Role Of Brain-derived Neurotrophic Factor Research Articles

Alteration of BDNF in the medial prefrontal cortex and the ventral hippocampus impairs extinction of avoidance.

Brain-derived neurotrophic factor (BDNF) is critical for establishing activity-related neural plasticity. There is increasing interest in the mechanisms of active avoidance and its extinction, but little is known about the role of BDNF in these processes. Using the platform-mediated avoidance task combined with local infusions of an antibody against BDNF, we show that blocking BDNF in either prelimbic (PL) or infralimbic (IL) medial prefrontal cortex during extinction trainingimpairs subsequent recall of extinction of avoidance, differing from extinction of conditioned freezing. By combining retrograde tracers with BDNF immunohistochemistry, we show that extinction of avoidance increases BDNF expression in ventral hippocampal (vHPC) neurons, but not amygdala neurons, projecting to PL and IL. Using the CRISPR/Cas9 system, we further show that reducing BDNF production in vHPC neurons impairs recall of avoidance extinction. Thus, the vHPC may mediate behavioral flexibility in avoidance by driving extinction-relatedplasticity via BDNFergic projections to both PL and IL. These findings add to the growing body of knowledge implicating the hippocampal-prefrontal pathway in anxiety-related disorders and extinction-based therapies.

Abstract 114: A Role for Brain-derived Neurotrophic Factor in Duchenne Cardiomyopathy

Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB) harbor cardioprotective qualities that may attenuate CM. In a small cohort of DMD patients we found that BDNF blood levels positively correlated with preserved ejection fraction (EF) and less fibrosis, and carriers of the common BDNF single nucleotide polymorphism rs6265 (Val66-Met) tended to exhibit earlier age of onset of fibrosis with subsequent progression to LV dysfunction, compared to non-carriers. We thus hypothesized that BDNF/TrkB signaling delays CM progression in DMD. To test this hypothesis, we administered the TrkB agonist 7,8-dihydroxyflavone (DHF) to mdx 4cv ; mTR KO mice in their drinking water for 26 weeks, beginning at 8 weeks of age. Based on echocardiography, DHF treatment preserved cardiac output compared to vehicle-treated controls. Conversely, mdx 4cv ; mTR KO mice injected intraperitoneally with the TrkB inhibitor (K252a) displayed bradycardia and PR interval prolongation, as measured by EKG, as well as acute (10-20 min) reduction in percent EF and fractional shortening, as measured by echocardiography. K252a also significantly reduced sarcomere shortening in isolated murine cardiomyocytes. BDNF might also contribute to cardiac repair. Using humanized BDNF polymorphic mice, which have the Val66-Met mutation, we found that post-myocardial infarction cardiac dysfunction was significantly exacerbated in Met/Met mice compared to Val/Val littermate controls. Finally, we evaluated the role of BDNF/TrkB in human cardiomyocytes differentiated from induced pluripotent cells obtained from DMD patients (DMD iPSC-CMs) and found that they highly express BDNF protein in lysates and supernatants. DMD iPSC-CMs also expressed a truncated version of TrkB that lacks the tyrosine kinase domain essential for canonical BDNF/TrkB signaling. Nonetheless, DMD iPSC-CMs responded to treatment with recombinant BDNF, including increased phosphorylation of GSK-3α, mTOR, AMPK, and MSK1/2. Considered together, our results indicate that BDNF plays a protective role in the dystrophic heart and might represent a novel therapeutic candidate for DMD cardiomyopathy.

Potential Role of Brain-Derived Neurotrophic Factor and Dopamine Receptor D2 Gene Variants as Modifiers for the Susceptibility and Clinical Course of Wilson's Disease.

