Lower Expression Of Brain-derived Neurotrophic Factor Research Articles

Rapid ejaculator rats are more susceptible to anxiety compared with normal ejaculator rats.

By observation of Sprague-Dawley male rats with different ejaculatory behaviors, we have identified distinct behavioral characteristics in rapid ejaculator rats. To validate these differential behaviors, we conducted multifaceted behavioral experiments on rapid ejaculator rats and normal rats. Through mating experiments, 42 male rats were categorized into 5 rapid ejaculator rats, 29 normal ejaculator rats, and 8 sluggish ejaculator rats according to their ejaculation frequency. We selected 5 rats exhibiting rapid ejaculation and 5 rats with normal ejaculation for participation in the Morris water maze, open-field test, and balance beam experiments. The open-field tests revealed that rapid ejaculator rats spent shorter time in the center region (1.23 ± 1.21 vs. 6.56 ± 2.40 s, P = 0.0041), less entered the center region (0.80 ± 0.75 vs. 3.40 ± 1.50, time, P = 0.0145), traveled shorter distances (17,003.77 ± 3339.42 vs. 25,037.90 ± 5499.94 mm, P = 0.0371), and had a lower average speed compared with normal rats (66.09 ± 62.36 vs. 195.56 ± 83.41 mm/s, P = 0.0377). However, no significant differences were observed in the Morris water maze and balance beam experiments (0.25 ± 0.05 vs. 0.26 ± 0.07, P = 0.7506;16.40 ± 3.77 vs. 16.25 ± 2.05, P = 0.9515). These behavioral results indicated that the rapid ejaculator rats were more prone to anxiety. To further substantiate this claim, we examined Brain-derived neurotrophic factor expression levels in the hippocampus of rat brains using immunohistochemistry and western blotting. The results demonstrate lower Brain-derived neurotrophic factor expression in the hippocampus of rapid ejaculator rats compared with that in normal rats (P = 0.0093). Thus, our experiments indicate that rapid ejaculator rats exhibit a higher propensity for anxiety, potentially linked to their abnormal neurophysiologic state. It is concluded that rapid ejaculator rats may be more susceptible to anxiety on a pathophysiological basis.

Spontaneously hypertensive rats vs. Wistar Kyoto and Wistar rats: An assessment of anxiety, motor activity, memory performance, and seizure susceptibility

Spontaneously hypertensive rats (SHRs) are widely accepted for modeling essential hypertension and Attention deficit hyperactivity disorder (ADHD). However, data concerning central nervous system changes associated with behavioral responses of this strain and usage of Wistar Kyoto (WKY) rats as controls are confounding. The objective of the present study was to assess the impact of anxiety and motor activity on the cognitive responses of SHRs compared to Wistar and WKY rats. In addition, the role of brain-derived neurotrophic factor (BDNF) in the hippocampus on cognitive behavior and seizure susceptibility in the three strains was evaluated. In Experiment#1, SHR demonstrated impulsive responses in the novelty suppression feeding test accompanied by impaired spatial working and associative memory in the Y maze and object recognition test compared with the Wistar rat but not WKY rats. In addition, the WKY rats exhibited diminished activity compared to Wistar rats in an actimeter. In Experiment#2, the seizure susceptibility was assessed by 3-min electroencephalographic (EEG) recording after two consecutive injections of pentylenetetrazol (PTZ) (20+40 mg/kg). The WKY rats were more vulnerable to rhythmic metrazol activity (RMA) than the Wistar rats. In contrast, Wistar rats were more prone to generalized tonic-clonic seizures (GTCS) than WKY rats and SHRs. Control SHR had lower BDNF expression in the hippocampus compared to Wistar rats. However, while the BDNF levels were elevated in the Wistar and WKY rats after PTZ injection, no change in this signaling molecule was observed in the SHR in the seizure condition. The results suggest Wistar rats as a more appropriate control of SHR than WKY rats for studying memory responses mediated by BDNF in the hippocampus. The higher vulnerability to seizures in Wistar and WKY rats compared to SHR might be linked to PTZ-induced decreased expression of BDNF in the hippocampus.

