BDNF is necessary for maintenance of noradrenergic innervations in the aged rat brain

In the axon terminals of the locus coeruleus (LC) neurons, a high level of axonal branching was occurred in the middle-aged brain, and the increased branching was maintained in the aged brain. In the present study, we hypothesized that neurotrophic support is necessary for the morphological age-related changes seen in the noradrenergic innervations from the LC to frontal cortex. Through immunohistochemical and quantitative image analyses, we examined the age-dependent effects of brain-derived neurotrophic factor (BDNF) on the noradrenergic axon terminals in the frontal cortex of F344 rats. We continuously infused BDNF into the frontal cortex of young (6-months-old), middle-aged (13-months-old), or aged (25-months-old) rats. Exogenous BDNF infusion caused a marked increase in the density of noradrenergic axons in the aged brain, but no trophic action of BDNF was observed in the young and middle-aged brain. Neutralization of endogenous BDNF with a specific function-blocking antibody to BDNF led to a reduction in noradrenergic axons in the frontal cortex of 19-month-old rats. The present results suggest that BDNF is not involved in the augmentation of noradrenergic innervations in the aging brain, but it is necessary for the maintenance of noradrenergic innervations in the aged brain.     

Effects of BDNF infusion on the axon terminals of locus coeruleus neurons of aging rats

Using in vivo electrophysiological techniques and continuous local infusion methods, we examined the effects of brain-derived neurotrophic factor (BDNF) and its specific antibody (anti-BDNF) on the noradrenergic axon terminals of the locus coeruleus (LC) neurons in the frontal cortex of aging rats. Recently, we observed that LC neurons with multiple-threshold antidromic responses (multi-threshold LC neurons) increased critically between 15 and 17 months of age. To examine whether the BDNF is involved in this change occurred in the aging brain, we continuously infused BDNF into the frontal cortex for 14 days. Exogenous BDNF produced a marked increase in the multi-threshold LC neurons in the 13-month-old brain, accompanied with a decrease in threshold current. However, no morphological change in the noradrenergic axons was observed in the BDNF-infused cortex. In contrast, infusion of anti-BDNF led to a dose-dependent reduction of the multi-threshold LC neurons in the 19-month-old brain, accompanied with an increase in threshold current. These findings suggest that BDNF may contribute to functional changes in the presynaptic axon terminals of LC neurons in the aging brain.     

Septal cholinergic afferents regulate expression of brain-derived neurotrophic factor andβ-nerve growth factor mRNA in rat hippocampus

Summary In situ hybridization was used to study the expression of members of the nerve growth factor family of trophic factors in rat hippocampus following stimulation of afferent cholinergic and glutamatergic pathways with quisqualate. A transient increase in brain-derived neurotrophic factor (BDNF) and-nerve growth factor (NGF) mRNA expression in the hippocampus was seen 4 h after a quisqualate injection into the medial septal nucleus. Both BDNF and NGF mRNA levels increased more than 4-fold in the granule layer of the dentate gyrus and for BDNF mRNA also in the pyramidal cells of CA1, while the levels of BDNF mRNA in CA3 increased 2-fold. The increase in BDNF and NGF mRNA levels were completely prevented by pretreatment with systemic injections of either scopolamine or diazepam. A quisqualate injection into the entorhinal cortex, containing glutamatergic afferents to the hippocampus, resulted in a 15-, 5- and 17-fold increase in the expression of BDNF mRNA in the ipsilateral granule cells, CA3 and CA1 pyramidal cells, respectively. Similar increases were also seen in the hippocampus contralateral to the injections. In contrast, the level of NGF mRNA did not increase significantly in any of the subfields in the hippocampus. The increase in BDNF mRNA after cortex injections was attenuated by diazepam but not by scopolamine. These findings imply that increased activity in afferent cholinergic and glutamatergic pathways to the hippocampus differentially regulate expression of the NGF family of neurotrophic factors in the hippocampus.     

Age-related deficits as working memory load increases: relationships with growth factors

Young and aged female rats were tested on a water radial-arm maze designed to measure performance as working memory load increased, followed by brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin 3 (NT3) protein assessments in hippocampus and frontal cortex. Aged rats showed deficiencies in both working and reference memory. There were also profound age-related working memory load effects. Aged rats made more errors as working memory load increased and showed learning only during early trials when memory load was low, while young rats exhibited learning over all trials. Neurotrophin assessment showed that frontal cortex NGF and BDNF levels were positively, and hippocampal NT3 negatively, correlated with number of errors made during specific trials in aged animals. Comparison to untested rats showed that testing increased NT3, but not BDNF or NGF, protein levels in both age groups. Findings suggest that young rats learn to handle a higher working memory load as testing progresses, while aged rats do not, and that frontal cortex and hippocampal neurotrophin levels may relate to working memory proficiency in aged female rats.     