Wilson's disease (WD), an inborn error of copper metabolism caused by mutations in the ATPase copper transporting beta (ATP7B) gene, manifests variable age of onset and different degrees of hepatic and neurological disturbances. This complex phenotypical outcome of a classical monogenic disease can possibly be explained by modifier loci regulating the clinical course of the disease. The brain-derived neurotropic factor (BDNF), critical for the survival, morphogenesis, and plasticity of the neurons, and the dopamine receptor D2 (DRD2), one of the most abundant dopamine receptors in the brain, have been highlighted in the pathophysiology of various neuropsychiatric diseases. This study aims to identify the potential association between BDNF and DRD2 gene polymorphisms and WD and its clinical characteristics. A total of 164 WD patients and 270 controls from India were included in this study. Two BDNF polymorphisms [p.Val66Met (c.G196A) and c.C270T] and the DRD2 Taq1A (A2/A1 or C/T) polymorphism were examined for their association with WD and some of its clinical attributes, using polymerase chain reaction, restriction fragment length digestion, and bidirectional sequencing. The C allele and CC genotype of BDNF C270T were significantly overrepresented among controls compared to WD patients. In addition, a significantly higher proportion of the allele coding for Val and the corresponding homozygous genotype of BDNF Val66Met polymorphism was found among WD patients with age of onset later than 10years. Furthermore, the A1A1 genotype of DRD2 Taq1A polymorphism was significantly more common among WD patients with rigidity. Our data suggest that both BDNF and DRD2 may act as potential modifiers of WD phenotype in the Indian context.

Abstract 5220: The role of brain-derived neurotrophic factor in ovarian cancer initiation and progression

Abstract Ovarian cancer is one of the most devastating cancers in women. A fundamental step toward improving detection and treatment of this lethal disease is to understand the mechanism of its initiation and progression. In this study we demonstrated the role of brain-derived neurotrophic factor (BDNF) in ovarian cancer initiation and progression, particularly, the high-grade serous ovarian carcinoma (HGSOC). BDNF was discovered in the brain as a growth factor and chemoattractant inducing the migration, survival, and differentiation of neurons. It is also secreted by the ovary into the follicular fluid and by the adipocytes in the omentum and peritoneum. BDNF suppresses anoikis, the apoptosis induced by lack of proper cell to extra-cellular matrix (ECM) attachment. BDNF has been associated with tumor progression in colon, breast, lung, and gastric cancers. In ovarian tumors both BDNF and its receptor tropomyosin receptor kinase B (TrkB) are expressed. Their overexpression is associated with poor survival. Fallopian tube epithelial cells (FTEs) are hypothesized to be the cell of origin of HGSOC. We used 3 immortalized human normal FTE cell lines to demonstrate the effects of BDNF on the survival, mobility, and adhesion of FTEs in vitro. CellTiter luminescent cell viability assays were conducted to evaluate the effects of BDNF on the short-term and long-term survival of FTEs in 3D culture conditions. Caspase-3 activity assays were used to quantify the extent of which BDNF inhibited anoikis in FTEs. Trans-well and 3D bioprinting migration assays were used to determine whether BDNF could promote the mobility of FTEs. The ECM-coated beads were co-cultured with FTEs in a 3D model and their attachment to ECM was quantified in order to evaluate the effects of BDNF on the cell adhesion. The BDNF-activated intracellular pathways were identified using Western blots, RNA microarray, RT-QPCR analyses. Our data demonstrated that TrkB was expressed by the FTEs in human and mouse fallopian tubes. BDNF significantly enhanced the survival of FTE cell lines in the serum-free 3D culture condition. Their enhanced survival was also evidenced by the decreased caspase-3 activity indicating the inhibition of anoikis. BDNF increased the ability of FTEs to migrate in the migrations assays. The BDNF-treated FTEs attached to the ECM-coated beads faster than the untreated cells. Western blots showed that BDNF activated the phosphorylation of TrkB, AKT, ERK, PLC-gamma1, and CREB. RNA microarray and QPCR data suggest that epithelial-mesenchymal transition (EMT), anti-oxidative stress, and ECM-related pathways were activated by BDNF leading to the enhanced survival, migration, and cell adhesion. These results revealed the potential role of BDNF to promote ovarian cancer initiation. Understanding this molecular pathway will lead to the development of more specific markers for early detection and better prevention and treatment strategies. Citation Format: Min Kang, Kay Y. Chong, Tobias M. Hartwich, Oluwagbemisola O. Madarikan, Jonah Nucci, Sarah L. Cady, Yang Yang-Hartwich. The role of brain-derived neurotrophic factor in ovarian cancer initiation and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5220.

Role of Brain-Derived Neurotrophic Factor in Endometriosis Pain.

