BDNF mRNA Levels Research Articles

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity.

Early life stress compromises brain development and can contribute to the development of mental illnesses. A common animal model used to study different facets of psychiatric disorders is social isolation from early life on. In rats, this isolation can induce long-lasting alterations in molecular expression and in behavior. Since social isolation models severe psychiatric symptoms, it is to be expected that it affects the overall wellbeing of the animals. As also promoted by the 3Rs principle, though, it is pivotal to decrease the burden of laboratory animals by limiting the number of subjects (reduce, replace) and by improving the animals’ wellbeing (refine). The aim of this study was therefore to test possible refinement strategies such as resocialization and mere adult social isolation. We examined whether the alternatives still triggered the necessary phenotype while minimizing the stress load on the animals. Interestingly, we did not find reduced wellbeing-associated burrowing performance in isolated rats. The hyperactive phenotype seen in socially isolated animals was observed for rats undergoing the adult-only isolation, but resocializing ameliorated the locomotor abnormality. Isolation strongly affected markers of neuroplasticity in the prefrontal cortex independent of timing: mRNA levels of Arc, Bdnf and the pool of Bdnf transcripts with the 3’ long UTR were reduced in all groups. Bdnf splice variant IV expression was reduced in lifelong-isolated animals. Some of these deficits normalized after resocialization; likewise, exon VI Bdnf mRNA levels were reduced only in animals persistently isolated. Conversely, social deprivation did not affect the expression of Gad67 and Pvb, two GABAergic markers, whereas changes occurred in the expression of dopamine d1 and d2 receptors. As adult isolation was sufficient to trigger the hyperactive phenotype and impaired neuroplasticity in the prefrontal cortex, it could be a candidate for a refinement strategy for certain research questions. To fully grade the severity of post-weaning social isolation and the alternatives, adult isolation and resocialization, a more profound and multimodal assessment approach is necessary.

Leptin regulates exon-specific transcription of the Bdnf gene via epigenetic modifications mediated by an AKT/p300 HAT cascade

Leptin is an adipocyte-derived hormone with pleiotropic functions affecting appetite and mood. While leptin’s role in the regulation of appetite has been extensively studied in hypothalamic neurons, its function in the hippocampus, where it regulates mood-related behaviors, is poorly understood. Here, we show that the leptin receptor (LepRb) colocalizes with brain-derived neurotrophic factor (BDNF), a key player in the pathophysiology of major depression and the action of antidepressants, in the dentate gyrus of the hippocampus. Leptin treatment increases, whereas deficiency of leptin or leptin receptors decreases, total Bdnf mRNA levels, with distinct expression profiles of specific exons, in the hippocampus. Epigenetic analyses reveal that histone modifications, but not DNA methylation, underlie exon-specific transcription of the Bdnf gene induced by leptin. This is mediated by stimulation of AKT signaling, which in turn activates histone acetyltransferase p300 (p300 HAT), leading to changes in histone H3 acetylation and methylation at specific Bdnf promoters. Furthermore, deletion of Bdnf in the dentate gyrus, or specifically in LepRb-expressing neurons, abolishes the antidepressant-like effects of leptin. These findings indicate that leptin, acting via an AKT-p300 HAT epigenetic cascade, induces exon-specific Bdnf expression, which in turn is indispensable for leptin-induced antidepressant-like effects.

Hypertriglyceridemia-induced brain-derived neurotrophic factor in rat submandibular glands