Intra-mPFC injection of sodium butyrate promotes BDNF expression and ameliorates extinction recall impairment in an experimental paradigm of post-traumatic stress disorder.

Objective(s):Therapeutic strategies that facilitate extinction are promising in the treatment of post-traumatic stress disorder (PTSD). Brain-derived neurotrophic factor (BDNF) has a crucial role in neural plasticity, a process needed for the retention of fear extinction. In this study, we investigated the effects of local administration of a histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu), on BDNF transcription and behavioral markers of extinction in the single prolonged stress (SPS) model of PTSD. Materials and Methods:NaBu was infused into the infralimbic (IL) subregion of the medial prefrontal cortex (mPFC) of male rats. The freezing response was recorded as the criterion to assess fear strength on the day of extinction as well as 24 hr later in the retention test. Other behavioral tests were also measured to evaluate the anxiety level, locomotor activity, and working memory on the retention day. HDAC activity and BDNF mRNA expression were evaluated after the behavioral experiments. Results: NaBu facilitated the recall of fear extinction in SPS rats (P<0.0001). SPS rats had higher HDAC activity (P<0.0001) and lower BDNF expression (P<0.05) than non-SPS animals. Also, anxiety was higher in the SPS group (P<0.0001), but locomotor activity (P=0.61) and working memory (P=0.36) were not different between SPS and Non-SPS groups.Conclusion:Our findings provide evidence that the mechanism of action of NaBu in the improvement of extinction recall is mediated, in part, by enhancing histone acetylation and reviving BDNF expression in IL.

Brain derived neurotrophic factor deficiency exacerbates inflammation-induced anhedonia in mice

Brain-derived neurotrophic factor (BDNF) is implicated in the pathology of major depression and influences the inflammatory response. Prolonged immune system activation can cause depression symptoms, and individuals with low BDNF expression may be vulnerable to inflammation-induced depression. We tested the hypothesis that BDNF deficient mice are vulnerable to the induction of depressive-like behavior following peripheral immune challenge. BDNF heterozygous (BDNF+/-) or wild-type (BDNF+/+) littermate mice were injected intraperitoneally (i.p.) with endotoxin (lipopolysaccharide, LPS) to trigger an acute pro-inflammatory response. After resolution of the acute sickness response, central expression of inflammatory genes, kynurenine metabolites, and depressive-like behaviors across multiple dimensions (symptoms) were measured. BDNF+/- mice displayed an exaggerated neuroinflammatory response following peripheral immune challenge. Pro-inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) were overexpressed in BDNF+/- mice relative to BDNF+/+ littermate control mice. While behavioral despair and anxiety-like behavior was not different between genotypes, LPS-induced anhedonia-like behavior was significantly more pronounced in BDNF+/- mice relative to BDNF+/+ mice. The kynurenine pathway mediates the many depressive-like behavioral effects of peripheral LPS, and similar to pro-inflammatory cytokine gene expression, indoleamine 2,3-dioxygenase (IDO) expression and kynurenine metabolism was exaggerated in BDNF+/- mice. Genetic BDNF deficiency results in a dysregulated neuroinflammatory and metabolic response to peripheral immune challenge and in a specific vulnerability to the development of inflammation-induced anhedonia.

H3K9me2 regulation of BDNF expression in the hippocampus and medial prefrontal cortex is involved in the depressive-like phenotype induced by maternal separation in male rats.

