Regulation Of Brain-derived Neurotrophic Factor Expression Research Articles

MeCP2 controls hippocampal brain-derived neurotrophic factor expression via homeostatic interactions with microRNA‑132 in rats with depression.

Major depressive disorder (MDD) is a considerable public health concern, which affects patients worldwide. MDD is associated with psychosocial impairment, poor quality of life, and significant disability, morbidity and mortality. Stress is a major factor in depression, which impairs the structural and functional plasticity of the hippocampus. Previous studies have demonstrated that chronic unpredictable mild stress is able to downregulate the expression of brain‑derived neurotrophic factor (BDNF) and methyl‑CpG‑binding protein 2 (MeCP2), and alter the expression levels of certain microRNAs (miR). The aim of the present study was to investigate the regulatory association between BDNF, MeCP2 and miR-132 in an animal model of chronic stress‑induced depression. ELISA, western blot and qPCR were used to detect the expression levels of BDNF, MeCP2 and miR-132 in the peripheral blood samples of patients with MDD and in the hippocampi of depressed animals. In addition, a dual luciferase reporter gene system was used to determine whether miR-132 directly targets BDNF or MeCP2. The present study demonstrated that, as compared with normal subjects, miR‑132 expression was increased in the peripheral blood samples of patients with MDD, whereas the expression of MeCP2 and BDNF was decreased; thus, the expression levels of MeCP2 and BDNF were negatively correlated with those of miR‑132. In addition, in an animal model of chronic stress‑induced depression, increased expression levels of miR‑132, and decreased levels of MeCP2 and BDNF were detected in the hippocampi. Furthermore, knockdown of MeCP2 expression in primary hippocampal neurons increased the expression of miR‑132 and decreased the expression levels of BDNF. The results of the present study demonstrated that miR‑132 may directly target MeCP2, but not BDNF, and control its expression at the transcriptional and translational level. miR‑132 was also shown to negatively regulate BDNF expression. The reduced expression levels of BDNF, as induced by MeCP2 knockdown, were enhanced by miR‑132 mimics, and were rescued by miR‑132 inhibitors. These results suggested that homeostatic interactions between MeCP2 and miR‑132 may regulate hippocampal BDNF levels, which may have a role in the pathogenesis of MDD.

Angelica gigas ameliorate depression-like symptoms in rats following chronic corticosterone injection.

BackgroundRepeated injection of corticosterone (CORT) induces dysregulation in the hypothalamic-pituitary-adrenal (HPA) axis, resulting in depression. We examined the effects of Angelica gigas extract (AGN) treatment in a rat model of depressive and anxiety-like behaviors, induced by chronic CORT exposure.MethodsMale rats received 10, 20, or 50 mg/kg AGN (i.p.) 30 min prior to a daily injection of CORT for 21 consecutive days. Activation of the HPA axis in response to the repeated CORT injections was confirmed by measuring serum levels of CORT and the expression of corticotropin-releasing factor in the hypothalamus.ResultsDaily AGN administration significantly reversed the depression and anxiety-like behavioral abnormalities. It also blocked increases in tyrosine hydroxylase expression in the locus coeruleus, and suppressed the decreased expression levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB mRNAs in the hippocampus.ConclusionsThese findings indicate that administration of AGN prior to high-dose exogenous CORT significantly improved helpless behaviors, possibly by modulating the central noradrenergic system and regulation of BDNF expression in rats. Thus, AGN may be a useful agent for the treatment or alleviation of psychiatric disorders associated with depression and anxiety disorders.

