not impede essential physiological functions carried out by glia in the CNS. © 2019 International Parkinson and Movement Disorder Society.

Involvement of hippocampal miR-664-3p in electroacupuncture induced improvement of learning-memory ability of cerebral ischemia-reperfusion rats

To explore the effect of electroacupuncture (EA) on learning-memory ability and its correlation with miR-664-3p levels in the hippocampus in cerebral ischemia-reperfusion injury (CI/RI) rats. A total of 27 male SD rats were randomly divided into sham operation, CI/RI model and EA groups (n＝9 in each group). The CI/RI model was established by occlusion of the middle cerebral artery (MACO) according to the modified Longa methods. EA was applied to "Baihui" (GV20) and "Shenting" (GV24) for 20 min, once a day for 7 days. The Morris water maze tests (place navigation tasks and spatial probe trials) were used to evaluate the rats' learning-memory ability. After EA intervention, the hippocampal tissue was collected to measure the mRNA and miRNA expression profiles by using high-throughput next generation sequencing. Bioinformatics analyses including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to screen the most abundant differentially-expressed miRNAs and mRNAs, particularly the target genes of miR-664-3p. Their biological functional categories including the key biochemical metabolic pathways and signaling pathways involved in CI and EA effect in the left hippocampus tissue were analyzed. The average escape latency of place navigation tests was significantly longer in the CI/RI model group than in the sham operation group (P<0.01), and obviously shorter in the EA group than in the model group (P<0.01); and the times of escape-platform quadrant crossing of the spatial probe trials were considerably fewer in the CI/RI model group than in the sham operation group (P<0.05), and markedly more in the CI/RI EA group than in the model group (P<0.05). Combined analysis of miRNA and mRNA showed that the differentially-expressed target genes of miR-664-3p were significantly up-regulated after CI/RI relevant to the sham operation rats (P<0.05) and notably down-regulated in the EA group relevant to the CI/RI model group (P<0.05). The GO analysis displayed that the target genes of miR-664-3p were significantly enriched in the category of cell transportation activity, ion binding，and transmembrane transporter activity, the production of precursor metabolites and energy, transportation, signal transduction，localization, etc. KEGG analysis showed that the target genes of miR-664-3p in this study were mainly enriched in the thyroid hormone pathway, Hippo signaling pathway, MAPK signal transduction pathway，cAMP signaling pathway, neurotrophic factor signal transduction pathway, etc. EA of GV20 and GV24 can improve the learning-memory ability of CI/RI rats, which is closely related to its effect in down-regulating the levels of hippocampal target genes of miR-664-3p involving cellular transmembrane transportation，cell to environment interaction，cell-cell communication, etc.

Methanol stem bark extract of Adansonia digitata ameliorates chronic unpredictable mild stress-induced depression-like behavior: Involvement of the HPA axis, BDNF, and stress biomarkers pathways.

Background Adansonia digitata L. (Malvaceae) is used locally in the management of depressive illnesses, and its antidepressant-like effect has been previously reported. The present study was aimed at determining the effect of the methanol extract of the stem bark of A. digitata (MEAD) on chronic unpredictable mild stress (CUMS) and the possible mechanism responsible for its antidepressant activity. Methods Acute toxicity of MEAD was determined using the OECD guideline 420. The CUMS model was used to induce depression, and behavioral tests such as sucrose preference test (SPT), open field test (OFT), novel-object recognition test (NORT), and tail suspension test (TST) were carried out in mice. The concentrations of plasma cortisol and brain-derived neurotrophic factor (BDNF) protein in the brain were assessed using enzyme-linked immunosorbent assay kits. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were assessed using colorimetric methods. Results The LD50 was established to be ≥5000 mg/kg. On CUMS-induced depression, MEAD significantly (p ≤ 0.05) and dose dependently reversed the weight loss, increased the line-crossing activity in OFT, increased sucrose consumption in SPT, decreased the duration of immobility in TST, and increased the novelty exploration time in NORT. The MEAD extract significantly (p ≤ 0.05) and dose dependently increased the levels of BDNF, decreased the levels of plasma cortisol, increased the levels of total SOD activity, and decreased the levels of plasma MDA. Conclusion Our findings show that MEAD ameliorates CUMS-induced depressive-like behavior and its effect is possibly mediated via the neuroendocrine, neurotrophic, and oxidative stress pathways.

Adeno-associated virus-mediated over-expression of CREB-regulated transcription coactivator 1 in the hippocampal dentate gyrus ameliorates lipopolysaccharide-induced depression-like behaviour in mice.

Depression is a highly complex global disabling psychiatric disorder. Unfortunately, the currently available antidepressants are not effective in a significant percentage of patients. Therefore, the underlying mechanisms of depression must be explored at the molecular level to discover new candidate molecular targets for depression treatment. Behavioural and molecular depression-like endophenotypes have been observed in cyclic AMP response element-binding protein-regulated transcription coactivator 1 (Crtc1) knockout mice; however, the underlying mechanism for these endophenotypes remains unclear. This work investigated the role of hippocampal CREB-regulated transcription coactivator 1 (CRTC1) in depression using a recombinant adeno-associated virus (AAV) system to alter Crtc1 gene expression and explore its potential mechanism. We found that shRNA-mediated Crtc1 gene knockdown (AAV-shCRTC1) in the dentate gyrus regions of the ventral hippocampus directly resulted in depression-like behaviours and down-regulation ofbrain-derived neurotrophic factor and neuropeptide VGF levels. A widely used depression model induced by lipopolysaccharide administration (0.5mg/kg, i.p.) was applied in our study and was validated by increased immobility time in the tail-suspension and forced swim tests and decreased sucrose consumption in the sucrose preference test. Importantly, CRTC1 over-expression mediated by AAV-CRTC1 in the ventral dentate gyrus regions prevented lipopolysaccharide-induced depressive-like behaviours, the down-regulation of brain-derived neurotrophic factor and VGF, and the accumulation of pro-inflammatory cytokines such as interleukin-6, interleukin 1-β and tumour necrosis factor α in mice. Together, our findings indicate that CRTC1 is a key factor in depression-like behaviour and provide an important reference for finding a novel drug target in the neuroinflammatory and neurotrophic pathways for curing depressive disorders. Cover Image for this issue: doi: 10.1111/jnc.14500.