Brain-derived neurotrophic factor (BDNF) is a regulator for the formation and maintenance of chronic pain in various chronic disorders and has been shown to increase in the serum of women with endometriosis. However, BDNF expression in the peritoneal fluid (PF) and ectopic lesions and its role in endometriosis pain remain unclear. Thus, this study aims to determine the BDNF concentrations in serum and PFs and BDNF expression levels in ectopic lesions and endometriotic stromal cells (ESCs) of women with endometriosis (n = 60). The obtained results were then compared with those of women without endometriosis (n = 38). Brain-derived neurotrophic factor concentrations in serum and PF, as well as the BDNF expression levels in ectopic lesions and endometriotic cells, were evaluated through enzyme-linked immunosorbent assay, immunohistochemical staining, quantitative real-time polymerase chain reaction, and Western blot analysis. As a result, BDNF concentrations in serum and PF were significantly higher in women with endometriosis with pain (2284.3 ± 51.5 pg/mL, n = 23; 58.8 ± 6.4 pg/mL, n = 16) than in women with endometriosis without pain (1999.8 ± 61.1 pg/mL, n = 37; 31.7 ± 2.9 pg/mL, n = 25; P < .01). Moreover, BDNF messenger RNA (mRNA) expression levels in ectopic lesions (8.97 ± 1.44, n = 29) were significantly higher than eutopic (0.97 ± 0.14, n = 16; P < .01) and control endometrium (1.23 ± 0.19, n = 18; P < .01) and were correlated with endometriosis pain ( P < .05). Furthermore, increased BDNF mRNA and protein expression levels in ESCs induced by estradiol or interleukin 1β were removed using a phosphorylated extracellular-regulated protein kinase 1/2 inhibitor. These results suggest that BDNF may play an important role in the pathogenesis of endometriosis pain.

Maternal voluntary exercise ameliorates learning deficit in rat pups exposed, in utero, to valproic acid; role of BDNF and VEGF and their receptors

In utero exposure to therapeutic doses of valproic acid (VPA) during pregnancy can produce physical malformation and CNS abnormalities in the offspring. There is evidence indicating that even lower doses of VPA during pregnancy could cause cognitive impairment in offspring. It has been demonstrated that maternal exercise has positive effects on offspring's cognitive function. In this study we evaluated the preventive potential of maternal voluntary exercise on cognitive deficits induced by in utero exposure to VPA, in rat pups. Furthermore, the alteration of hippocampal brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) and their respective receptors were measured. In treatment groups, pregnant rats received VPA (10 and 20 mg/kg) daily on the gestation days (GD) 7 for twelve days with or without access to a running wheel. In control groups, rats received saline with or without access to a running wheel. On postnatal day (PND) 30, learning and memory of rat pups were assessed using the Morris Water Maze (MWM) task. Also, on PND 30, hippocampal BDNF and VEGF were measured by ELISA and western blot analysis respectively. VEGFR (VEGF receptor) and TrkB (Tyrosine receptor kinase B, the receptor for BDNF) expressions were assessed using immunofluorescence staining. Results revealed that maternal voluntary exercise enhanced learning in offspring but had little effect on memory retention. Exposure to VPA during pregnancy disturbed learning and memory in rat pups. Maternal voluntary exercise could ameliorate some aspects of cognitive deficit induced by VPA. TrkB and VEGFR2 expression were enhanced in pups from running mothers. VPA, at both doses, suppressed exercise induced expression of these two receptors. Voluntary exercise and to a much greater extent VPA administration increased hippocampal BDNF. Voluntary exercise of mothers caused an enhance expression of VEGF in rat pups as did VPA administration, although to a smaller amount.

Effects of levothyroxine on learning and memory deficits in a rat model of Alzheimer’s disease: the role of BDNF and oxidative stress

The effect of levothyroxine (L-T4) on the learning and memory impairment induced by streptozotocin (STZ) and brain tissue oxidative damage in rats was evaluated. An animal model of the Alzheimer’s disease (AD) was established by intracerebroventricular injection of STZ (3 mg/kg) in male Wistar rats (250 ± 50 g). After that, the rats were treated for 3 weeks with L-T4 (10, 100 μg/kg) or normal saline. Passive avoidance (PA) learning and spatial memory were evaluated using shuttle box and Morris water maze (MWM), respectively. Finally, the rats were euthanized, their blood samples were collected for further thyroxine assessment and their brains were removed after decapitation in order to measure the oxidative stress parameters and brain-derived neurotrophic factor (BDNF). In the MWM, latency (s) increased in the AD rats compared with the normal control group while it decreased in the 10 μg/kg L-T4 injected AD rats compared with the AD group. In the PA, the latency for entering the dark compartment was lower in the AD group than in the normal control group and it decreased in the 10 μg/kg L-T4 injected AD rats. The low dose of L-T4 (10 μg/kg) reduced malondialdehyde concentration but increased thiols concentration, superoxide dismutase, catalase activities and BDNF level in hippocampal tissues of the AD rats. Injection of L-T4 (10 μg/kg) alleviated memory deficits and also improved factors of oxidative stress and BDNF level in the STZ-induced AD rats.