Increased production of BDNF in colonic epithelial cells induced by fecal supernatants from diarrheic IBS patients

Colonic brain-derived neurotrophic factor (BDNF) plays an essential role in pathogenesis of abdominal pain in diarrhea-predominant irritable bowel syndrome (IBS-D), but regulation on its expression remains unclear. We investigated the role of fecal supernatants (FSN) from IBS-D patients on regulating BDNF expression in colonic epithelial cells of human and mice. Using human Caco-2 cells, we found that IBS-D FSN significantly increased BDNF mRNA and protein levels compared to control FSN, which were remarkably suppressed by the serine protease inhibitor. To further explore the potential mechanisms, we investigated the impact of protease-activated receptor-2 (PAR-2) on BDNF expression. We found a significant increase in PAR-2 expression in Caco-2 after IBS-D FSN stimulation. Knockdown of PAR-2 significantly inhibited IBS-D FSN-induced upregulation of BDNF. Moreover, we found that phosphorylation of p38 MAPK, not NF-κB p65, contributed to PAR-2-mediated BDNF overexpression. To confirm these results, we intracolonically infused IBS-D or control FSN in mice and found that IBS-D FSN significantly elevated colonic BDNF and visceral hypersensitivity in mice, which were both suppressed by the inhibitor of serine protease or antagonist of PAR-2. Together, our data indicate that activation of PAR-2 signaling by IBS-D FSN promotes expression of colonic BDNF, thereby contributing to IBS-like visceral hypersensitivity.

Inhibition of miR-15a Promotes BDNF Expression and Rescues Dendritic Maturation Deficits in MeCP2-Deficient Neurons

In both the embryonic and adult brain, a critical step in neurogenesis is neuronal maturation. Deficiency of MeCP2 leads to Rett syndrome, a severe neurodevelopmental disorder. We have previously shown that MeCP2 plays critical roles in the maturation step of new neurons during neurogenesis. MeCP2 is known to regulate the expression of brain-derived neurotrophic factor (BDNF), a potent neurotrophic factor for neuronal maturation. Nevertheless, how MeCP2 regulates BDNF expression and how MeCP2 deficiency leads to reduced BDNF expression remain unclear. Here, we show that MeCP2 regulates the expression of a microRNA, miR-15a. We find that miR-15a plays a significant role in the regulation of neuronal maturation. Overexpression of miR-15a inhibits dendritic morphogenesis in immature neurons. Conversely, a reduction in miR-15a has the opposite effect. We further show that miR-15a regulates expression levels of BDNF, and exogenous BDNF could partially rescue the neuronal maturation deficits resulting from miR-15a overexpression. Finally, inhibition of miR-15a could rescue neuronal maturation deficits in MeCP2-deficient adult-born new neurons. These results demonstrate a novel role for miR-15a in neuronal development and provide a missing link in the regulation of BDNF by MeCP2.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects sympathetic tone in a gender-specific way.

The Val/Val genotype of the brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) has been reported to affect human anxiety-related phenotypes. Substantial research has demonstrated that anxiety is associated with sympathetic activation, while sex steroid hormones have been shown to exert differential actions in regulating BDNF expression. Thus, we examined whether the BDNF variant modulates autonomic function in a gender-dependent manner. From 708 adults initially screened for medical and psychiatric illnesses, a final cohort of 583 drug-free healthy Han Chinese (355 males, 228 females; age 34.43±8.42 years) was recruited for BDNF genotyping (Val/Val: 136, 23.3%, Val/Met: 294, 50.4%, and Met/Met: 153, 26.2%). Time- and frequency-domain analyses of heart rate variability (HRV) were used to assess autonomic outflow to the heart. Significant genotype-by-gender interaction effects were found on HRV indices. Even after adjusting for possible confounders, male participants bearing the Val/Val genotype had significant increases in low frequency (LF), LF% and LF/high frequency (HF) ratio, indicating altered sympathovagal balance with increased sympathetic modulation, compared to male Met/Met homozygotes. Females, however, showed an opposite but non-significant pattern. These results suggest that the studied BDNF polymorphism is associated with sympathetic control in a gender-specific way. The findings here support the view that male subjects with the Val/Val genotype have increased risk of anxiety by association with sympathetic activation.