Treadmill Exercise Alleviates Circadian Rhythm Disruption-Induced Memory Deficits by Activation of Glucocorticoid Receptor and Brain-Derived Neurotrophic Factor-Dependent Pathway.

PurposeCircadian rhythm affects learning process, memory consolidation, and long-term memory. In this study, the alleviating effect of exercise on circadian rhythm disruption-induced memory deficits was investigated.MethodsBMAL1 knockdown transgenic mice (BMAL1 TG) were used as the BMAL1-TG group and the BMAL1-TG with treadmill exercise group. Female C57BL/6J mice of the same age were used as the wildtype group and the wildtype with treadmill exercise group. The mice in the treadmill exercise groups performed running on a motorized treadmill under the dark-dark conditions for 8 weeks. Short-term memory, nonspatial object memory, and spatial learning memory were determined using stepdown avoidance test, novel object-recognition test, and radial 8-arm maze test. Immunohistochemistry for doublecortin and 5-bromo-2’-deoxyuridine was conducted for the determination of hippocampal neurogenesis. Using the western blot analysis, we determined the expressions of glucocorticoid receptor (GR) and factors related to the neurogenesis and memory consolidation, such as brain-derived neurotrophic factor, tyrosine kinase B, p44/42 mitogen-activated protein kinase, cyclic AMP-responsive element binding protein, phosphatidylinositol 3-kinase, protein kinas B, protein kinase C alpha, early-growth-response gene 1.ResultsCircadian rhythm disruption impaired memory function through inhibiting the expressions of GR and the factors related to neurogenesis and memory consolidation. Treadmill exercise improved memory function via enhancing the expressions of GR and above-mentioned factors.ConclusionsTreadmill exercise acts as the zeitgeber that improves memory function under the circadian rhythm disrupted conditions.

The memory improving effects of round scad (Decapterus maruadsi) hydrolysates on sleep deprivation-induced memory deficits in rats via antioxidant and neurotrophic pathways.

Sleep deprivation negatively influences memory formation and consolidation, which leads to memory impairment associated with oxidative stress and neurotrophic pathways. In this study, a sleep-deprived rat model was used to evaluate the protective effects of round scad hydrolysates (RSH, 333 and 666 mg per kg bw) on memory impairment and the underlying mechanisms. The result of the Morris water maze test revealed that RSH significantly reversed the cognition deficits induced by sleep deprivation. Moreover, RSH supplementation alleviated oxidative stress by increasing the activities of glutathione peroxidase and superoxide dismutase and the ratio of glutathione/oxidized glutathione in the brain. Furthermore, RSH significantly up-regulated the expression of antioxidant defense-related proteins, including nuclear factor E2-related factor 2 (Nrf2) and its downstream heme oxygenase-1 (HO-1), as well as the phosphorylation of Akt in rats. Moreover, RSH improved the expression of brain-derived neurotrophic factor (BDNF), the phosphorylation of cAMP response element-binding (CREB) and tropomyosin-related kinase B (TrkB) in vivo, indicating that RSH can also promote the expression of proteins related to the neurotrophic pathway. Additionally, UPLC-qTOF-MS/MS was further used to identify the peptides in RSH. The results indicated that RSH mainly consists of low molecular weight peptides with hydrophobic, aromatic and positively charged amino acids in sequence. Taken together, these findings demonstrate that RSH exerts memory-improving actions by regulating the antioxidant and neurotrophic pathways, and RSH can be a potential functional ingredient for the prevention and protection of cognitive deficits.

Brain-derived Neurotrophic Factor Pathway after Downhill and Uphill Training in Rats

The elevation of brain-derived neurotrophic factor (BDNF) levels in the brain and the subsequent phosphorylation of its cognate tropomyosin-related kinase B (TrkB) receptors at tyrosine 816 (pTrkB) are largely involved in the positive effect of aerobic exercise on brain functioning. Although BDNF levels were reported to increase in proportion with exercise intensity, the effect of the type of contraction is unknown. Therefore, the cerebral BDNF/TrkB pathway was investigated after uphill and downhill treadmill activities at equivalent intensity to preferentially induce eccentric and concentric contractions, respectively. A treadmill activity (30 min·d for seven consecutive days) either in a horizontal position at two different speeds to modulate intensity (experiment 1) or at three different inclinations (null, -10%, and +5%) but at equivalent intensity to modulate the type of contraction (experiment 2) was induced in rats. Both experiments included sedentary rats. Levels of BDNF, pTrkB, synaptophysin (marker of synaptogenesis), endothelial nitric oxide synthase phosphorylated at serine 1177 (peNOS), and c-fos levels (indicators of elevation in blood flow in the cerebrovasculature and neuronal activity, respectively) were measured in motor- and cognition-related brain regions using Western blotting analysis. Experiment 1 indicated that treadmill activity induces an intensity-dependent increase in peNOS, c-fos, and BDNF levels. Experiment 2 showed that intensity of exercise as well as activation of the cerebral BDNF pathway, and synaptogenesis did not differ among horizontal, uphill, and downhill treadmill activities. The cerebral response of the BDNF pathway to a treadmill activity is dependent on exercise intensity, but not on the type of contraction (eccentric vs concentric).