Early life stress (ELS) induces a depressive-like phenotype and increases the risk of depression. Brain-derived neurotrophic factor (BDNF) has been confirmed to be involved in the pathophysiology of depression. However, the mechanism by which ELS alters the epigenetic regulation of BDNF and changes susceptibility to depression has not been fully clarified. The present study used maternal separation (MS) and chronic unpredicted mild stress (CUMS) to establish an MS animal model and a depressive animal model. We assessed depressive-like behaviours, including anhedonia, locomotor activity, anxiety-like behaviour, and spatial memory, using the sucrose preference test, the open field test, the elevated plus maze test, and the Morris water maze test. We also investigated BDNF and H3K9me2 expression in the hippocampus and medial prefrontal cortex (mPFC) by immunohistochemistry, western blotting, and qPCR analysis. Additionally, we used Unc0642, a small molecule inhibitor of histone methyltransferase (G9a), as an intervention. The results showed that CUMS induced depressive-like behaviours in rats and resulted in increased H3K9me2 expression and decreased BDNF expression in the hippocampus and mPFC. More importantly, adult MS rats experiencing CUMS had more severe depressive behaviours, had higher expression of H3K9me2 in the hippocampus and mPFC, and had lower expression of BDNF in the hippocampus and mPFC. In addition, administration of the G9a inhibitor reversed most of the changes. Our study suggests that ELS changed BDNF and H3K9me2 expression in the rat brain, resulting in a depressive-like phenotype.

Functional analysis of brain derived neurotrophic factor (BDNF) in Huntington's disease.

The aim of this study is to determine the molecular functions of brain derived neurotrophic factor (BDNF) in Huntington’s disease (HD). A total of 1,675 differentially expressed genes (DEGs) were overlapped from HD versus control and BDNF-low versus high groups. Five co-expression modules were constructed using weight gene correlation network analysis, among which the blue and turquoise modules were most strongly correlated with HD and low BDNF. Functional enrichment analyses revealed DEGs in these modules significantly enriched in GABAergic synapse, phagosome, cyclic adenosine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), renin-angiotensin system (Ras), Ras-associated protein-1 and retrograde endocannabinoid signaling pathways. The intersection pathways of BDNF, such as cAMP, MAPK and Ras signaling pathways, were identified in global regulatory network. Further performance evaluation of low BDNF accurately predicted HD occurrence according to the area under the curve of 82.4%. In aggregate, our findings highlighted the involvement of low BDNF expression in HD pathogenesis, potentially mediated by cAMP, MAPK and Ras signaling pathways.

S-adenosylmethionine reduces the inhibitory effect of Aβ on BDNF expression through decreasing methylation level of BDNF exon Ⅳ in rats

The structure of brain-derived neurotrophic factor (BDNF) gene is complex, which is composed of eight non-coding exons and one coding exon, each of them has its own unique promoter. Multiple BDNF transcripts have distinct functional properties and epigenetic modulation of BDNF gene transcription is implicated in the neurological disorders. In the present study, rat models with amyloid-β (Aβ) intrahippocampal injection and PC12 cells were used to explore the role of DNA methylation in the promoters of BDNF exon Ⅳ and exon Ⅵ in BDNF suppression caused by Aβ. We found that Aβ inhibited BDNF expression accompanying with hypermethylation in BDNF exon Ⅳ promoter, meanwhile, S-adenosylmethionine (SAM), primary methyl donor, reversed the low BDNF expression through demethylation in BDNF exon Ⅳ promoter. No methylation change was observed in BDNF exon Ⅵ promoter. The alteration of DNA methylation caused by Aβ or SAM was mediated by DNA methyltransferase 3A (DNMT3A). These data suggest that methylation change in BDNF exon Ⅳ is involved in the regulation of BDNF expression by Aβ or SAM, and further support the view of specific epigenetic modifications of a certain BDNF gene transcript.

Elevated Thyroid Peroxidase Antibody Increases Risk of Post-partum Depression by Decreasing Prefrontal Cortex BDNF and 5-HT Levels in Mice.