In Vivo Regulation of Brain-Derived Neurotrophic Factor in Dorsal Root Ganglia Is Mediated by Nerve Growth Factor-Triggered Akt Activation during Cystitis

The role of brain-derived neurotrophic factor (BDNF) in sensory hypersensitivity has been suggested; however the molecular mechanisms and signal transduction that regulate BDNF expression in primary afferent neurons during visceral inflammation are not clear. Here we used a rat model of cystitis and found that the mRNA and protein levels of BDNF were increased in the L6 dorsal root ganglia (DRG) in response to bladder inflammation. BDNF up-regulation in the L6 DRG was triggered by endogenous nerve growth factor (NGF) because neutralization of NGF with a specific NGF antibody reduced BDNF levels during cystitis. The neutralizing NGF antibody also subsequently reduced cystitis-induced up-regulation of the serine/threonine kinase Akt activity in L6 DRG. To examine whether the NGF-induced Akt activation led to BDNF up-regulation in DRG in cystitis, we found that in cystitis the phospho-Akt immunoreactivity was co-localized with BDNF in L6 DRG, and prevention of the endogenous Akt activity in the L6 DRG by inhibition of phosphoinositide 3-kinase (PI3K) with a potent inhibitor LY294002 reversed cystitis-induced BDNF up-regulation. Further study showed that application of NGF to the nerve terminals of the ganglion-nerve two-compartmented preparation enhanced BDNF expression in the DRG neuronal soma; which was reduced by pre-treatment of the ganglia with the PI3K inhibitor LY294002 and wortmannin. These in vivo and in vitro experiments indicated that NGF played an important role in the activation of Akt and subsequent up-regulation of BDNF in the sensory neurons in visceral inflammation such as cystitis.

The ganglioside GQ1b regulates BDNF expression via the NMDA receptor signaling pathway

Gangliosides are sialic acid-containing glycosphingolipids which play a role in neuronal functions. Among the gangliosides, tetrasialoganglioside GQ1b shows neurotrophic factor-like actions, such as increasing neurite outgrowth, cell proliferation, and long-term potentiation. In addition, we recently reported that GQ1b improves spatial learning and memory performance in naïve rats. However, it is still unknown how GQ1b exerts its diverse neuronal functions. Thus, we hypothesized that GQ1b might influence synaptic activity by regulating brain-derived neurotrophic factor (BDNF) expression, which is an important protein for synaptic plasticity and cognition. Interestingly, GQ1b treatment increased BDNF expression in GQ1b-null SH-SY5Y cell lines and rat primary cortical neurons. Additionally, we confirmed whether the observed effects were due to GQ1b or due to a ganglioside with fewer sialic acid molecules (GT1b and GD1b) created by the sialidases present on the plasma membranes, by directly applying GT1b and GD1b or GQ1b co-treated with a sialidase inhibitor. Treatment with GT1b or GD1b had no effect on BDNF expression, whereas co-treatment with a sialidase inhibitor and GQ1b significantly increased BDNF levels. Moreover, GQ1b restored the decreased BDNF expression induced by the ganglioside synthesis inhibitor, D-PDMP, in rat primary cortical neurons. GQ1b treatment significantly increased BDNF levels, whereas pretreatment with the N-methyl-d-aspartate (NMDA) receptor antagonist D-AP5 blocked the effects of GQ1b on BDNF expression, suggesting that GQ1b regulates BDNF expression via the NMDA receptor signaling. Finally, we performed an intracerebroventricular GQ1b injection, which resulted in increased prefrontal and hippocampal BDNF expression in vivo. These findings demonstrate, for the first time, that tetrasialoganglioside GQ1b regulates BDNF expression in vitro and in vivo.

Transcription Factor SCIRR69 Involved in the Activation of Brain-Derived Neurotrophic Factor Gene Promoter II in Mechanically Injured Neurons

The spinal cord injury and regeneration-related gene #69 (SCIRR69), which was identified in our screen for genes upregulated after spinal cord injury, encode a protein belonging to the cAMP response element-binding protein (CREB)/ATF family of transcription factors. Our previous study showed that SCIRR69 functions as a transcriptional activator. However, the target gene regulated by SCIRR69 and its roles in injured neurons remain unknown. In this study, we showed that SCIRR69 is widely distributed in the central nervous system. Full-length SCIRR69 is an endoplasmic reticulum-bound protein. Following mechanical injury to neurons, SCIRR69 was induced and proteolytically cleaved by site-1 and site-2 proteases, and the proteolytically cleaved SCIRR69 (p60-SCIRR69) was translocated to the nucleus where it bound to brain-derived neurotrophic factor (BDNF) gene promoter II. In addition, loss- and gain-of-function studies confirmed that SCIRR69 is involved in the regulation of BDNF expression in injured neurons. As expected, the culture supernatants of PC12 cells stably expressing p60-SCIRR69 contained higher levels of BDNF, and more remarkably promoted neurite outgrowth in a spinal cord slice culture model in vitro than the supernatants of control cells. These results suggest that SCIRR69 is a novel regulator of the BDNF gene and may play an important role in the repair and/or regeneration of damaged neural tissues by specifically activating BDNF promoter II.