ObjectivesSalivary glands produce brain-derived neurotrophic factor (BDNF), which increases plasma BDNF content. Salivary BDNF influences the hippocampus and enhances anxiety-like behaviors. Dyslipidemia affects the brain, promoting depression and anxiety-like behaviors. This study was performed to investigate whether hypertriglyceridemia influences salivary BDNF expression. MethodsHypertriglyceridemia was induced in rats by high-fat diet intake for 10 weeks. BDNF protein levels in the saliva and submandibular glands were measured using enzyme-linked immunosorbent assay (ELISA). Bdnf mRNA levels in the submandibular gland were determined using real-time polymerase chain reaction. ResultsA hypertriglyceridemia rat model was established. Body weight did not differ between the control and hypertriglyceridemia groups. Bdnf mRNA and protein expression was increased in the submandibular gland in the hypertriglyceridemia group compared to the control group. BDNF expression was also significantly increased in the saliva of the hypertriglyceridemia group. ConclusionsThis is first study to show that hypertriglyceridemia induces BDNF expression in the rat submandibular gland and suggests that salivary BDNF is associated with lipid metabolism.

Electroacupuncture Modulates Spinal BDNF/TrκB Signaling Pathway and Ameliorates the Sensitization of Dorsal Horn WDR Neurons in Spared Nerve Injury Rats.

Neuropathic pain is more complex and severely affects the quality of patients’ life. However, the therapeutic strategy for neuropathic pain in the clinic is still limited. Previously we have reported that electroacupuncture (EA) has an attenuating effect on neuropathic pain induced by spared nerve injury (SNI), but its potential mechanisms remain to be further elucidated. In this study, we designed to determine whether BDNF/TrκB signaling cascade in the spinal cord is involved in the inhibitory effect of 2 Hz EA on neuropathic pain in SNI rats. The paw withdrawal threshold (PWT) of rats was used to detect SNI-induced mechanical hypersensitivity. The expression of BDNF/TrκB cascade in the spinal cord was evaluated by qRT-PCR and Western blot assay. The C-fiber-evoked discharges of wide dynamic range (WDR) neurons in spinal dorsal horn were applied to indicate the noxious response of WDR neurons. The results showed that 2 Hz EA significantly down-regulated the levels of BDNF and TrκB mRNA and protein expression in the spinal cord of SNI rats, along with ameliorating mechanical hypersensitivity. In addition, intrathecal injection of 100 ng BDNF, not only inhibited the analgesic effect of 2 Hz EA on pain hypersensitivity, but also reversed the decrease of BDNF and TrκB expression induced by 2 Hz EA. Moreover, 2 Hz EA obviously reduced the increase of C-fiber-evoked discharges of dorsal horn WDR neurons by SNI, but exogenous BDNF (100 ng) effectively reversed the inhibitory effect of 2 Hz EA on SNI rats, resulting in a remarkable improvement of excitability of dorsal horn WDR neurons in SNI rats. Taken together, these data suggested that 2 Hz EA alleviates mechanical hypersensitivity by blocking the spinal BDNF/TrκB signaling pathway-mediated central sensitization in SNI rats. Therefore, targeting BDNF/TrκB cascade in the spinal cord may be a potential mechanism of EA against neuropathic pain.

Sigma-1 (σ1) receptor activity is necessary for physiological brain plasticity in mice

The sigma-1 receptor (S1R) is a membrane-associated protein expressed in neurons and glia at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs). S1R interacts with different partners to regulate cellular responses, including ER stress, mitochondrial physiology and Ca2+ fluxes. S1R shapes cellular plasticity by directly modulating signaling pathways involved in inflammatory responses, cell survival and death. We here analyzed its impact on brain plasticity in vivo, in mice trained in a complex maze, the Hamlet test. The device, providing strong enriched environment (EE) conditions, mimics a small village. It has a central agora and streets expanding from it, leading to functionalized houses where animals can Drink, Eat, Hide, Run, or Interact. Animals were trained in groups, 4 h/day for two weeks, and their maze exploration and topographic memory could be analyzed. Several groups of mice were considered: non-trained vs. trained; repeatedly administered with saline vs. NE-100, a selective S1R antagonist; and wildtype vs. S1R KO mice. S1R inactivation altered maze exploration and prevented topographic learning. EE induced a strong plasticity measured through resilience to behavioral despair or to the amnesic effects of scopolamine, and increases in S1R expression and bdnf mRNA levels in the hippocampus; increases in neurogenesis (proliferation and maturation); and increases of histone acetylation in the hippocampus and cortex. S1R inactivation altered all these parameters significantly, showing that S1R activity plays a major role in physiological brain plasticity. As S1R is a major resident protein in MAMs, modulating ER responses and mitochondrial homeostasy, MAM physiology appeared impacted by enriched environment.

Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer's Disease.

The nicotinic derivatives, cotinine (COT), and 6-hydroxy-L-nicotine (6HLN), showed promising cognitive-improving effects without exhibiting the nicotine’s side-effects. Here, we investigated the impact of COT and 6HLN on memory impairment and the oxidative stress in the Aβ25-35-induced rat model of Alzheimer’s disease (AD). COT and 6HLN were chronically administered to Aβ25-35-treated rats, and their memory performances were assessed using in vivo tasks (Y-maze, novel object recognition, and radial arm maze). By using in silico tools, we attempted to associate the behavioral outcomes with the calculated binding potential of these nicotinic compounds in the allosteric sites of α7 and α4β2 subtypes of the nicotinic acetylcholine receptors (nAChRs). The oxidative status and acetylcholinesterase (AChE) activity were determined from the hippocampal tissues. RT-qPCR assessed bdnf, arc, and il-1β mRNA levels. Our data revealed that COT and 6HLN could bind to α7 and α4β2 nAChRs with similar or even higher affinity than nicotine. Consequently, the treatment exhibited a pro-cognitive, antioxidant, and anti-AChE profile in the Aβ25-35-induced rat model of AD. Finally, RT-qPCR analysis revealed that COT and 6HLN positively modulated the bdnf, arc, and il-1β genes expression. Therefore, these nicotinic derivatives that act on the cholinergic system might represent a promising choice to ameliorate AD conditions.

Reciprocal Interplay Between Astrocytes and CD4+ Cells Affects Blood-Brain Barrier and Neuronal Function in Response to β Amyloid.

Background: In Alzheimer’s disease (AD) neuronal degeneration is associated with gliosis and infiltration of peripheral blood mononuclear cells (PBMCs), which participate in neuroinflammation. Defects at the blood-brain barrier (BBB) facilitate PBMCs migration towards the central nervous system (CNS) and in particular CD4+ T cells have been found in areas severely affected in AD. However, the role of T cells, once they migrate into the CNS, is not well defined. CD4+ cells interact with astrocytes able to release several factors and cytokines that can modulate T cell polarization; similarly, astrocytic properties are modulated after interaction with T cells.Methods: In in vitro models, astrocytes were primed with β-amyloid (Aβ; 2.5 μM, 5 h) and then co-cultured with magnetically isolated CD4+ cells. Cytokines expression was evaluated both in co-cultured CD4+ cells and astrocytes. The effects of this crosstalk were further evaluated by co-culturing CD4+ cells with the neuronal-like SH-SY5Y cell line and astrocytes with endothelial cells.Results: The pattern of cytokines and trophic factors expressed by CD4+ cells were strongly modulated in the presence of Aβ-primed astrocytes. Specifically, the percentage of IL-4+ and IFNγ+ CD4+ cells was significantly increased and reduced, respectively. Further, increased BDNF mRNA levels were observed in CD4+ cells. When SH-SY5Y cells were co-cultured with astrocyte-conditioned CD4+ cells and exposed to Aβ, the reduction of the presynaptic protein synaptophysin was prevented with a BDNF-dependent mechanism. In astrocytes co-cultured with CD4+ cells, reduced mRNA levels of inflammatory cytokines and VEGF were observed. This was paralleled by the prevention of the reduction of claudin-5 when astrocytes were co-cultured with endothelial cells.Conclusion: Following Aβ exposure, there exists reciprocal crosstalk between infiltrating peripheral cells and astrocytes that in turn affects not only endothelial function and thus BBB properties, but also neuronal behavior. Since astrocytes are the first cells that lymphocytes interact with and are among the principal players in neuroinflammation occurring in AD, understanding this crosstalk may disclose new potential targets of intervention in the treatment of neurodegeneration.