Role of brain-derived neurotrophic factor in the pathogenesis of distention-associated abdominal pain in bowel obstruction.

Previous studies found that visceral sensitivity is increased in bowel obstruction (BO). We hypothesized that mechanical stress-induced expression of BDNF in smooth muscle cells (SMC) of the distended bowel plays a critical role in visceral hypersensitivity in BO by altering voltage-gated K+ channel (Kv ) activity in sensory neurons. Partial colon obstruction was maintained in rats for 7days. Colon-projecting neurons in the dorsal root ganglia (DRG, T13 to L2) were isolated for electrophysiological and gene expression studies. Compared to controls, membrane excitability of colon-projecting DRG neurons was markedly enhanced in BO. The densities of total Kv and transient A-type (IA ) K+ currents, but not sustained delayed IK current, were significantly reduced in the neurons in BO. The mRNA expression of IA subtype Kv 1.4 in colon neurons was down-regulated in BO. Expression of BDNF mRNA and protein was dramatically increased in colonic smooth muscle of the distended segment, but not in the non-distended aboral segment. Mechanical stretch of colon SMC in vitro increased BDNF expression. Treatment with anti-BDNF antibody restored total Kv and IA currents of neurons from BO rats. Administration of Trk B inhibitor ANA-12 blocked BO-associated changes of neuronal excitability, Kv activity and gene expression in obstruction. Mechanical stress-induced expression of BDNF in colon SMC plays a critical role in visceral hypersensitivity in BO by suppressing A-type K+ currents and gene expression in sensory nerve. These findings help to identify therapeutic targets for distention-associated abdominal pain in the gut.

11.2 THE IMPACT OF AEROBIC EXERCISE ON COGNITIVE FUNCTIONING AND BIOMARKERS OF COGNITIVE CHANGE IN INDIVIDUALS WITH SCHIZOPHRENIA

BackgroundIndividuals with schizophrenia (SZ) display substantial cognitive deficits across multiple domains. These deficits have been identified as major determinants of poor functioning and disability, representing a serious public health concern and an important target for interventions. At present, available treatments offer only minimal to limited benefits to ameliorate these deficits. Thus, there remains an urgent need to identify novel treatments for cognitive deficits in people with SZ. Emerging evidence from studies of animals, clinical and non-clinical populations suggest that Aerobic Exercise (AE) is efficacious in improving cognition via up-regulation of Brain-Derived Neurotrophic Factor (BDNF). Yet, the impact of AE on cognition and daily-functioning, and the role of BDNF, have not been investigated in schizophrenia. Additionally, limited information is available on the putative link between inflammation markers to cognitive functioning.MethodsEmploying a single-blind RCT design, 33 individuals with schizophrenia were randomized to receive “treatment as usual” (n=17; TAU) or attend a 12-week, 3 times-per-week, 60-minutes AE program (n=16) utilizing active-play video-games (Xbox-360 Kinect) and traditional AE equipment.ResultsAt baseline, cognitive functioning was associated with serum BDNF (r=.51, p=.01), along with TNF-alpha (r=-.38, p=.03), IL-12 (r=-.36, p=.04) and IL-6 (r=-.33, p=.06). Twenty-six participants completed the study (79%). Following the intervention, the AE participants improved their cognitive functioning (MCCB) by 15.1% (vs. -2.0% in the TAU group; p=.03). Hierarchical multiple-regression analyses indicated changes in AF and serum BDNF predicted 25.4% and 14.6% of the cognitive improvement, respectively. Additionally, changes in aerobic fitness (VO2peak ml/kg/min) correlated with informant-reported improvements in work-related daily-functioning skills (SLOF; r=.51, p=.01). Fidelity with target training intensity, was correlated with cognitive improvement (r=.70, p=.02).DiscussionThe results indicate AE is effective in enhancing cognitive and daily functioning skills in people with schizophrenia and provide support for the impact of AE-related BDNF up-regulation on cognition. Additional studies are needed to establish the link between inflammation markers and cognitive functioning and the potential impact of AE on this putative pathway. Overall, low aerobic fitness represents a modifiable risk-factor for cognitive dysfunction in schizophrenia for which AE training offer a relatively safe, non-stigmatizing, and side-effect-free intervention.

