TrkB mRNA Levels Research Articles

Preventing social defeat stress-induced behavioural and neurochemical alterations by repeated treatment with a mix of Centella asiatica, Echinacea purpurea and Zingiber officinale standardized extracts.

Background: Prolonged exposure to stress is a risk factor for the onset of several disorders. Modern life is burdened by a pervasive prevalence of stress, which represents a major societal challenge requiring new therapeutic strategies. In this context, botanical drug-based therapies can have a paramount importance. Methods: Here we studied the preventive effects of a repeated treatment (p.o. daily, 3weeks) with a combination of Centella asiatica (200mg/kg), Echinacea purpurea (20mg/kg) and Zingiber officinale (150mg/kg) standardized extracts, on the chronic social defeat stress (CSDS) deleterious outcomes. After 10days of CSDS exposure, male mice' performances were evaluated in paradigms relevant for social (social interaction test), emotional (tail suspension test), cognitive (novel object recognition) domains as well as for pain perception (cold plate and von Frey tests) and motor skills (rotarod). Mice were then sacrificed, the spinal cords, hippocampi and frontal cortices dissected and processed for RT-PCR analysis. Results: Extracts mix treatment prevented stress-induced social aversion, memory impairment, mechanical and thermal allodynia and reduced behavioural despair independently of stress exposure. The treatment stimulated hippocampal and cortical BDNF and TrkB mRNA levels and counteracted stress-induced alterations in pro- (TNF-α, IL-1β and IL-6) and anti-inflammatory (IL4, IL10) cytokines expression in the same areas. It also modulated expression of pain related genes (GFAP and Slc1a3) in the spinal cord. Conclusion: The treatment with the extracts mix obtained from C. asiatica, E. purpurea and Z. officinale may represent a promising strategy to promote resilience and prevent the deleterious effects induced by extended exposure to psychosocial stress.

Antidepressant Effect and Mechanism of Picea mariana Essential Oil on Reserpine-Induced Depression Model Mice.

The disturbance of brain biochemical substances serves as a primary cause and aggravating factor of depression. This study aimed to investigate the principal components of Picea mariana and its effect on reserpine-induced depression mice,w ith its relationship with brain central transmitters and related proteins. The main constituents of P. mariana essential oil (PMEO) were analyzed by GC-MS spectrometry. The quiescent time in the tail suspension test (TST) and forced swim test (FST), along with the weight change of the mice was detected. The number of normal neurons was quantified through Nissl staining. Immunohistochemistry was employed to determine the levels of 5HT-1A and 5HT-2A in the brain. Western blotting was utilized to detect 5HT-2A, CRF and TrkB protein levels. RT-qPCR was used to detect the mRNA levels of 5HT-1A, 5HT-2A, TrkB, CRF, and BDNF. The main active ingredients of PMEOs were (-) -bornyl acetate (44.95%), γ-Terpinene (14.17%), and β-Pinene (10.12%). PMEOs effectively improved the retardation and weight loss due to anorexia in depression-like mice. This improvement was associated with an increase in the number of normal neurons. After administering different doses of PMEOs, the levels of 5HT-1A, 5HT-2A, CRF, and TrkB were found to be increased in brain tissue. RT-qPCR revealed that the mRNA levels of CRF, 5HT-1A, and 5HT-2A were generally upregulated, whereas TrkB and BDNF were downregulated. PMEO can effectively alleviate depression induced by reserpine, which may be attributed to its regulation of 5HT-1A, 5HT-2A, CRF and TrkB protein expression, thus reducing brain nerve injury.

Network Pharmacology Combined with Animal Models to Investigate the Mechanism of ChangPu YuJin Tang in the Treatment of Tourette Syndrome.