Salvianolic Acid B improves cognitive impairment by inhibiting neuroinflammation and decreasing Aβ level in Porphyromonas gingivalis-infected mice.

Amyloid-β (Aβ) accumulation is one of the main pathological hallmarks of Alzheimer’s disease (AD). Porphyromonas gingivalis (P. gingivalis), the pathogen of chronic periodontitis, could cause Aβ accumulation and was identified in the brain of AD patients. Salvianolic Acid B (SalB) has been proven to have the neuroprotective effect. Whether SalB could protect against P. gingivalis-induced cognitive impairment is still unknown. In this study, a P. gingivalis-infected mouse model was employed to study the neuroprotective role of SalB. The results showed that SalB (20 and 40 mg/kg) treatment for 4 weeks could shorten the escape latency and improve the percentage of spontaneous alternation in the P. gingivalis-infected mice. SalB inhibited the levels of reactive oxygen species and malondialdehyde, while increased the levels of antioxidative enzymes (superoxide dismutase and glutathione peroxidase). SalB decreased the levels of IL-1β and IL-6, increased the mRNA levels of bdnf and ngf in the brain of P. gingivalis-infected mice. In addition, SalB obviously decreased the level of Aβ. SalB elevated the protein expression of ADAM10, while downregulated BACE1 and PS1. SalB increased the protein expression of LRP1, while decreased RAGE. In conclusion, SalB could improve cognitive impairment by inhibiting neuroinflammation and decreasing Aβ level in P. gingivalis-infected mice.

The selenocompound 1-methyl-3-(phenylselanyl)-1H-indole attenuates depression-like behavior, oxidative stress, and neuroinflammation in streptozotocin-treated mice

Major depressive disorder (MDD) is a chronic mental illness affecting a wide range of people worldwide. The pathophysiology of MDD is not completely elucidated, but it is believed that oxidative stress and neuroinflammation are involved. In light with this, the aim of the present study was to investigate whether a single administration of the antioxidant 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI) was able to reverse the streptozotocin-induced depression-like behavior, oxidative stress, and neuroinflammation in mice. MFSeI (10 mg/kg) was administered intragastrically (i.g.) 24 h after the intracerebroventricular injection of STZ (0.2 mg/4 μL/per mouse). Thirty minutes after MFSeI administration, behavioral tests and neurochemical analyses were performed. Fluoxetine (10 mg/kg, i.g.) was used as a positive control. MFSeI and fluoxetine were able to reverse the STZ-induced depression-like behavior, as evidenced by decreased immobility time in the forced swimming test and increased grooming time in the splash test. Mechanistically, MFSeI reversed the increased levels of reactive species and lipid peroxidation in the prefrontal cortices and hippocampi of STZ-treated mice. Additionally, neuroinflammation (i.e. expression of NF-κB, IL-1β, and TNF-α) and the reduced mRNA levels of BDNF in the and hippocampi of depressed mice were reversed by treatment with MFSeI. Fluoxetine did not improve the STZ-induced alterations at the levels of reactive species, NF-κB and BDNF in the prefrontal cortices neither the levels of TNF-α in both brain regions. Together, these data suggest that the MFSeI may be a promising compound with antidepressant-like action, reducing oxidative stress and modulating inflammatory pathways in the brain of depressed mice.