Antidepressant effects of aqueous extract of saffron and its effects on CREB, P-CREB, BDNF, and VGF proteins in rat cerebellum.

ObjectiveThe role of BDNF (brain-derived neurotrophic factor), CREB (cAMP response element binding) and VGF neuropeptide has been proved in antidepressant activity of long term saffron administration in the rat hippocampus. In this study we evaluated the role of these proteins in antidepressant activity of saffron in long term administration in the rat cerebellum.MethodsSaffron aqueous extract (40 and 80 mg/kg/day) and imipramine (10 mg/kg/day) were administered intraperitoneally for 21 days to rats. At the end of experiment, animals were sacrificed and cerebellums were separated. The protein levels of BDNF, VGF, CREB and P- CREB in the rat cerebellum were evaluated using western blot analysis.ResultsSaffron aqueous extract (80mg/kg/day) caused significant increase in protein level of P-CREB in long term treatment in the rat cerebellum. The increases in the protein levels of VGF, CREB and BDNF were not significant.ConclusionIn summary, our results showed that antidepressant effect of saffron in rat cerebellum might be due to the enhanced phosphorylation of CREB.

Brain-derived neurotrophic factor modulates cholesterol homeostasis and Apolipoprotein E synthesis in human cell models of astrocytes and neurons.

In the central nervous system, cholesterol is critical to maintain membrane plasticity, cellular function, and synaptic integrity. In recent years, much attention was focused on the role of cholesterol in brain since a breakdown of cholesterol metabolism has been associated with different diseases. Brain-derived neurotrophic factor (BDNF) was previously reported to elicit cholesterol biosynthesis and promote the accumulation of presynaptic proteins in cholesterol-rich lipid rafts, but no data are available on its ability to modulate physiological mechanisms involved in cholesterol homeostasis. Major aim of this research was to investigate whether BDNF influences cholesterol homeostasis, focusing on the effect of the neurotrophin on Apolipoprotein E (ApoE) synthesis, cholesterol efflux from astrocytes and cholesterol incorporation into neurons. Our results show that BDNF significantly stimulates cholesterol efflux by astrocytes, as well as ATP binding cassette A1 (ABCA1) transporter and ApoE expression. Conversely, cholesterol uptake in neurons was downregulated by BDNF. This effect was associated with the increase of Liver X Receptor (LXR)-beta expression in neuron exposed to BDNF. The level of apoptosis markers, that is, cleaved caspase 3 and poly ADP ribose polymerase (PARP), was found increased in neurons treated with high cholesterol, but significantly lower when the cells were exposed to cholesterol in the presence of BDNF, thus suggesting a neuroprotective role of the neurotrophin, likely through its reducing effect of neuronal cholesterol uptake. Interestingly, cholesterol stimulates BDNF production by neurons. Overall, our findings evidenced a novel role of BDNF in the modulation of ApoE and cholesterol homeostasis in glial and neuronal cells.

Expression of brain-derived neurotrophic factor in kidneys from normal and cyclosporine-treated rats