ChangPu YuJin Tang (CPYJT) is a Chinese herbal formula that has been shown to be an effective therapeutic strategy for pediatric patients with Tourette Syndrome (TS). Using an integrated strategy of network pharmacology and animal model, the aim of this study was to investigate the mechanism of CPYJT in the treatment of TS. Compound libraries of CPYJT were established using databases, such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The TCMSP database and Swiss Target Prediction database were used to predict the targets. The above results were constructed into a CPYJT-Drug-Component-Target network. Moreover, TS targets were predicted using GeneCards and other databases. The targets corresponding to the potential ingredients in CPYJT and the targets corresponding to TS were taken as the intersections to construct the CPYJT-TS network. The target network was analysed by PPI using the string database. GO and KEGG enrichment analyses were performed on the target network. The whole process was performed using Cytoscape 3.7.2 to make visual network diagrams of the results. CPYJT was characterised by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS). Transmission Electron Microscopy (TEM) was used to observe the structural changes of CPYJT on the neuronal cells of the IDPN model rats. RT-PCR and Western Blot were used to analyse the changes in the mRNA and protein expression levels of BDNF, TrkB, PI3K, and AKT in the cortex, striatum, and thalamus brain regions after CPYJT administration in IDPN model rats. Network pharmacology and UHPLC-MS studies revealed that CPYJT acted on the TS through multiple neurotransmitters and the BDNF/TrkB and PI3K/AKT signalling pathways. CPYJT ameliorated neurocellular structural damage in the cortex, striatum, and thalamus of TS model rats. Additionally, CPYJT up-regulated the levels of BDNF, TrkB, PI3k, and AKT in the cortex, striatum, and thalamus of TS model rats. It was found that CPYJT protected neuronal cells from structural damage in multiple brain regions and affected the expression levels of BDNF, TrkB, PI3K, and Akt in the cortex, striatum, and thalamus during TS treatment.

Conditioned morphine tolerance promotes neurogenesis, dendritic remodelling and pro-plasticity molecules in the adult rat hippocampus.

Structural neuroplasticity of the hippocampus in the form of neurogenesis and dendritic remodelling underlying morphine tolerance is still less known. Therefore, in this study, we aimed to assess whether unconditioned- and conditioned-morphine tolerance can trigger structural neuroplasticity in the dorsal and ventral parts of the adult male rat hippocampus. Evaluation of the levels of neurogenesis markers (Ki67 and DCX) by immunohistochemistry shows that conditioned morphine tolerance is sufficient to increase the baseline topographic level of hippocampal neurogenesis in adult rats. Dendritic spine visualization by Golgi staining shows that the behavioural testing paradigms themselves are sufficient to trigger the hippocampus subregion-specific changes in the dendritic remodelling along the apical dendrites of hippocampal CA1 pyramidal neurons and dentate granule cells in adult rats. Quantitative reverse transcription polymerase chain reaction of Bdnf, Trkb, Rac-1 and RhoA mRNA levels as pro-plasticity molecules, shows that the conditioned morphine tolerance is effective in changing Bdnf and RhoA mRNA levels in the ventral hippocampus of adult rats. In summary, we demonstrate that the acquisition of morphine tolerance promotes adult neurogenesis, dendritic remodelling and pro-plasticity molecules such as Bdnf/Trkb in the rat hippocampus. Indeed, the structural neuroplasticity of the hippocampus may underlie the newly formed aberrant memory and could provide the initial basis for understanding the neurobiological mechanisms of morphine-tolerance plasticity in the hippocampus.

BDNF-TrkB/proBDNF-p75NTR pathway regulation by lipid emulsion rescues bupivacaine-induced central neurotoxicity in rats

Bupivacaine (BPV) can cause severe central nervous system toxicity when absorbed into the blood circulation system. Rapid intravenous administration of lipid emulsion (LE) could be used to treat local anaesthetic toxicity. This study aimed to investigate the mechanism by which the BDNF-TrkB/proBDNF-p75NTR pathway regulation by LE rescues BPV induced neurotoxicity in hippocampal neurons in rats. Seven- to nine-day-old primary cultured hippocampal neurons were randomly divided into 6 groups: the blank control group (Ctrl), the bupivacaine group (BPV), the lipid emulsion group (LE), the bupivacaine + lipid emulsion group (BPV + LE), the bupivacaine + lipid emulsion + tyrosine kinase receptor B (TrkB) inhibitor group (BPV + LE + K252a), the bupivacaine + lipid emulsion + p75 neurotrophic factor receptor (p75NTR) inhibitor group (BPV + LE + TAT-Pep5). All hippocampal neurons were incubated for 24 h, and their growth state was observed by light microscopy. The relative TrkB and p75NTR mRNA levels were detected by real-time PCR. The protein expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, TrkB, p75NTR and cleaved caspase-3 were detected by western blotting. The results showed that primary hippocampal neuron activity was reduced by BPV. As administration of LE elevated hippocampal neuronal activity, morphology was also somewhat improved. The protein expression and mRNA levels of TrkB and p75NTR were decreased when BPV induced hippocampal neuronal toxicity, while the expression of BDNF was increased. At the same time, BPV increased the original generation of cleaved caspase-3 protein content by hippocampal neurons, while the content of cleaved caspase-3 protein in hippocampal neurons cotreated with LE and BPV was decreased. Thus, this study has revealed LE may reduce apoptosis and promote survival of hippocampal neurons by regulating the BDNF-TrkB pathway and the proBDNF-p75NTR pathway to rescue BPV induced central neurotoxicity in rats.