Post-partum depression (PPD) is a common mental disease in the perinatal period that profoundly affects mothers and their offspring. Some clinical studies have found that PPD is related to thyroid peroxidase antibodies (TPOAbs); however, the mechanism underlying this relationship is unclear. Female C57BL/6 mice immunized with adenovirus encoding the cDNA of the full-length mTPO (mTPO-Ad) were used to establish the isolated TPOAb-positive mouse model in the present study. Maternal depressive-like behaviors were assessed using the forced swimming test (FST), sucrose preference test (SPT), and tail suspension test (TST) post-partum. The serum TPOAb titer was measured by enzyme-linked immunosorbent assay (ELISA) before pregnancy and post-partum. Furthermore, in the prefrontal cortex, the mRNA and protein expression levels of brain-derived neurotrophic factor (BDNF) were measured, serotonin (5-HT) levels were measured by ultra-high-performance liquid chromatography–tandem mass-spectrometry (UHPLC–MS/MS), and total thyroxine (TT4) levels were determined by ELISA. Compared with the controls, the mice immunized with mTPO-Ad displayed depressive behaviors, with a significantly lower sucrose preference (SP) at the 12-h time point and a longer immobility time in the FST and TST, which were accompanied by a lower expression of BDNF and 5-HT but no change in the TT4 concentration in the prefrontal cortex. Together, these findings suggest that elevated TPOAb may increase the risk of subsequent PPD and decrease the concentration of BDNF and 5-HT in the prefrontal cortex.

S-adenosylmethionine Administration Attenuates Low Brain-Derived Neurotrophic Factor Expression Induced by Chronic Cerebrovascular Hypoperfusion or Beta Amyloid Treatment.

Chronic cerebrovascular hypoperfusion is a high-risk factor for Alzheimer's disease (AD) as it is conducive to beta amyloid (Aβ) over-production. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family widely expressed in the central nervous system. The structure of the rat BDNF gene is complex, consisting of eight non-coding exons (I-VIII) and one coding exon (IX). The BDNF gene is transcribed from multiple promoters located upstream of different 5' non-coding exons to produce a heterogeneous population of BDNF mRNAs. S-adenosylmethionine (SAM) produced in the methionine cycle is the primary methyl donor and the precursor of glutathione. In this study, a cerebrovascular hypoperfusion rat model and an Aβ intrahippocampal injection rat model were used to explore the expression profiles of all BDNF transcripts in the hippocampus with chronic cerebrovascular hypoperfusion or Aβ injection as well as with SAM treatment. We found that the BDNF mRNAs and protein were down-regulated in the hippocampus undergoing chronic cerebrovascular hypoperfusion as well as Aβ treatment, and BDNF exons IV and VI played key roles. SAM improved the low BDNF expression following these insults mainly through exons IV and VI. These results suggest that SAM plays a neuroprotective role by increasing the expression of endogenous BDNF and could be a potential target for AD therapy.

Editorial: Cell and molecular signaling, and transport pathways involved in growth factor control of synaptic development and function.