BackgroundAccumulating evidence suggests that a decrease in brain-derived neurotrophic factor (BDNF) level induces a variety of psychiatric and neurological disorders. However, the expression and role of BDNF in the kidney have not been explored. The present study examined the expression of BDNF and tropomyosin-related kinase (Trk) receptors in an experimental model of chronic cyclosporine A (CsA) nephropathy.MethodsSprague-Dawley rats on a salt-deplete diet were treated daily for four weeks with vehicle or CsA. Urine profiles, apoptotic cell death, oxidative stress (8-hydroxy-2′-deoxyguanosine, 8-OHdG), and expression of BDNF and Trk receptors (TrkB and TrkC) were compared between groups. The impact of vasopressin infusion on the urine-concentrating ability was examined by measuring the expression of aquaporin-2 (AQP-2) and BDNF and urine profiles in normal and CsA-treated rats.ResultsCompared with the vehicle-treated rats, rats given CsA had enhanced urine volume and declined urine osmolality. Immunohistochemistry and immunoblotting showed that BDNF and Trk receptors were constitutively expressed in kidneys from vehicle-treated rats. This was confirmed by double immunofluorescent staining for Na-K-ATPase-α1, AQP-1, and AQP-2. By contrast, the expression of these factors decreased in kidneys from CsA-treated rats (BDNF: 51.1 ± 19.5% vs. 102.0 ± 30.3%, p < 0.01). Downregulation of BDNF was accompanied by impairment of urine osmolality, and this was reversed by exogenous infusion of vasopressin. Notably, the number of TUNEL-positive cells correlated negatively with BDNF expression and positively with urinary 8-OHdG excretion.ConclusionsBDNF is expressed in the collecting duct of the kidney and may be associated with urine-concentrating ability in an experimental model of chronic CsA-induced nephropathy. Our study provides a new avenue for further investigation of chronic CsA nephropathy.

Methamphetamine binge administration during late adolescence induced enduring hippocampal cell damage following prolonged withdrawal in rats

A recent study from our laboratory demonstrated that binge methamphetamine induced hippocampal cell damage (i.e., impaired cell genesis) in rats when administered specifically during late adolescence (postnatal day, PND 54-57) and evaluated 24 h later (PND 58). The results also suggested a possible role for brain-derived neurotrophic factor (BDNF) regulating cell genesis and survival. This subsequent study evaluated whether these effects persisted in time as measured following prolonged withdrawal. Male Sprague-Dawley rats were treated (i.p.) with BrdU (2 × 50 mg/kg, 3 days, PND 48-50) followed by a binge paradigm (3 pulses/day, every 3 h, 4 days, PND 54-57) of methamphetamine (5 mg/kg, n = 14, M) or saline (0.9% NaCl, 1 ml/kg, n = 12, C). Following 34 days of forced withdrawal (PND 91), rats were killed 45 min after a challenge dose of saline (Sal: C-Sal, n = 6; M-Sal, n = 7) or methamphetamine (Meth: C-Meth, n = 6; M-Meth, n = 7). Neurogenesis markers (Ki-67: cell proliferation; NeuroD: early neuronal survival; BrdU: prolonged cell survival, 41–43 days old cells) were evaluated by immunohistochemistry while neuroplasticity markers (BDNF and Fos forms) were evaluated by Western blot. The main results showed that a history of methamphetamine administration (PND 54-57) induced enduring hippocampal cell damage (i.e., observed on PND 91) by decreasing cell survival (BrdU + cells) and mature-BDNF (m-BDNF) protein content, associated with neuronal survival, growth and differentiation. Interestingly, m-BDNF regulation paralleled hippocampal c-Fos protein content, indicating decreased neuronal activity, and thus reinforcing the persisting negative effects induced by methamphetamine in rat hippocampus following prolonged withdrawal.

Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex

Brain-derived neurotrophic factor (BDNF) is known to play a critical role early in the development of cortical GABAergic interneurons. Recently our laboratory and others have shown protracted development of specific subpopulations of GABAergic interneurons extending into adolescence. BDNF expression also changes significantly across adolescent development. However the role of BDNF in regulating GABAergic changes across adolescence remains unclear. Here, we performed a week-by-week analysis of the protein expression and cell density of three major GABAergic interneurons, parvalbumin (PV), somatostatin (SST) and calretinin (Cal) in the medial prefrontal cortex from prepubescence (week 3) to adulthood (week 12). In order to assess how BDNF and sex might influence the adolescent trajectory of GABAergic interneurons we compared WT as well as BDNF heterozygous (+/−) male and female mice. In both males and females PV expression increases during adolescent development in the mPFC. Compared to wild-types, PV expression was reduced in male but not female BDNF+/− mice throughout adolescent development. This reduction in protein expression corresponded with reduced cell density, specifically within the infralimbic prefrontal cortex. SST expression increased in early adolescent WT females and this upregulation was delayed in BDNF+/−. SST cell density also increased in early adolescent mPFC of WT female mice, with BDNF+/− again showing a reduced pattern of expression. Cal protein expression was also sex-dependently altered across adolescence with WT males showing a steady decline but that of BDNF+/− remaining unaltered. Reduced cell density in on the other hand was observed particularly in male BDNF+/− mice. In females, Cal protein expression and cell density remained largely stable. Our results show that PV, SST and calretinin interneurons are indeed still developing into early adolescence in the mPFC and that BDNF plays a critical, sex-specific role in mediating expression and cell density.