Lamina-specific association between reduced mRNA levels of tyrosine kinase b and glutamate decarboxylase 67 in the orbitofrontal cortex in bipolar disorder: A possible reflective of defective connectivity in bipolar disorder

IntroductionLamina-specific alterations of inhibitory circuitries have been considered the crucial pathogenesis of perceptual, cognitive and behavioral symptoms presented in schizophrenia and mood disorders. Especially, with emerging evidences indicating the close lamina-specific relationship between synaptic defects and γ-Aminobutyric acid (GABA)-related gene dysfunctions, it has been suggested the mRNA dysregulations of Tyrosine kinase B (TrkB) and Glutamate decarboxylase 67 (GAD67) could particularly be implicated in middle and deep layers of neocortex of patients with major psychiatric disorders.ObjectivesGiving inquiries of whether defects of these mRNA levels in Orbitofrontal cortex (OFC) would be involved as lamina-specific patterns in individuals with schizophrenia and mood disorders.MethodsWe examined mRNA levels of BDNF, TrkB and GAD67 in each OFC layer I through VI. We analyzed data from postmortem brain tissue of the Stanley Neuropathology Consortium Integrative Database (SNCID). SNCID consists of 15 subjects in each of four groups (schizophrenia, bipolar disorder, major depression without psychotic features, and unaffected controls). All groups were matched for age, sex, race, brain pH and post-mortem interval.ResultsWe found TrkB mRNA levels to be significantly reduced in layer VI in both groups with schizophrenia (25.8%) and bipolar disorder (35.7%) compared with controls. GAD67 mRNA levels were also significantly reduced in layer III and IV in patients with schizophrenia (23.4% and 22.7%, respectively) and bipolar disorder (31.2% and 24.9%, respectively) compared with controls. Individuals with major depression showed only trends toward decreased mRNA levels of GAD67 in layer III and IV and of TrkB in layer VI compared with controls. TrkB mRNA levels in layer VI were significantly correlated with GAD67 mRNA levels in layer III (ρ=0.581, p=0.037) and IV (ρ=0.857, p<0.001) in subjects with bipolar disorder, but not in those with schizophrenia. When analyzed with partial correlation controlling the effects of pH and PMI, significance of correlation remained only between GAD67 mRNA in layer IV and TrkB mRNA in layer VI in individuals with bipolar disorder (ρ=0.768, p=0.006).ConclusionsThe resulting lamina-specific decreases in inhibitory tone across layers of OFC may contribute to the unrestrained irritability and violent behaviors in common shared by both patients with schizophrenia and bipolar disorder. Nonetheless, our findings indicate the obvious correlations between lamina-specifically altered TrkB and GAD67 mRNA levels in OFC might be a candidate for endophenotype of bipolar disorder.Disclosure of InterestNone Declared

From microRNA to protein, linking the neurotrophic hypothesis of depression to the Wistar Kyoto rat

Animal models of depression offer an alternative research-platform to clinical studies where limitations such as incomplete medical histories, patient heterogeneity, and difficulty tracking comorbidities leading to depression can be more easily overcome. In that context the Wistar Kyoto (WKY) rat strain has for many years been used as an endogenous model of depression. Here we want to further explore the depressive-like phenotype of the WKY rats to extend its validity as a preclinical model of depression.For this purpose, 49 microRNAs (miRNAs), which have been linked to the neurotrophic hypothesis of depression were selected and their levels were examined in hippocampus, prefrontal cortex, and blood from the WKY rats. Subsequently, miRNA/target mRNA/protein relationships were explored.Seventeen miRNAs across brain and blood exhibited significant regulation (>30%). Fifteen of 17 miRNAs were upregulated in the WKY rats, when compared to the Wistar Hannover Galas rats. This was coupled with general downregulation of corresponding mRNA targets in both brain regions. We observed decreased Trkb mRNA levels in both brain regions, which was coupled with increased miR-103-1 and miR-212 levels (targeting Trkb).While the relationship between mRNA and protein was not entirely linear, we did observe downregulation of TrkB protein in the prefrontal cortex and downregulation of fully mature glycosylated TrkB in both brain regions. This may indicate disruption of the BDNF-TrkB pathway in WKY rats.In conclusion, this study identifies several molecular alterations in brain and blood from the WKY rats and highlights the WKY rat strain as a viable model of depression.