Since the discovery of nerve growth factor (NGF) more than a half century ago (Levi-Montalcini and Cohen, 1960), the prototypic neurotrophin family has included brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Neurotrophins bind to the Trk family of receptors, as well as the p75 receptor, to activate multiple intracellular signaling cascades (reviewed by Reichardt, 2006). BDNF receptor tropomyosin receptor kinase B (TrkB) signaling has been extensively studied for its roles in the central nervous system (CNS) ranging from cell survival, axonal and dendritic growth and synapse formation. The pathway mediates long-lasting activity-modulated synaptic changes on excitatory and inhibitory neurons and plays critical roles in circuit development and maintenance. In addition to BDNF, many studies have identified other “growth” or signaling factors in the CNS that play important roles in the development, maintenance, and control of synaptic and circuit function. However, details of the intracellular signaling systems downstream of these events are frequently unexplored. In this Research Topic, we have collected original studies and review articles that present cellular and molecular mechanisms concerning activity-dependent synapse formation and their implications for behavior and brain disorders. Vadodaria and Jessberger discuss synapse maturation in adult-born dentate granule cells and the role of BDNF-TrkB and several other signaling pathways that activate Cdc42, Rac1, and RhoA (Vadodaria and Jessberger, 2013). These small Rho GTPases regulate polymerization of actin and microtubules, and are consequently involved in aspects of neuronal maturation ranging from cell migration, to dendritic arborization, spine maturation, and synaptic integration of these newborn hippocampal neurons. Kellner et al. show that BDNF is critical for activity-dependent maintenance of mature spines through F-actin polymerization (Kellner et al., 2014). Integrity of this spine cytoskeleton is also critical for the vesicular transport, carried out by molecular motor proteins. For example, Myosin Va is a plus end actin, vesicular motor protein that carries postsynaptic density protein 95 (PSD-95), Synapse-associated protein 90/postsynaptic density-95-associated protein (SAPAP) and Shank, an essential glutamate receptor scaffold complex along actin to the postsynaptic membrane at the tip of dendritic spines (Hammer and Wagner, 2013; Yoshii et al., 2013). Furthermore, BDNF-TrkB signaling triggers transport of the vesicles containing PSD-95 and its associated complex to postsynaptic membranes via activation of PI3-kinase-Akt pathway (Yoshii and Constantine-Paton, 2007). BDNF-TrkB signaling pathway also regulate the molecular assembly of synaptic membrane. Zonta and Miniciello discuss the emerging role of lipid raft, the detergent resistant lipid microdomain enriched with cholesterol and sphingolipid, in synaptic plasticity as a result of neurotrophin signaling (Zonta and Minichiello, 2013). When BDNF binds to the TrkB receptor, the ligand-receptor complex shifts to lipid rafts via activation of tyrosine kinase Fyn (Pereira and Chao, 2007; Suzuki et al., 2007). Lipid raft is enriched in postsynaptic membrane, and facilitates localization of palmitoylated proteins such as PSD-95, which is a critical regulator of synaptic plasticity at excitatory synases. Palmitoylation of PSD-95 in the cell body is also mediated by BDNF-TrkB signaling via activation of phospholipase Cγ (PLCγ) and protein kinase C (PKC). The PKC inhibitors chelerythrine as well as a synthetic zeta inhibitory peptide (ZIP) designed to block the brain-specific PKC isoform protein kinase Mζ (PKMζ) were used to demonstrate this effect (Yoshii et al., 2011). However, additional studies in the hippocampus began to raise concerns about the specificity of ZIP (Lee et al., 2013; Volk et al., 2013). A follow-up study by Yoshii and Constantine-Paton in this Topic confirmed that, while both chelerythrine and ZIP could suppress the postsynaptic localization of PSD-95, PKMζ knock-down with RNA interference did not exhibit this effect. The result indicates that the ZIP peptide, widely used as a “specific” PKMζ antagonist, may block another PKC variant that is the kinase actually involved in PSD-95 palmitoylation in cell body. BDNF is critical for mechanisms underlying various modalities of sensory processing, cognition and behaviors. These roles have been studied in hippocampal learning and memory (reviewed by Minichiello, 2009), in maturation and plasticity of the CNS and also in neurological disease (reviewed by Yoshii and Constantine-Paton, 2010). It is not surprising that BDNF is associated with brain disorders such as epilepsy, autism, depression, and schizophrenia since all of these have chronic effects on synaptic function. However, Andersen and Sonntag have studied the effect of juvenile exposure to psychostimulants on the risk of cocaine addiction in adulthood. They found that treatment with methylphenidate, frequently used to improve attention in children, has a long-lasting suppressive effect on cocaine-induced increases in BNDF expression (Andersen and Sonntag, 2014). Further studies will hopefully identify the mechanisms underlying the critical period effect on addiction as well as long term effect of stimulants. Neurotrophic factors also affect feeding. Maekawa et al. have shown that low BDNF expression in the ventromedial hypothalamus correlates with blood glucose level, increased leptin secretion and eating, and visceral fat accumulation in a type 2 diabetic rat line (Maekawa et al., 2013). The results indicate BDNF and leptin play major roles in central regulation of energy metabolism and dysregulation of the neurotrophin signaling result in obesity. Harvey discusses that leptin regulates synaptic functions (Harvey, 2013). This dietary hormone activates extracellular-signal-regulated kinase (ERK) and facilitates GluN2B-mediated synaptic depression during early postnatal development while it regulates LTP through PI3-kinase pathway in adult hippocampus (Moult and Harvey, 2011). It is now clear that variety of synaptogenic growth factors are wider than previously thought. Two articles review diversity of these factors. Williams and Umemori discuss members of the fibroblast growth factor (FGF) family in the context of synaptic development (Williams and Umemori, 2014). FGFs have been shown to organize presynaptic vesicle clustering. Remarkably, FGF7-null mice exhibit a specific deficit in hippocampal inhibitory synapse formation while FGF22-null mice are deficient in excitatory synapses (Terauchi et al., 2010). Furthermore, FGF7-null animals are prone to develop epilepsy after kindling, while FGF22-null are resistant to this seizure induction. Poon et al. provide a comprehensive review of Netrin, Wnt, transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), all of which were first identified for their roles other than synaptogenesis (Poon et al., 2013). For example, UNC-6/netrin and its receptor UNC-5 were originally described as axonal guidance molecules. However, UNC-6 and UNC-5 facilitate localization of presynaptic proteins to axons by excluding them from dendrites (Poon et al., 2008). Consequently, these pathway are all involved in regulating axonodendritic polarity. The field of neuronal growth factors is continuing to grow, and new discoveries, some which are highlighted in this volume, will prompt new questions. For example, do these growth factors work together, competitively or separately? Is there cell-type specificity for each factor? Do they play a deterministic or a modulatory role in synaptic specificity during development ? Advances in genomics and proteomics will help us understand not only single cascade but also multiple signaling pathways as network. Various genetic tools allow spacial and temporal controls of gene expression and neuronal activities (Boyden et al., 2005; Arenkiel and Ehlers, 2009; Konermann et al., 2013). Super-resolution microscopy enables observations of signaling molecules at synapse and organelles in unprecedented manner. Multi-photon microscopy has been invaluable to study a wide range of structures from individual spines to neuronal circuitry. Applications of these new technologies will create exciting opportunities to tackle the above and other questions.