Brain-derived neurotrophic factor as a biomarker for cognitive recovery in acute schizophrenia: 12-week results from a prospective longitudinal study

It is generally accepted that impaired cognitive function is a core feature of schizophrenia. There is evidence for the role of brain-derived neurotrophic factor (BDNF) in cognitive function. Olanzapine was reported to yield cognitive improvement in patients with schizophrenia. In this study, we performed a prospective, open-label, 12-week observation trial to investigate whether peripheral BDNF may represent a potential biomarker for the effect of cognitive improvement induced by olanzapine in patients with schizophrenia. In total, 95 patients with acute schizophrenia were enrolled in the study. We also recruited 72 healthy individuals for a control group. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate symptom severity and treatment response. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Plasma BDNF levels were measured with an enzyme-linked immunosorbent assay. Of the 95 patients consented into the study, 68 completed the 12-week follow up. Our results showed that schizophrenia patients with acute exacerbation had significantly poorer performance than that of the controls (Ps < 0.01). A significantly decreased plasma level of BDNF in patients was observed compared with the controls (F = 7.77, P = 0.006). A significant improvement in each PANSS subscore and total score was observed when the patients completed this study (Ps < 0.01). Additionally, 12-week olanzapine treatment exhibited significant improvements in RBANS immediate memory, attention, and total scores (P = 0.018, 0.001, and 0.007, respectively). Along with the clinical improvement, plasma BDNF levels after 12-week olanzapine monotherapy (4.67 ± 1.74ng/ml) were also significantly increased compared with those at baseline (3.38 ± 2.11ng/ml) (P < 0.01). Spearman's correlation analysis showed that the increase in plasma levels of BDNF is significantly correlated with the change in the RBANS total scores (r = 0.28, P = 0.02) but not with the change in the PANSS total scores (r = - 0.18, P = 0.13). There is a significant correlation of BDNF increase with the change of RBANS attention subscore (r = 0.27, P = 0.028). Our findings suggest that olanzapine improves psychiatric symptoms and cognitive dysfunction, particularly attention and immediate memory, in patients with acute schizophrenia, in parallel with increased plasma BDNF levels. Plasma BDNF levels may be a potential biomarker for cognitive recovery in acute schizophrenia.

Suicide attempt, clinical correlates, and BDNF Val66Met polymorphism in chronic patients with schizophrenia.

Recent evidence suggests the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of suicidal behavior. Because schizophrenia patients usually have high suicide rates and numerous studies have suggested that BDNF may contribute to the psychopathology of schizophrenia, we hypothesized that the functional polymorphism of BDNF (Val66Met) was associated with suicide attempts in patients with schizophrenia in a Chinese Han population. This polymorphism was genotyped in 825 chronic schizophrenia patients with (n = 123) and without (n = 702) suicide attempts and 445 healthy controls without a history of suicide attempts using a case-control design. The schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale. There were no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls. However, we found the Val allele (p = .023) and the Val/Val genotypes (p = .058) to be associated with a history of suicide attempts. Moreover, some clinical characteristics, including age and cigarettes smoked each day, interacted with the BDNF gene variant and appeared to play an important role in suicide attempts among schizophrenia patients. The BDNF Val66Met polymorphism itself and its interaction with some clinical variables may influence suicide attempts among schizophrenia patients. (PsycINFO Database Record

Role of brain-derived neurotrophic factor during the regenerative response after traumatic brain injury in adult zebrafish.