Biphasic Response of Astrocytic Brain-Derived Neurotrophic Factor Expression following Corticosterone Stimulation.

Novel research studies indicate multivarious interactions of glucocorticoid hormones (GCs) with the brain-derived neurotrophic factor (BDNF), regulating important aspects of neuronal cell physiology. While there is recent evidence of the chronic effects of GC stimulation on BDNF levels, as well as of the role of BDNF stimulation in the type of genomic effects following activation of GC-sensitive receptors, no data exist concerning the acute effects of GC stimulation on BDNF/TrkB gene expression. To address this question, we conducted a chrono-pharmacological study on rodent glial cells, astrocytes, which express the BDNF receptor, TrkB, following corticosterone administration. mRNA levels of BDNF and TrkB were estimated 1, 6, 12 and 24 h post-treatment. Selective inhibitors for GC-sensitive receptors and TrkB were used to decipher the molecular pathways of the effects observed. Our data support a biphasic response of BDNF expression after corticosterone stimulation. This response is characterized by a rapid TrkB phosphorylation-dependent upregulation of BDNF mRNA within the first hour, followed by a glucocorticoid receptor (GR)-dependent downregulation of BDNF mRNA, evident at 6, 12 and 24 h, with a direct impact on the protein levels of mature BDNF. Finally, a second pulse of corticosterone administration 1 h prior to the 6, 12 or 24 h timepoints normalized BDNF expression for the corresponding timepoint (i.e., mRNA levels became indifferent from baseline). These results present for the first time a biphasic regulation of the neurotrophin system based on glucocorticoid rhythmicity, further indicating complex trophic responses to temporal hormonal mechanisms in the brain microenvironment.

MTOR and HDAC2 are simultaneously activated during electrically induced kindling of seizures

Although neurotrophic pathways and epigenetic processes are believed to be significant contributors to epileptogenesis and epilepsy, therapies using modulators of these targets are still lacking. BDNF-TrkB-mTOR signalling and the REST/NRSF-coREST-HDAC2 system are critical pathways responsible for neurotrophic and epigenetic processes, respectively. In our study, we assessed whether these two pathways are activated in a kindling model of seizures. We assessed the protein and mRNA levels of BDNF, TrkB, mTOR, REST/NRSF, coREST and HDAC2 in the brain. The study results showed increased expression of BDNF and decreased coREST in rats subjected to electrical kindling compared to control animals. We also revealed increased expression of both mTOR and HDAC2 in the brain tissue of electrically stimulated animals. mRNA production did not follow the intensified mTOR and HDAC2 protein synthesis. Furthermore, increased expression of BDNF, mTOR and HDAC2 was observed in animals that did not fulfil the kindling criteria in comparison to fully kindled rats. In conclusion, our results suggest that during epileptogenesis, the BDNF/mTOR neurotrophic pathway is mainly activated, with TrkB playing a less important role. Furthermore, the epigenetic transcription factor REST/NRSF was not found to be critical for HDAC2 activation. The simultaneous activation of both mTOR and HDAC2 systems during epileptogenesis confirms multifactorial neuronal adaptation, including neurotrophic and epigenetic processes. Our results may indicate that similar to cancer studies, the coadministration of regulators of both system should be considered a new potential strategy for preventing epileptogenesis.

A behavioral and molecular study; ameliorated anxiety-like behavior and cognitive dysfunction in a rat model of chronic unpredictable stress treated with oregano extract.