Neonatal DEX exposure leads to hyperanxious and depressive-like behaviors as well as a persistent reduction of BDNF expression in developmental stages

Brain-derived neurotrophic factor (BDNF), which regulates the neuronal survival, differentiation and synaptic plasticity, has been proved to play a critical role in the pathology and treatment of several psychiatric disorders including depression. Dexamethaone (DEX) is indicated for a number of conditions in perinatal medicine, however, the long-term impact of early-life DEX exposure on BDNF expression in hippocampus remains unknown. Here we found that neonatal DEX(ND) exposure leads to insignificant change of BDNF expression levels in the adulthood, albeit increased hyperanxious and depressive-like behaviors. However, the bdnf mRNA and BDNF protein levels were significantly reduced in all the hippocampal subregions during the developmental stages, including the perinatal period and puberty. We conclude that early life DEX exposure leads to a persistent disturbance of BDNF signaling during the developmental stages, which might be associated with the life-long impairment of hippocampal function.

Brain-derived neurotrophic factor in 5-HT neurons regulates susceptibility to depression-related behaviors induced by subchronic unpredictable stress

Chronic stress is a major risk factor for the development of depression. Brain-derived neurotrophic factor (BDNF) plays an important role in neural functions and exhibits antidepressant effects. However, studies on depression-related behavioral response to BDNF have mainly focused on the limbic system, whereas other regions of the brain still require further exploration. Here, we report that exposure to chronic unpredictable stress (CUS) can induce depression-associated behaviors in mice. CUS could decrease total Bdnf mRNA and protein levels in the dorsal raphe nucleus (DRN), which correlated with depression-related behaviors. A corresponding reduction in exon-specific Bdnf mRNA was observed in the DRN of CUS mice. Bdnf was highly expressed in 5- Hydroxytryptamine (5-HT) neurons from the DRN. Selective deletion of Bdnf in 5-HT neurons alone could not induce anhedonia and behavioral despair in male or female mice, as indicated by the unchanged female urine sniffing time and preference for sucrose/saccharin. However, it could increase the latency to food in female mice, but not in male mice as shown by novelty-suppressed food test. Nevertheless, enhanced stress-induced susceptibility is observed in these male mice as suggested by the decrease in female urine sniffing time, and for female mice by the reduced sucrose preference and increased immobility in forced swim test. Furtherly, total Bdnf mRNA levels in DRN were correlated with depression-related behaviors of female, but not male 5-HT neurons specific Bdnf knockout mice. Our results indicate that BDNF might act on 5-HT neurons to regulate depression-related behaviors and stress vulnerability in a sex-dependent manner.

GPR39 protects against corticosterone-induced neuronal injury in hippocampal cells through the CREB-BDNF signaling pathway

BackgroundThe release of zinc from glutamatergic terminals in the hippocampal CA3 region can activate postsynaptic GPR39 receptors and regulate cognition and depression. However, the role and mechanism of GPR39 in the stress-induced depression is still poorly understood. MethodsIn this study, hippocampal cells (HT-22) were treated with corticosterone (CORT). Then the effects of stress on the activity, mitochondrial function and apoptosis of HT-22 cells were observed. The effects of GPR39 on CORT-induced stress injury were analyzed by both siRNA and agonist (TC-G-1008). ResultsCompared with the 500 nM CORT group, the cell viability, apoptosis, mitochondrial membrane potential, and expression levels of BCL-2, CREB and BDNF mRNA were significantly decreased in the GPR39 siRNA+500 nM CORT group, while the expression levels of caspase3, caspase9, AIF and BAX mRNA were significantly increased in the GPR39 siRNA+500 nM CORT group. Compared with the 1 μM CORTgroup, the cell viability, apoptosis, mitochondrial membrane potential, and expression levels of BCL-2, CREB and BDNF were significantly increased in the GPR39 agonist+1 μΜ CORT group, while the expression levels of caspase3, caspase9, AIF and BAX mRNA were significantly decreased in the GPR39 siRNA+500 nM CORT group. Compared with the control group, the mRNA and protein levels of GPR39, CREB and BDNF were significantly increased, and the mRNA and protein levels of CREB and BDNF were significantly decreased after 50 μM zinc sulfate treatment for 6 h. ConclusionsGPR39 may play a neuroprotective role in CORT-induced cell injury via the improvement of CREB-BDNF expression, by inhibiting pro-apoptotic proteins and by upregulating anti-apoptotic proteins.