Puerarin attenuates neuronal degeneration in the substantia nigra of 6-OHDA-lesioned rats through regulating BDNF expression and activating the Nrf2/ARE signaling pathway

An increasing number of studies suggest that oxidative stress is associated with the Parkinsonian process. This study evaluated the potential neuroprotective role of puerarin (PR) on lesioned substantia nigra (SN) induced by 6-hydroxydopamine (6-OHDA). Data from a rotational test showed that PR treatment significantly decreased apomorphine-induced rotations. Both the dopamine (DA) content in the SN and the endogenous expression of brain-derived neurotrophic factor (BDNF) were also elevated by the treatment. Pathological examination showed that dopaminergic neuronal degeneration in the SN was attenuated by PR treatment. Meanwhile, the contents of γ-glutamylcysteine synthetase (γ-GCS), glutathione (GSH) and catalase (CAT) in SN tissue were gradually elevated. Additionally, cytochrome c oxidase (COX) mRNA expression in the SN was markedly up-regulated. At the same time, nuclear factor E2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keapl) levels were progressively increased by the PR treatment. Our findings indicated that puerarin effectively protects against 6-OHDA-mediated oxidative stress injury in SN neurons, in which the underlying mechanisms are involved in modulating BDNF expression and activating the Nrf2/ARE signaling pathway.

Alterations of Serum Levels of BDNF-Related miRNAs in Patients with Depression

Depression is a serious and potentially life-threatening mental disorder with unknown etiology. Emerging evidence shows that brain-derived neurotrophic factor (BDNF) and microRNAs (miRNAs) play critical roles in the etiology of depression. Here this study was aimed to identify and characterize the roles of BDNF and its putative regulatory miRNAs in depression. First, we identified that miR-182 may be a putative miRNA that regulates BDNF levels by bioinformatic studies, and characterized the effects of miR-182 on the BDNF levels using cell-based studies, side by side with miR-132 (a known miRNA that regulates BDNF expression). We showed that treatment of miR-132 and miR-182 respectively decreased the BDNF protein levels in a human neuronal cell model, supporting the regulatory roles of miR-132 and miR-182 on the BDNF expression. Furthermore, we explored the roles of miR-132 and miR-182 on the BDNF levels in depression using human subjects by assessing their serum levels. Compared with the healthy controls, patients with depression showed lower serum BDNF levels (via the enzyme-linked immunosorbent assays) and higher serum miR-132 and miR-182 levels (via the real-time PCR). Finally, the Pearson’s (or Spearman’s) correlation coefficient was calculated to study whether there was a relationship among the Self-Rating Depression Scale score, the serum BDNF levels, and serum BDNF-related miRNA levels. Our results revealed that there was a significant negative correlation between the SDS scores and the serum BDNF levels, and a positive correlation between the SDS scores and miR-132 levels. In addition, we found a reverse relationship between the serum BDNF levels and the miR-132/miR-182 levels in depression. Collectively, we provided evidence supporting that miR-182 is a putative BDNF-regulatory miRNA, and suggested that the serum BDNF and its related miRNAs may be utilized as important biomarkers in the diagnosis or as therapeutic targets of depression.