Antidepressant-like effects of cordycepin in a mice model of chronic unpredictable mild stress.

Cordycepin (3′-deoxyadenosine), a major bioactive component isolated from Cordyceps militaris, has multiple pharmacological activities. This study is attempted to investigate whether cordycepin (COR) possesses beneficial effects on chronic unpredictable mild stress- (CUMS-) induced behavioral deficits (depression-like behaviors) and explore the possible mechanisms. ICR mice were subjected to chronic unpredictable mild stress for 42 consecutive days. Then, COR and fluoxetine (FLU, positive control drug) were administered for 21 consecutive days at the last three weeks of CUMS procedure. The classical behavioral tests, open field test (OFT), sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST), were applied to evaluate the antidepressant effects of COR. Then the serotonin (5-HT) and noradrenaline (NE) concentrations in hippocampal were evaluated by HPLC; tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in hippocampal were evaluated, and the proteins of TNF-α, IL-6, NF-κBP65 5-HT2A receptor (5-HT2AR), and brain-derived neurotrophic factor (BDNF) in hippocampal were evaluated by Western blot. Our results indicated that 6 weeks of CUMS exposure induced significant depression-like behavior, with low 5-HT and NE levels, high TNF-α and IL-6 in brain and high hippocampal TNF-α, IL-6, P-NF-κBP65, and 5-HT2AR levels, and low BDNF expression levels. Whereas, chronic COR (20, 40 mg/kg) treatments reversed the behavioral deficiency induced by CUMS exposure, treatment with COR normalized the change of TNF-α, IL-6, 5-HT, and NE levels, which demonstrated that COR could partially restore CUMS-induced 5-HT receptor impairments and inflammation. Besides, hippocampal BDNF expressions were also upregulated after COR treatments. In conclusion, COR remarkably improved depression-like behavior in CUMS mice and its antidepressant activity is mediated, at least in part, by the upregulating BDNF and downregulating 5-HT2AR levels and inflammation in hippocampus.