Piperine ameliorated memory impairment and myelin damage in lysolecethin induced hippocampal demyelination

AimsWe still do not have effective treatment for hippocampal demyelination and memory deficit, the two common comorbidities in multiple sclerosis (MS). This study aimed to assess the therapeutic effect of Piperine (the main alkaloid of black pepper) in an experimental model of demyelination. Main methodsDemyelination was induced in male Wistar rats by bilateral injection of lysolecithin (LPC) into the CA1 region of the hippocampus. Piperine (5, 10, 20 mg/kg) was daily injected intraperitoneally three days post LPC injection for ten days. The spatial memory was examined by the Morris water maze task. Demyelination and astrocyte activation were assessed by an immunohistological study. The gene expression analysis of TNF-α, IL1-β, NF-κB, IL-10, Foxp3, iNOS, Nrf2, HO1, MBP, and BDNF was done using qPCR. The total antioxidant capacity of hippocampal tissue was measured using FRAP assay. Key findingsOur results showed that piperine improved the memory performance and myelin repair in the hippocampal demyelination model. Piperine inhibited iNOS expression concomitant with enhanced expression levels of Nrf2, HO1 and the total antioxidant capacity in the hippocampal tissue. Piperine treatment significantly reduced the gene expression level of TNF-α, IL1-β, NF-κB, and glial activation in the injured area; however, the mRNA level of IL-10, Foxp3, BDNF and MBP were significantly increased. SignificanceWe found piperine to be an effective treatment for spatial memory impairment and myelin repair in the hippocampal demyelination model. However, further experimental evidence is needed to investigate the precise mechanisms underlying piperine as a promising therapeutic target in MS patients.

On the interaction between BDNF and serotonin systems: The effects of long-term ethanol consumption in mice.

We investigated the effect of chronic (6 weeks) consumption of 10% alcohol on the principal elements of BDNF (BDNF, proBDNF, p75, and TrkB receptors) and 5-HT (5-HT, 5-HIAA, tryptophan hydroxylase-2 [Tph-2], 5-HT transporter [5-HTT], 5-HT1A, 5-HT2A, and 5-HT7 receptors) systems in the brain of C57Bl/6 mice. BDNF mRNA level in the raphe nuclei area and BDNF protein level in the hippocampus were lowered in ethanol-treated mice. The increase in proBDNF protein level in the raphe nuclei area, cortex, and amygdala and the increase of p75 receptor protein levels in the raphe nuclei area were revealed after ethanol exposure. Alcohol intake reduced the protein level and increased the activity of Tph-2, the key enzyme for serotonin biosynthesis in the brain, and increased the main 5-HT metabolite 5-HIAA level and 5-HIAA/5-НТ ratio as well as the 5-HT7 receptor mRNA level in the raphe nuclei area. In the cortex, 5-HT2A receptor protein level was reduced, and 5-HIAA/5-HT ratio was increased. These data showed considerable impact of alcoholization on the BDNF system, resulting in proBDNF and p75 receptor expression enhancement. Alcohol-induced changes in BDNF and 5-HT systems were revealed in the raphe nuclei area where the majority of the cell bodies of the 5-HT neurons are localized, as well as in the cortex, hippocampus, and amygdala. Our data suggest that the BDNF/5-HT interaction contributes to the mechanism underlying chronic alcohol-induced neurodegenerative disorders.

7,8-Dihydroxyflavone alleviated the high-fat diet and alcohol-induced memory impairment: behavioral, biochemical and molecular evidence.