Antidepressant‐like effects of lobeline in a chronic mild stress model

Recently, we have demonstrated that lobeline, a neuronal nicotinic acetylcholine receptor (nAChR) ligand, has antidepressant‐like effects in mice. The objective of the present study was to determine the effects of lobeline in a chronic mild stress (CMS) model. Adult C57BL/6J mice were exposed to CMS for six weeks. Saline or lobeline (1 or 4 mg/kg, s.c.) were administered once daily during the last two weeks of CMS. Compared to unstressed group, mice exposed to CMS showed increased immobility time in forced swim test, a measure for depression‐like behavior, which was reversed by chronic lobeline treatment (unstressed: 256 ± 8, CMS: 385 ± 24, CMS + lobeline 1 mg/kg: 213 ± 39, CMS + lobeline 4 mg/kg: 266 ± 19 sec). Mice were sacrificed 24 h after chronic treatment to determine brain‐derived neurotrophic factor (BDNF) expression in hippocampus and prefrontal cortex. CMS significantly (p < 0.05) reduced BDNF expression in hippocampus which was reversed by chronic treatment with 1 mg/kg lobeline (CMS: 60 ± 13%, CMS + lobeline 1 mg/kg: 141 ± 12% of unstressed group). However, BDNF expression in prefrontal cortex was not changed by CMS or drug treatment. Overall, the results indicate that lobeline has antidepressant‐like effects likely involving nAChR signaling and regulation of BDNF expression in hippocampus. (Supported in part by SDSURF‐JRF)

Serum BDNF concentrations show strong seasonal variation and correlations with the amount of ambient sunlight.

Earlier findings show seasonality in processes and behaviors such as brain plasticity and depression that in part are regulated by Brain-Derived Neurotrophic Factor (BDNF). Based on this we investigated seasonal variation in serum BDNF concentrations in 2,851 persons who took part in the Netherlands Study of Depression and Anxiety (NESDA). Analyses by month of sampling (monthly n’s >196) showed pronounced seasonal variation in serum BDNF concentrations (P<.0001) with increasing concentrations in the spring-summer period (standardized regression weight (ß) = 0.19, P<.0001) and decreasing concentrations in the autumn-winter period (ß = −0.17, P<.0001). Effect sizes [Cohen’s d] ranged from 0.27 to 0.66 for monthly significant differences. We found similar seasonal variation for both sexes and for persons with a DSM-IV depression diagnosis and healthy control subjects. In explorative analyses we found that the number of sunshine hours (a major trigger to entrain seasonality) in the week of blood withdrawal and the 10 weeks prior to this event positively correlated with serum BDNF concentrations (Pearson’s correlation coefficients ranged: 0.05 – 0.18) and this could partly explain the observed monthly variation. These results provide strong evidence that serum BDNF concentrations systematically vary over the year. This finding is important for our understanding of those factors that regulate BDNF expression and may provide novel avenues to understand seasonal dependent changes in behavior and illness such as depression. Finally, the findings reported here should be taken into account when designing and interpreting studies on BDNF.

Brain-derived neurotrophic factor (BDNF) reverses the effects of rapid eye movement sleep deprivation (REMSD) on developmentally regulated, long-term potentiation (LTP) in visual cortex slices

Work in this laboratory demonstrated a role for rapid eye movement sleep (REMS) in critical period (CP), postnatal days (P) 17–30, synaptic plasticity in visual cortex. Studies in adolescent rats showed that REMS deprivation (REMSD) reinitiates a developmentally regulated form of synaptic plasticity that otherwise is observed only in CP animals. Subsequent work added that REMSD affects inhibitory mechanisms that are thought to be involved in terminating the CP. Neurotrophins are implicated in the synaptic plasticity that underlies CP maturation and also final closure of the CP in visual cortex. Expression of brain-derived neurotrophic factor (BDNF) is dependent upon neuronal activity, and REMSD may block BDNF expression. We propose that REMS contributes to the maturation of visual cortex through regulation of BDNF expression and consequent, downstream increase in cortical inhibitory tone. In this study, osmotic minipumps delivered BDNF into visual cortex on one side of brain. The opposite hemisphere was not implanted and served as an internal control. We tested the hypothesis that BDNF is blocked by REMSD in late-adolescent rats and investigated whether replacing BDNF prevents induction of LTPWM-III by theta burst stimulation (TBS). We also assessed relative inhibitory tone in visual cortex with paired-pulse stimulation (PPS) in animals that were similarly REMSD- and BDNF-infused. After REMSD, both hemispheres were prepared in parallel for in vitro synaptic plasticity studies (LTPWM-III or PPS). In visual cortex of REMSD rats on the side receiving BDNF infusions (8 of 8 animals), TBS consistently failed to induce LTPWM-III. In contrast, LTPWM-III was obtained (5 of 5 animals) in the matched, non-infused hemisphere, as expected in rats of this age. REMSD animals that were unilaterally infused with saline produced LTPWM-III in both hemispheres. PPS studies in another group of REMSD animals that were unilaterally BDNF-infused displayed age-appropriate inhibition of the second response on the BDNF-infused side (5/5), whereas on the non-infused side facilitation was observed (3/3). Intracortical infusion of BDNF in REMSD adolescent rats appears to restore neurochemical processes necessary for termination of the CP for developmentally regulated synaptic plasticity in visual cortex. The results suggest that REMSD blocks BDNF expression and also maturation of inhibitory processes in adolescent visual cortex. These data support REMS’ function in brain development.