ObjectiveChronic stress is considered a severe risk factor leading to various disorders, including anxiety and cognitive decline. The present study aimed to investigate the effects of Origanum vulgare (oregano) extract on improving anxiety‐like behavior and learning and memory defection caused by chronic unpredictable stress (CUS).MethodA 10‐day CUS protocol was executed on male rats, and on day 10, their anxiety, learning, and memory status were evaluated. After that, in addition to the CUS, the rats were treated with the oregano extract for 2 weeks. Then, the expression of BDNF, TrkB, and TLR2/4 genes in the hippocampus and prefrontal cortex of the rats was evaluated. Also, the liver‐ and kidney‐related serum parameters, including triglycerides, total cholesterol, HDL, LDL, creatinine, urea, serum glucose, alanine aminotransferase, and aspartate aminotransferase were assessed. Further, the extract's lethal effect and its impact on animals’ body weight were investigated.ResultsBehavioral tests confirmed the anxiety‐like behavior and learning–memory function impairment caused by CUS. In contrast, the administration of the extract could significantly alleviate the mental deficiencies and diminished anxiety‐like behaviors. Molecular assessments showed that CUS could markedly decrease the BDNF and TrkB genes’ expression levels while increasing that of TLR2 and TLR4. In contrast, in extract‐treated animals, mRNA levels of BDNF and TrkB considerably increased, yet TLR2 and TLR4 mRNA levels reduced. Additionally, consumption of the extract caused weight gain, while having no lethality and detrimental effect on the liver and kidneys functions.ConclusionsThese findings indicate the anxiolytic properties of the extract and its improving effect on cognitive dysfunction.

Fat Intake and Obesity-related Parameters Predict Striatal BDNF Gene Expression and Dopamine Metabolite Levels in Cafeteria Diet-fed Rats

Modern westernized diet is a major risk factor associated with the current obesity epidemic. To study the effects of dietary choices of Western societies, the cafeteria diet has been validated as a preclinical model of obesity. We aimed to investigate the behavioral and metabolic alterations induced by a cafeteria diet on gene expression and neurotransmitter contents involved in neural plasticity and reward processing. Male Wistar rats were exposed to either standard or cafeteria diet for 9 weeks. Food intake and body weight were scored daily. Behavioral effects were assessed in the elevated plus-maze (EPM) and open field (OFT) tests. Serum biochemical parameters, brain monoamines, and BDNF, TrkB, CRF, CREB, and Dnmt3A mRNA levels were analyzed in reward-related brain regions. We found that cafeteria-diet rats consumed more energy and food than the control group, leading to increased body weight gain and adiposity. The cafeteria-diet rats showed an anxiolytic-like effect in the OFT, but not in the EPM. The cafeteria diet increased BDNF expression in the dorsal striatum (DS), and norepinephrine, 5-HT, TrkB, CREB, and Dnmt3A levels in the hippocampus. Additionally, multiple regression analysis showed that accumbal DOPAC and BDNF mRNA levels were robustly predicted by hyperphagia, fat mass accumulation, and body weight gain only in the cafeteria group. Overall, cafeteria diet-induced hyperphagia could lead to alterations in hedonic and motivational control of food intake through changes in dopamine metabolism and BDNF signaling in the nucleus accumbens and the DS.

Influence of N-Arachidonoyl Dopamine and N-Docosahexaenoyl Dopamine on the Expression of Neurotrophic Factors in Neuronal Differentiated Cultures of Human Induced Pluripotent Stem Cells under Conditions of Oxidative Stress.

Oxidative stress (OS) is implicated in the pathogenesis of several neurodegenerative diseases. We have previously shown that N-acyl dopamines (N-ADA and N-DDA) protect the neural cells of healthy donors and patients with Parkinson’s disease from OS. In this study, we assessed the effects of N-acyl dopamines on the expression of neurotrophic factors in human-induced pluripotent stem cell-derived neuronal cultures enriched with dopaminergic neurons under conditions of OS induced by hydrogen peroxide. We showed that hydrogen peroxide treatment increased BDNF but not GDNF mRNA levels, while it did not affect the secretion of corresponding proteins into the culture medium of these cells. Application of N-acyl dopamines promoted BDNF release into the culture medium. Under conditions of OS, N-DDA also increased TRKB, TRKC and RET mRNA levels. Furthermore, N-acyl dopamines prevented cell death 24 h after OS induction and promoted the expression of antioxidant enzymes GPX1, GPX7, SOD1, SOD2 and CAT, as well as reduced the BAX/BCL2 mRNA ratio. These findings indicate that stimulation of the expression of neurotrophic factors and their receptors may underlie the neuroprotective effects of N-acyl dopamines in human neurons.

Maternal omega-3 fatty acid supplementation against prenatal lead exposure induced cognitive impairment in offspring mice.