Involvement of Brain‐Derived Neurotrophic Factor and Neurogenesis in Oestradiol Neuroprotection of the Hippocampus of Hypertensive Rats

The hippocampus of spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)-salt hypertensive rats shows decreased cell proliferation and astrogliosis as well as a reduced number of hilar cells. These defects are corrected after administration of 17β-oestradiol (E(2) ) for 2 weeks. The present work investigated whether E(2) treatment of SHR and of hypertensive DOCA-salt male rats modulated the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin involved in hippocampal neurogenesis. The neurogenic response to E(2) was simultaneously determined by counting the number of doublecortin-immunopositive immature neurones in the subgranular zone of the dentate gyrus. Both hypertensive models showed decreased expression of BDNF mRNA in the granular zone of the dentate gyrus, without changes in CA1 or CA3 pyramidal cell layers, decreased BDNF protein levels in whole hippocampal tissue, low density of doublecortin (DCX)-positive immature neurones in the subgranule zone and decreased length of DCX+ neurites in the dentate gyrus. After s.c. implantation of a single E(2) pellet for 2 weeks, BDNF mRNA in the dentate gyrus, BDNF protein in whole hippocampus, DCX immunopositive cells and the length of DCX+ neurites were significantly raised in both SHR and DOCA-salt-treated rats. These results indicate that: (i) low BDNF expression and deficient neurogenesis distinguished the hippocampus of SHR and DOCA-salt hypertensive rats and (ii) E(2) was able to normalise these biologically important functions in the hippocampus of hypertensive animals.

BDNF genotype moderates the relation between physical activity and depressive symptoms.

To test whether the BDNF gene interacts with exercise to predict depressive symptoms. Physical activity is associated with a range of positive health outcomes, including fewer depressive symptoms. One plausible mechanism underlying these findings involves Brain-Derived Neurotrophic Factor (BDNF), a protein hypothesized to limit or repair the damage caused by stress. Physical activity increases expression of BDNF, which may enhance brain health. BDNF expression is controlled by the BDNF gene. Compared with individuals without a BDNF met allele, met-allele carriers have a lower expression of BDNF, which has been associated with Major Depressive Disorder. Eighty-two healthy adolescent girls were genotyped for the BDNF val66met polymorphism, and their depressive symptoms and physical activity were assessed using questionnaires. BDNF genotype, Children's Depression Inventory, and the Physical Activity Questionnaire for Older Children and Adolescents. The BDNF polymorphism was found to moderate the relation between exercise and depressive symptoms: being physically active was protective for girls with a BDNF met allele (fewer depressive symptoms) but not for girls with the val/val polymorphism. By integrating psychological and biological factors, the present study enhances our understanding of how physical activity contributes to resilience to psychopathology.

Brain-derived neurotrophic factor: role in depression and suicide.

Depression and suicidal behavior have recently been shown to be associated with disturbances in structural and synaptic plasticity. Brain-derived neurotrophic factor (BDNF), one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons and in synaptic plasticity. Several lines of evidence suggest that BDNF is involved in depression, such that the expression of BDNF is decreased in depressed patients. In addition, antidepressants up-regulate the expression of BDNF. This has led to the proposal of the "neurotrophin hypothesis of depression". Increasing evidence demonstrates that suicidal behavior is also associated with lower expression of BDNF, which may be independent from depression. Recent genetic studies also support a link of BDNF to depression/suicidal behavior. Not only BDNF, but abnormalities in its cognate receptor tropomycin receptor kinase B (TrkB) and its splice variant (TrkB.T1) have also been reported in depressed/suicidal patients. It has been suggested that epigenetic modulation of the Bdnf and Trkb genes may contribute to their altered expression and functioning. More recently, impairment in the functioning of pan75 neurotrophin receptor has been reported in suicide brain specimens. pan75 neurotrophin receptor is a low-affinity neurotrophin receptor that, when expressed in conjunction with low availability of neurotropins/Trks, induces apoptosis. Overall, these studies suggest the possibility that BDNF and its mediated signaling may participate in the pathophysiology of depression and suicidal behavior. This review focuses on the critical evidence demonstrating the involvement of BDNF in depression and suicide.