Identification of a novel Brain Derived Neurotrophic Factor (BDNF)-inhibitory factor: Regulation of BDNF by Teneurin C-terminal Associated Peptide (TCAP)-1 in immortalized embryonic mouse hypothalamic cells

The teneurins are a family of four large transmembrane proteins that are highly expressed in the central nervous system (CNS) where they have been implicated in development and CNS function. At the tip of the carboxyl terminus of each teneurin lies a 43-amino acid sequence, that when processed, could liberate an amidated 41-residue peptide. We have called this region the teneurin C-terminal associated peptide (TCAP). Picomolar concentrations of the synthetic version of TCAP-1 inhibit stress-induced cocaine reinstatement in rats. Because cocaine-seeking is associated with increased brain derived neurotrophic factor (BDNF) in the brain, we examined whether synthetic mouse TCAP-1 has the potential to regulate BDNF expression in immortalized mouse neurons. Immortalized mouse neurons (N38; mHypoE38) show strong FITC-labeled [K8]-TCAP-1 uptake and BDNF labeling in the cytosol. Moreover, FITC-labeled [K8]-TCAP-1 bound competitively to membrane fractions. In culture, the labeled TCAP-1 peptide could be detected on cell membranes within 15min and subsequently became internalized in the cytosol and trafficked toward the nucleus. Administration of 10−8M unlabeled TCAP-1 to cultures of the N38 cells resulted in a significant decrease of total cell BDNF immunoreactivity over 4h as determined by western blot and ELISA analyses. Real-time PCR, utilizing primers to the various BDNF transcripts showed a significant decline of promoter IIB- and VI-driven transcripts. Taken together, these studies indicated that in vitro, TCAP-1 induces a significant decline in BDNF transcription and protein labeling in embyronic mouse immortalized hypothalamic neurons. Thus, TCAP-1 may act as a novel BDNF inhibitory factor.

Brain Derived Neurotrophic Factor (BDNF) Expression Is Regulated by MicroRNAs miR-26a and miR-26b Allele-Specific Binding

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an essential role in neuronal development and plasticity. MicroRNA (miRNAs) are small non-coding RNAs of about 22-nucleotides in length regulating gene expression at post-transcriptional level. In this study we explore the role of miRNAs as post-transcriptional inhibitors of BDNF and the effect of 3′UTR sequence variations on miRNAs binding capacity. Using an in silico approach we identified a group of miRNAs putatively regulating BDNF expression and binding to BDNF 3′UTR polymorphic sequences. Luciferase assays demonstrated that these miRNAs (miR-26a1/2 and miR-26b) downregulates BDNF expression and that the presence of the variant alleles of two single nucleotide polymorphisms (rs11030100 and rs11030099) mapping in BDNF 3′UTR specifically abrogates miRNAs targeting. Furthermore we found a high linkage disequilibrium rate between rs11030100, rs11030099 and the non-synonymous coding variant rs6265 (Val66Met), which modulates BDNF mRNA localization and protein intracellular trafficking. Such observation led to hypothesize that miR-26s mediated regulation could extend to rs6265 leading to an allelic imbalance with potentially functional effects, such as peptide's localization and activity-dependent secretion. Since rs6265 has been previously implicated in various neuropsychiatric disorders, we evaluated the distribution of rs11030100, rs11030099 and rs6265 both in a control and schizophrenic group, but no significant difference in allele frequencies emerged. In conclusion, in the present study we identified two novel miRNAs regulating BDNF expression and the first BDNF 3′UTR functional variants altering miRNAs-BDNF binding.