Maternal lead exposure is associated with poor outcomes in fetal brain development such as cognitive dysfunction. Here, we aimed to reveal the effect and mechanism of omega-3 fatty acids in ameliorating maternal lead exposure-induced cognitive impairment in mouse offspring. The activity levels of locomotor and anxiety, memory and learning capacity, spatial working memory, and cognitive behavioral function were determined using the open field test, Morris water maze, Y-maze, and nest-building test, respectively. The protein levels of brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were measured using enzyme-linked immunosorbent assay or Western blot. The mRNA levels of BDNF, tyrosine kinase B (TrkB) and cyclic AMP response element binding protein (CREB) were measured by real-time qPCR. Malondialdehyde (MDA) and anti-oxidants, including SOD, GSH and CAT, were measured using bioassay kits. We found that supplementing omega-3 significantly improved cognitive behavioral function in offspring after prenatal lead exposure. The protein and mRNA levels of BDNF, TrkB and CREB in the prenatal lead exposure group were significantly upregulated by omega-3 supplementation. The MDA level in the prenatal lead exposure group was markedly elevated compared with the control group, which was significantly reduced by omega-3. Omega-3 restored anti-oxidants SOD, GSH and CAT to control levels after prenatal lead exposure. Omega-3 significantly upregulated Nrf2 nuclear expression and HO-1 expression after prenatal lead exposure. Overall, omega-3 supplementation significantly elevated the BDNF/TrkB/CREB pathway and restores anti-oxidants by upregulating the Nrf2/HO-1, thereby improving cognitive function in offspring after prenatal lead exposure.

Association of BDNF / TrkB and NGF / TrkA Levels in Postmortem Brain with Major Depression and Suicide.

Suicide Attempts are the main complications of Major Depressive Episodes and are difficult to predict. There is still a lack of knowledge about its neurochemical aspects. There is increasing evidence that Brain-derived neurotrophic factor (BDNF) and Nerve growth factor (NGF) play a role in the pathophysiology and treatment of depression by binding and activating cognate receptors Tyrosine Kinase B (TrkB) and Tyrosie Kinase A (TrkA), respectively. This study was conducted to examine whether BDNF and / or TrkB as well as NGF and / or TrkA expression profiles were changed in the hippocampus of postmortem brain of individuals with depression who committed suicide. This study was conducted with the brain tissue of 61 victims who died as a result of suicide due to depression and 25 people who died due to traffic accidents. The psychiatric history of the cases was determined by the psychological autopsy method. Samples were taken from the hippocampus region of the brain at the forensic medicine institution. After storage under appropriate conditions, protein and mRNA levels of BDNF, TrkB, NGF and TrkA were determined in the genetics laboratory. Average age of the suicide group was 30 and the average age of the control group was 24.5. The suicide group consisted of 70.5% male and 29.5% female cases. There was no significant difference between the groups in terms of age (p=0.062) and gender (p=0.718). BDNF, NGF, TrkA and TrkB values were found to be lower in the suicide group compared to the control group and there was a significant difference between the groups (p≤0.001; p=0.001; p=0.001; p=0.011). Given the importance of BDNF and NGF and their cognate receptors in mediating physiological functions, including cell survival and synaptic plasticity, our findings regarding decreased expression of BDNF, TrkB, NGF and TrkA in both protein and mRNA levels of postmortem brains of suicide victims suggests that it may play an important role in the pathophysiological aspects of its behavior. Further studies in this context may be useful both in understanding the molecular basis of suicide and in designing therapeutic models targeting these molecular pathways.

Daily oscillation of cognitive factors is modified in the temporal cortex of an amyloid β(1-42)-induced rat model of Alzheimer’s disease

Alzheimer’s disease (AD) is a devastating disease characterized by loss of synapses and neurons in the elderly. Accumulation of the β-amyloid peptide (Aβ) in the brain is thought to be central to the pathogenesis of AD. ApoE plays a key role in normal and physiological clearance of Aß, since it facilitates the peptide intra- and extracellular proteolytic degradation. Besides the cognitive deficit, AD patients also show alterations in their circadian rhythms. The objective of this study was to investigate the effects of an i.c.v. injection of Aβ (1-42) peptide on the 24 h rhythms of Apo E, BMAL1, RORα, Bdnf and trkB mRNA and Aβ levels in the rat temporal cortex. We found that an i.c.v. injection of Aβ aggregates phase shifts daily Bdnf expression as well as Apo E, BMAL1, RORα, Aβ and decreased the mesor of TrkB rhythms. Thus, elevated Aβ peptide levels might modify the temporal patterns of cognition-related factors, probably; by affecting the clock factors rhythms as well as in the 24 h rhythms of Apo E.