Alcoholism and obesity impart a deleterious impact on human health and affects the quality of life. Chronic consumption of alcohol and western diet has been reported to cause memory deficits. 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, comprises antioxidant and anti-inflammatory properties in treating various neurological disorders. The current study was aimed to determine the protective effect and molecular mechanism of 7,8-DHF against alcohol and high-fat diet (HFD)-induced memory deficits in rats. The adult male Wistar rats were given alcohol (3-15%) and HFD ad libitum for 12weeks in different experimental groups. 7,8-DHF (5mg/kg) was intraperitoneally injected daily for the last 4weeks (9th-12th week). The alcohol and HFD administration caused cognitive impairment as evaluated through the Morris water maze (MWM) test in alcohol, HFD, and alcohol + HFD-fed animals. The last 4-week treatment of 7,8-DHF (5mg/kg; i.p.) attenuated alcohol and HFD-induced memory loss. 7,8-DHF treatment also restored the glutathione (GSH) level along with attenuation of nitrite, malondialdehyde content (markers of oxidative and nitrosative stress), and reduction of the acetylcholinesterase activity in the hippocampus of alcohol and HFD-fed animals. Furthermore, the administration of 7,8-DHF caused downregulation of NF-κB, iNOS, and caspase-3 and upregulation of Nrf2, HO-1, and BDNF mRNA level in rat hippocampus. 7,8-DHF administration conferred beneficial effects against alcohol and HFD-induced memory deficit via its unique antioxidant, anti-inflammatory, anti-apoptotic potential, along with the activation of TrkB/BDNF signaling pathway in the hippocampus.

Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration.

Background: Rapid-acting antidepressants ketamine and (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) have overcome some of the major limitations of classical antidepressants. However, little is known about sex-specific differences in the behavioral and molecular effects of ketamine and (2R,6R)-HNK in rodents. Methods: We treated mice with an intraperitoneal injection of either saline, ketamine (30 mg kg−1) or (2R,6R)-HNK (10 mg kg−1). We performed a comprehensive behavioral test battery to characterize the Arc-CreERT2 × CAG-Sun1/sfGFP mouse line which enables targeted recombination in active populations. We performed a molecular study in Arc-CreERT2 × CAG-Sun1/sfGFP female mice using both immunohistochemistry and in situ hybridization. Results: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in sociability and anxiety tests. Moreover, ketamine and (2R,6R)-HNK had opposite effects in the forced swim test (FST) depending on gender. In addition, in male mice, ketamine-treated animals were less immobile compared to (2R,6R)-HNK, thus showing a different profile of the two drugs in the FST. At the molecular level we identified Bdnf mRNA level to be increased after ketamine treatment in female mice. Conclusion: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in social and anxiety behavior and a different pattern between ketamine and (2R,6R)-HNK in the FST in male and female mice. At the molecular level, female mice treated with ketamine showed an increase of Bdnf mRNA level, as previously observed in male mice.

Long noncoding RNA GAS5 enhanced by curcumin relieves poststroke depression by targeting miR-10b/BDNF in rats.

The treatment for post-stroke depression (PSD) is mainly based on a therapeutic strategy combining anti-stroke and anti-depressant drugs. In the present study, the therapeutic effect of curcumin on rats with PSD was detected by open field tests and tail suspension tests, as well as the examination of corticosterone and corticotropin-releasing hormone (CRH) levels in the serum and neurotransmitter 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and dopamine (DA) levels in the hippocampus. Curcumin notably alleviated depression compared to the controls. Furthermore, long noncoding RNA growth arrest-specific transcript 5 (GAS5) enhanced by curcumin contributed to activation of the BDNF/Trkβ signaling pathway to promote the expression of synaptic-related proteins. GAS5 was demonstrated to function as a sponge of miR-10b. GAS5 upregulation by curcumin could reduce miR-10b to compromise the BDNF mRNA levels. Taken together, these results revealed a novel mechanism of curcumin on PSD through the GAS5/miR-10b/BDNF regulatory axis.

Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome

The methyl-CpG-binding protein 2 gene, MECP2, is an X chromosome-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). Previous study has shown that re-expression of SUMO-modified MeCP2 in Mecp2-null neurons rescues synaptic and behavioral deficits in Mecp2 conditional knockout mice, whereas about 12-fold decrease in Wnt6 mRNA level was found in MeCP2K412R sumo-mutant mice. Here, we examined the role of Wnt6 in MeCP2 T158A mouse model of RTT. Results show that lentiviral delivery of Wnt6 to the amygdala ameliorates locomotor impairment and social behavioral deficits in these animals. MeCP2 T158A mice show decreased level of GSK-3β phosphorylation and increased level of β-catenin phosphorylation. They also show reduced level of MeCP2 SUMOylation. These alterations were also restored by lenti-Wnt6 transduction. Further, both BDNF and IGF-1 expressions are decreased in MeCP2 T158A mice. Overexpression of Wnt6 increases Bdnf and Igf-1 promoter activity in HEK293T cells in a dose-dependent manner. Lenti-Wnt6 transduction to the amygdala similarly increases the mRNA level and protein expression of BDNF and IGF-1 in MeCP2 T158A mice. Moreover, environmental enrichment (EE) similarly ameliorates the locomotor and social behavioral deficits in MeCP2 T158A mice. One of the mechanisms underlying EE is mediated through enhanced MeCP2 SUMOylation and increased Wnt6 expression in these animals by EE.

Exercise Plus Pharmacological Neuromodulation of Synaptic Inhibition Enhance Motor Function Recovery After Ischemic Stroke

The objective of this study was to examine the interactive effects of exercise and low-level inhibition of GABAA receptors on the recovery of motor function and BDNF expression in the primary motor cortex (M1) of a stroke rat model. Male Sprague–Dawley rats were divided into five groups: sham (SHAM), control (CON), exercise (EX), bicuculline (BIC), and bicuculline plus exercise (BICEX) groups. All rats, except those in the SHAM group, underwent middle cerebral artery occlusion (MCAO) surgery to induce an ischemic stroke. GABAA receptor antagonist, bicuculline (0.25 mg/kg, i.p.), was administered to the BIC and BICEX groups. The EX and BICEX groups exercised on a treadmill (11 m/min for 30 min). Each intervention started 3 days after the MCAO surgery and was carried out every day for 2 weeks. Following the intervention, bilateral M1 BDNF mRNA and protein expression levels were assessed using qRT-PCR and ELISA. Marginal recovery was found in the EX and BIC groups, whereas motor function recovery was enhanced with exercise in the presence of BIC administration specifically in the BICEX group. Furthermore, BDNF protein level in the ipsilateral M1 was significantly higher in the BICEX group than in other groups. This study indicated that exercise combined with low-level inhibition of GABAA receptors after stroke could facilitate the recovery of motor function accompanied by BDNF upregulation in the ipsilateral M1. Therefore, this study provides a novel insight of pharmacological neuromodulation into stroke rehabilitation.

Aminothioneine activates BDNF expression and enhances learning and memory in mice.

The previous study demonstrated that hot water extract of golden oyster mushrooms (Aminothioneine®) and ergothioneine, which is a hydrophilic antioxidant and contained at high levels in golden oyster mushrooms, increased neuronal differentiation in the hippocampal dentate gyrus of mice and have antidepressant-like effects in mice. Here, we investigated the effect of Aminothioneine on BDNF expression in primary cultures of cortical cells and learning and memory in mice. In primary cultures of rat cortical cells, Aminothioneine, but not ergothioneine, significantly increased expression levels of BDNF mRNA. Aminothioneine also increased the levels of BDNF expression in the hippocampus of mice. Aminothioneine significantly increased freezing behavior in the test session of the contextual fear conditioning test. In the test session of the novel object location recognition test, Aminothioneine-administered mice spent more time exploring the object at the novel location. Taken together, Aminothioneine increased expression levels of BDNF in cultured neurons and hippocampus of mice. Also, Aminothioneine enhances learning and memory in mice. Because it has been reported that higher expression levels of BDNF are associated with slower cognitive decline during aging, Aminothioneine could act as a memory stabilizer in an aging brain.