Decreased response to social defeat stress in μ-opioid-receptor knockout mice

Substantial evidence exists that opioid systems are involved in stress response and that changes in opioid systems in response to stressors affect both reward and analgesia. Reportedly, mice suffering chronic social defeat stress subsequently show aversion to social contact with unfamiliar mice. To further examine the role of opioid systems in stress response, the behavioral and neurochemical effects of chronic social defeat stress (psychosocial stress) were evaluated in μ-opioid-receptor knockout (MOR-KO) mice. Aversion to social contact was induced by chronic social defeat stress in wild-type mice but was reduced in MOR-KO mice. Moreover, basal expression of brain-derived neurotrophic factor (BDNF) mRNA in MOR-KO mice hippocampi was significantly lower than in wild-type mice. Psychosocial stress significantly decreased BDNF mRNA expression in wild-type mice but did not affect BDNF expression in MOR-KO mice; no difference in basal levels of plasma corticosterone was observed. These results suggest that the μ-opioid receptor is involved in the behavioral sequelae of psychosocial stress and consequent regulation of BDNF expression in the hippocampus, and may play an important role in psychiatric disorders for which stress is an important predisposing or precipitating factor, such as depression, posttraumatic stress disorder, and social anxiety disorder.

ERK1/2 and ERK5 have distinct roles in the regulation of brain‐derived neurotrophic factor expression

Neurotrophins play essential roles in the development, differentiation, and survival of neuronal and nonneuronal cells. Alterations in neurotrophin expression have been implicated in a variety of neurodegenerative disorders. Dysregulation of brain-derived neurotrophic factor (BDNF) has been implicated in deficits of long-term potentiation and cognition and may contribute to the development of Alzheimer's disease (AD). In this study, we used complementary pharmacological and molecular approaches to evaluate the role of ERK1/2 and ERK5, two members of the MAPK pathway associated with neuroprotection, in regulating BDNF expression in C6 glial cells and primary astrocytes. Our data revealed that U0126, an inhibitor of both ERK5 and ERK1/2, increased the levels of BDNF mRNA, whereas the MEK1/2-specific inhibitor PD184352 did not, suggesting that ERK5 exerts negative control over BDNF expression. This was supported by experiments in which RNAi-mediated depletion of ERK5 led to an increase in BDNF. In contrast, transfection with constitutively active MEK5 resulted in an inhibition of BDNF expression, confirming the inhibitory role of ERK5 in the regulation of BDNF. Interestingly, transfection with the dominant active mutant of MEK1 (MEKR4F), the upstream activator of ERK1/2, resulted in a modest increase in BDNF levels. Collectively, our data suggest that ERK5 and ERK1/2 exert opposite effects on BDNF expression and support the hypothesis that an imbalance of these two signaling pathways may contribute to the pathology of diseases in which neurotrophin dysregulation is noted.

Serum brain-derived neurotrophic factor and glucocorticoid receptor levels in lymphocytes as markers of antidepressant response in major depressive patients: A pilot study

Depressive patients often have altered cortisol secretion, an effect that likely derives from impaired activity of the glucocorticoid receptor (GR), the main regulator of the hypothalamus–pituitary–adrenal (HPA) axis. Glucocorticoids reduce the levels of brain-derived neurotrophic factor (BDNF), a downstream target of antidepressants. Antidepressants promote the transcriptional activity of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), a regulator of BDNF expression. To identify potential biomarkers for the onset of antidepressant action in depressive patients, GR and phospho-CREB (pCREB) levels in lymphocytes and serum BDNF levels were repeatedly measured during the course of antidepressant treatment. Thirty-four depressed outpatients (10 male and 24 female) were treated with venlafaxine (75 mg/day), and individuals exhibiting a 50% reduction in their baseline 17-Item Hamilton Depression Rating Scale score by the 6th week of treatment were considered responders. Responders showed an early improvement in parallel with a rise in BDNF levels during the first two weeks of treatment. Non-responders showed increased GR levels by the third week and reduced serum BDNF by the sixth week of treatment. In contrast, venlafaxine did not affect levels of pCREB. We conclude that levels of BDNF in serum and GR levels in lymphocytes may represent biomarkers that could be used to predict responses to venlafaxine treatment.