The Chronic Treatment With 5-HT2A Receptor Agonists Affects the Behavior and the BDNF System in Mice.

Serotonin 5-HT2A receptors and the brain-derived neurotrophic factor (BDNF) are involved in the pathophysiology and treatment of many psychiatric diseases. However, the interaction between 5-HT2A and BDNF is still poorly understood. In the present paper, the effects of chronic treatment with mixed 5-HT2A/2C receptor agonist DOI, highly selective 5-HT2A agonists TCB-2 and 25CN-NBOH on behavior and the BDNF system have been investigated. Chronic treatment of males of C57Bl/6 mice with DOI, TCB-2 and 25CN-NBOH (1 mg/kg, i.p., 14 days) resulted in desensitization of 5-HT2A receptors. Treatment with 25CN-NBOH significantly increased startle amplitude. At the same time all used drugs failed to affect anxiety, exploratory and stereotyped behavior as well as spatial memory and learning. TCB-2 and 25CN-NBOH increased the BDNF mRNA level. All 5-HT2A agonists increased the proBDNF level but failed to alter the mature BDNF protein level. TrkB and p75NTR mRNA levels were affected by all utilized agonists. All drugs decreased the total level as well as membrane TrkB protein one indicating downregulation of TrkB receptors. All agonists decreased the membrane p75NTR protein level. Thus, we have shown for the first time that the chronic activation of the 5-HT2A receptor with agonists has affected the BDNF system almost on all levels-transcription, proBDNF production, TrkB and p75NTR receptors' level. The obtained data suggested possible suppression in BDNF-TrkB signaling under chronic treatment with 5-HT2A agonists.

LTP of inhibition at PV interneuron output synapses requires developmental BMP signaling

Parvalbumin (PV)-expressing interneurons (PV-INs) mediate well-timed inhibition of cortical principal neurons, and plasticity of these interneurons is involved in map remodeling of primary sensory cortices during critical periods of development. To assess whether bone morphogenetic protein (BMP) signaling contributes to the developmental acquisition of the synapse- and plasticity properties of PV-INs, we investigated conditional/conventional double KO mice of BMP-receptor 1a (BMPR1a; targeted to PV-INs) and 1b (BMPR1a/1b (c)DKO mice). We report that spike-timing dependent LTP at the synapse between PV-INs and principal neurons of layer 4 in the auditory cortex was absent, concomitant with a decreased paired-pulse ratio (PPR). On the other hand, baseline synaptic transmission at this connection, and action potential (AP) firing rates of PV-INs were unchanged. To explore possible gene expression targets of BMP signaling, we measured the mRNA levels of the BDNF receptor TrkB and of P/Q-type Ca2+ channel α-subunits, but did not detect expression changes of the corresponding genes in PV-INs of BMPR1a/1b (c)DKO mice. Our study suggests that BMP-signaling in PV-INs during and shortly after the critical period is necessary for the expression of LTP at PV-IN output synapses, involving gene expression programs that need to be addressed in future work.

Excessive Treadmill Training Enhances Brain-Specific MicroRNA-34a in the Mouse Hippocampus.

Background: An imbalance between total training load and total recovery may cause overtraining (OT). The purpose of the present study was to verify the effects of OT on the expression of brain-derived neurotrophic factor (BDNF), its receptor tropomyosin receptor kinase B (TrkB) and p75 and the dynamic expression patterns of brain-specific miR-34a and miR-124 or inflammation-related miR-21 and miR-132 in the mouse hippocampus.Method: Eight weeks old C57BL/6J mice were randomly assigned to the control (CON), normal training (NT) and OT groups. An 8-week OT training protocol was applied to evaluate the phenotype of mice endurance (incremental load test, ILT) and cognitive capacity (Morris water maze test). We used qRT-PCR and immunoblotting to detect changes in the molecular level of hippocampal samples.Result: Compared with the CON, both NT and OT decreased bodyweight after 8-week training. After 8-week of training, NT increased the exhaustion velocity (EV) while the EV of OT was lower than NT. Mice in NT decreased the escape latency than CON. The percentage of time spent in the probe quadrant and the number of crossing platform times in NT were higher than CON and OT. The BDNF, p75 and TrkB mRNA levels were increased in NT than CON, only the p75 mRNA was increased in OT. The NT exhibited increased protein levels of BDNF and TrkB compared to CON. The protein expression of BDNF was decreased in OT than NT and CON. The protein level of p75 in the OT was higher than in NT and CON. In addition, the phosphorylation level of TrkB in OT was higher than CON and NT. Only the miR-34a level was increased in the OT. Moreover, the expression of miR-34a was found to be negatively correlated with the expression of BDNF, and the increase in miR-34a level was accompanied by a decrease in performance.Conclusion: In summary, the training-evoked increase in the BDNF level may help to improve performance, whereas this conditioning is lost after OT. Moreover, miR-34a potentially mediated changes in the expression of BDNF and may reflect the decrease in performance after OT.