Several mammalian animal models of traumatic brain injury have been used, mostly rodents. However, reparative mechanisms in mammalian brain are very limited, and newly formed neurons do not survive for long time. The brain of adult zebrafish, a teleost fish widely used as vertebrate model, possesses high regenerative properties after injury due to the presence of numerous stem cells niches. The ventricular lining of the zebrafish dorsal telencephalon is the most studied neuronal stem cell niche because its dorso-lateral zone is considered the equivalent to the hippocampus of mammals which contains one of the two constitutive neurogenic niches of mammals. To mimic TBI, stab wound in the dorso-lateral telencephalon of zebrafish was used in studies devoted to fish regenerative properties. Brain-derived neurotrophic factor, which is known to play key roles in the repair process after traumatic brain lesions, persists around the lesioned area of injured telencephalon of adult zebrafish. These results are extensively compared to reparative processes in rodent brain. Considering the complete repair of the damaged area in fish, it could be tempting to consider brain-derived neurotrophic factor as a factor contributing to create a permissive environment that enables the establishment of new neuronal population in damaged brain.

Environmental stimuli shape microglial plasticity in glioma.

In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, which contribute to tumor growth and to maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infiltrating myeloid cells, by modulating inflammatory gene expression. Under these conditions, the branching and patrolling activity of myeloid cells is increased, and their phagocytic activity is promoted. Modulation of gene expression depends on interferon-(IFN)-γ produced by natural killer (NK) cells. This modulation disappears in mice depleted of NK cells or lacking IFN-γ, and was mimicked by exogenous interleukin-15 (IL-15). Further, we describe a key role for brain-derived neurotrophic factor (BDNF) that is produced in the brain of mice housed in EE, in mediating the expression of IL-15 in CD11b+ cells. These data define novel mechanisms linking environmental cues to the acquisition of a pro-inflammatory, anti-tumor microenvironment in mouse brain.

Система мозгового нейротрофического фактора (BDNF) как мишень для создания лекарственных средств, восстанавливающих иннервацию

Мозговой нейротрофический фактор (BDNF) является одним из основных нейротрофических факторов, участвующих в поддержании функционирования и регенерации нервной системы. В последние годы BDNF рассматривают как многообещающую терапевтическую мишень, на основании полученных данных о том, что BDNF улучшает регенерацию нейронов. Цель обзора - суммировать данные об экспрессии BDNF, его сигнализации, эффектах и механизмах стимуляции реиннервации. Анализ исследований последних десятилетий позволяет сделать заключение о целесообразности и перспективности разработок, направленных на создание лекарственных препаратов на основе BDNF для регенерации компонентов нервной системы. Brain-derived neurotrophic factor (BDNF) is a major neurotrophic factor maintaining the nervous system function and regeneration. Based on reports indicating that BDNF enhances neuronal regeneration, in recent years, BDNF has been considered a promising therapeutic target. The aim of this review was to summarize current data on BDNF expression, signaling, and mechanisms for stimulation of reinnervation. Conclusion. Recent studies of the role of BDNF showed that continuation of research and development of BDNF-based drugs stimulating regeneration of nervous system components is advisable and promising.

06 LISWT Might Improve the Genitoperineal Sensation and Erectile Dysfunction in Neurogenic and Diabetic Patients

Recent scientific studies have shown different mechanisms for Low Intensity Shock Wave Therapy (LISWT) in treating Erectile Dysfunction (ED) that can be explained shortly by the following pathways: mechanical effect, vasculogenic effect, neurogenic effect, and stem cells stimulation and proliferation; all mediated through different growth factors: TGF-D1, BDNF, VEGF, and nitric oxide. The role of BDNF (Brain-Derived Neurotrophic factor) in promoting Cavernous Nerve regeneration in rats via SC-dependent Janus kinase (JAK)/signal transducer and activator of transcription (JAK/STAT) pathways led us to question and test the role of LISWT in improving the male genitoperineal sensation and Neurogenic ED in diabetic and neurogenic patients. A 48 year old man known to have syringomyelia disease, dyslipidemia, hypertension, and diabetes; with history of bilateral lower extremities paresthesia since the age of 32, perineal and genital numbness since the age of 29, was presented with severe numbness and mild to moderate ED. Patient received six weekly sessions of linear low intensity shock wave therapy (PiezoWave2 from Richard WOLF) with an energy flux density of 0.16mj/mm2 and frequency set to 8 Hz, wave focus penetration depth set to 10mm. Patient received 6000 shocks/session, 2000 shocks on the perineum (1000 each crus penis), 2000 shocks on dorsum penis, 2000 shocks on lateral aspect of penis (1000 each side). The IIEF-5 score and percentage of improvement of numbness (subjective improvement of the touch sensation) in the genitoperineal were documented during each session, after 1 month, 3 months, and 8 months of receiving LISWT.