Pre- and post-treatments with escitalopram protect against experimental ischemic neuronal damage via regulation of BDNF expression and oxidative stress

Selective serotonin re-uptake inhibitors (SSRI) have been widely used in treatment of major depression because of their efficacy, safety, and tolerability. Escitalopram, an SSRI, is known to decrease oxidative stress in chronic stress animal models. In the present study, we examined the neuroprotective effects of pre- and post-treatments with 20 mg/kg and 30 mg/kg escitalopram in the gerbil hippocampal CA1 region (CA1) after transient cerebral ischemia. Pre-treatment with escitalopram protected against ischemia-induced neuronal death in the CA1 after ischemia/reperfusion (I/R). Post-treatment with 30 mg/kg, not 20 mg/kg, escitalopram had a neuroprotective effect against ischemic damage. In addition, 20 mg/kg pre- and 30 mg/kg post-treatments with escitalopram increased brain-derived neurotrophic factor (BDNF) protein levels in the ischemic CA1 compared to vehicle-treated ischemia animals. In addition, 20 mg/kg pre- and 30 mg/kg post-treatments with escitalopram reduced microglia activation and decreased 4-hydroxy-2-nonenal and Cu,Zn-superoxide dismutase immunoreactivity and their levels in the ischemic CA1 compared to vehicle-treated ischemia animals after transient cerebral ischemia. In conclusion, these results indicated that pre- and post-treatments with escitalopram can protect against ischemia-induced neuronal death in the CA1 induced by transient cerebral ischemic damage by increase of BDNF as well as decrease of microglia activation and oxidative stress.

Tumor necrosis factor-α increases brain-derived neurotrophic factor expression in trigeminal ganglion neurons in an activity-dependent manner

Many chronic trigeminal pain conditions, such as migraine or temporo-mandibular disorders, are associated with inflammation within peripheral endings of trigeminal ganglion (TG) sensory neurons. A critical role in mechanisms of neuroinflammation is attributed to proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α (TNFα) that also contribute to mechanisms of persistent neuropathic pain resulting from nerve injury. However, the mechanisms of cytokine-mediated synaptic plasticity and nociceptor sensitization are not completely understood. In the present study, we examined the effects of TNFα on neuronal expression of brain-derived neurotrophic factor (BDNF), whose role in synaptic plasticity and sensitization of nociceptive pathways is well documented. We show that 4- and 24-h treatment with TNFα increases BDNF mRNA and protein, respectively, in neuron-enriched dissociated cultures of rat TG. TNFα increases the phosphorylated form of the cyclic AMP-responsive element binding protein (CREB), a transcription factor involved in regulation of BDNF expression in neurons, and activates transcription of BDNF exon IV (former exon III) and, to a lesser extent, exon VI (former exon IV), but not exon I. TNFα-mediated increase in BDNF expression is accompanied by increase in calcitonin gene-related peptide (CGRP), which is consistent with previously published studies, and indicates that both peptides are similarly regulated in TG neurons by inflammatory mediators. The effect of TNFα on BDNF expression is dependent on sodium influx through TTX-sensitive channels and on p38-mitogen-activated protein kinase. Moreover, electrical stimulation and forskolin, known to increase intracellular cAMP, potentiate the TNFα-mediated upregulation of BDNF expression. This study provides new evidence for a direct action of proinflammatory cytokines on TG primary sensory neurons, and reveals a mechanism through which TNFα stimulates de novo synthesis of BDNF in these neurons. Thus, TNFα should be considered in mechanisms of BDNF-dependent neuronal plasticity.