Peripheral blood BDNF-TrkB signaling in first-episode, drug-free patients with major depressive disorder and schizophrenia

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of psychiatric disorders, and studies have shown BDNF aberrations in major psychiatric diseases including schizophrenia (SCZ) and major depressive disorder (MDD). However, data from clinical studies were inconsistent. In this study, we recruited 34 patients with MDD, 77 patients with SCZ and 65 healthy control (HC) subjects to clarify the circulating BDNF levels in MDD and SCZ patients, and to assess whether serum BDNF levels were associated with the disease severity. Our results showed that serum BDNF levels were significantly decreased in the patients with SCZ (Mean difference = −4.517, 95%CI of difference = −7.854 to −1.180, p < 0.01) and MDD (Mean difference = −5.699, 95%CI of difference = −9.892 to −1.506, p < 0.01) when compared with HC subjects. Sub-group analyses suggested that BDNF levels were significantly reduced in the female SCZ (Mean difference = −5.700, 95%CI of difference = −10.21 to -1.189, p < 0.01) and MDD (Mean difference = −5.840, 95%CI of difference = −10.66 to −1.019, p < 0.05) patients, but not in male patients. Further analyses indicated that serum BDNF levels were not correlated with disease severity of MDD and SCZ. In addition, the transcriptional expression of TrkB was significantly down-regulated in the blood of MDD patients, but not in SCZ patients. However, there was no significant correlation between BDNF concentrations and TrkB mRNA levels. Taken together, our results revealed differential changes of BDNF-TrkB signaling in MDD and SCZ patients, therefore contributed to a better understanding of MDD and SCZ pathophysiology.

Effect of Hydrogen-Rich Water on Radiation-Induced Cognitive Dysfunction in Rats.

The goal of this work was to determine whether hydrogen-rich water (HRW) could attenuate radiation-induced cognitive dysfunction in rats and to explore the underlying mechanisms. Rats received 30 Gy whole-brain irradiation using a 6-MeV electron beam. Either purified water or HRW (0.8-0.9 ppm) was administrated at 10 min prior to irradiation, as well as a daily HRW treatment after irradiation for 30 consecutive days. The Morris water maze was used to test spatial memory in the rats. The concentration of glutathione (GSH), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG) and the super-oxidedismutase (SOD) activity in cerebral cortex, as well as brain-derived neurotrophic factor (BDNF) level in serum, were measured. Immunofluorescence staining was adopted to detect proliferating cells. The expression of BDNF-TrkB pathway-related genes and proteins were detected using qRT-PCR and Western blot. Models of cognitive dysfunction were successfully established using a 30 Gy dose of ionizing radiation. Compared to the radiation treated group, the radiation-HRW treated group showed significantly decreased escape latency (P < 0.05), but increased retention time, swimming distance of original platform quadrant (P < 0.05) and number of platform crossings (P < 0.05). Furthermore, the SOD, GSH (P < 0.05) and BDNF (P < 0.05) levels in the radiation-HRW treated group were higher compared to the radiation treated group. The MDA and 8-OHdG levels (P < 0.05) were decreased in the radiation-HRW treated group when compared to the radiation treated group. Additionally, treatment with HRW increased the number of BrdU+NeuN+ cells in the radiation treated group. The mRNA and protein levels of BDNF and TrkB (P < 0.05) in radiation-HRW treated group was higher than that in the radiation treated group. Collectively, our study indicates that HRW has a protective effect on radiation-induced cognitive dysfunction, and that the possible mechanisms mainly involve anti-oxidative and anti-inflammatory reactions, and its protection of newborn neurons by regulating the BDNF-TrkB signaling pathway.