Brain-derived neurotrophic factor and Glial cell line-derived neurotrophic factor expressions in the trigeminal root entry zone and trigeminal ganglion neurons of a trigeminal neuralgia rat model

Microvascular compression on the trigeminal root entry zone (TREZ) is the main etiology of trigeminal neuralgia (TN) patients. To investigate brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in the trigeminal ganglion (TG) and TREZ, immunofluorescence staining and Western blot were used in a rat TN model. Both BDNF and GDNF were observed in the TG neurons and TREZ. The expression of the BDNF dimer in the TG was increased in the TN group, while GDNF expression was decreased after compression injury. The BDNF dimer/pro-BDNF ratio in the TREZ of the TN group was higher than that in the sham group, but the GDNF expression in the TREZ was significantly lower than that in the sham group. These results suggested that compression injury in the TREZ of rats induced dynamic changes in BDNF and GDNF in both the TG and TREZ, and these changes are involved in the nociceptive transmission of the TN animal model.     

Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: differential regulation of specific exons by antidepressants and corticosterone

Earlier studies have implicated brain-derived neurotrophic factor in stress and in the mechanism of action of antidepressants. It has been shown that antidepressants upregulate, whereas corticosterone downregulates, brain-derived neurotrophic factor expression in rat brain. Whether various classes of antidepressants reverse corticosterone-mediated downregulation of brain-derived neurotrophic factor is unclear. Also not known is how antidepressants or corticosterone regulates brain-derived neurotrophic factor expression. To clarify this, we examined the effects of various classes of antidepressants and corticosterone, alone and in combination, on the mRNA expression of total brain-derived neurotrophic factor and of individual brain-derived neurotrophic factor exons, in rat brain. Normal or corticosterone pellet-implanted (100 mg, 21 days) rats were injected with different classes of antidepressants, fluoxetine, desipramine, or phenelzine, intraperitoneally for 21 days and killed 2 h after the last injection. mRNA expression of total brain-derived neurotrophic factor and of exons I-IV was measured in frontal cortex and hippocampus. Given to normal rats, fluoxetine increased total brain-derived neurotrophic factor mRNA only in hippocampus, whereas desipramine or phenelzine increased brain-derived neurotrophic factor mRNA in both frontal cortex and hippocampus. When specific exons were examined, desipramine increased expression of exons I and III in both brain areas, whereas phenelzine increased exon I in both frontal cortex and hippocampus but exon IV only in hippocampus. On the other hand, fluoxetine increased only exon II in hippocampus. Corticosterone treatment of normal rats decreased expression of total brain-derived neurotrophic factor mRNA in both brain areas, specifically decreasing exons II and IV. Treatment with desipramine or phenelzine of corticosterone pellet-implanted rats reversed the corticosterone-induced decrease in total brain-derived neurotrophic factor expression in both brain areas; however, fluoxetine reversed the decrease only partially in hippocampus. Interestingly, antidepressant treatment of corticosterone pellet-implanted rats increased only those specific exons that are increased during treatment of normal rats with each particular antidepressant. We found that although corticosterone and antidepressants both modulate brain-derived neurotrophic factor expression, and antidepressants reverse the corticosterone-induced brain-derived neurotrophic factor decrease, antidepressants and corticosterone differ in how they regulate the expression of brain-derived neurotrophic factor exon(s).     

高脂饮食对大鼠海马、大脑皮质和脊髓GDNF表达的影响

目的:探讨高脂饮食对大鼠海马、大脑皮质和脊髓胶质细胞源性神经营养因子(GDNF)的影响。方法:20只雄性SD大鼠随机分成两组:普通饮食组(ND)和高脂饮食组(HFD),每组10只,分别给子两组大鼠普通饮食和高脂饮食14周,测量各组大鼠体重脂肪重、Lee's指数和脂体比。应用real time RT-PCR检测各组大鼠海马、大脑皮质和脊髓GDNFmRNA的表达;应用Western Blot检测各组大鼠海马、大脑皮质和脊髓CDNF蛋白的表达;应用酶联免疫吸附实验(ELISA)检测各组大鼠海马、大脑皮质和脊髓肿瘤坏死因子-α(TNF-α)、白细胞介索-1β(IL-1β)和IL-6的水平。结果:高脂饮食导致大鼠体重、脂肪重,Lee's指数和脂体比均明显升高(P<0.05);HFD组大鼠海马、大脑皮质和脊髓GDNF mRNA表达水平较ND组均显著下降(P<0.01),HFD组大鼠海马、大脑皮质和脊髓GDNF蛋白表达水平较ND组均明显下降(P<0.05);HFD组大鼠海马、大脑皮质和脊髓中TNF-α、IL-1β和IL-6水平与ND组相比均明显升高(P<0.01)。结论:高脂饮食造成大鼠肥胖,降低了大鼠海马、大脑皮质和脊髓GDNF的表达水平,同时促进了炎症反应的发生。     

Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain.

To study possible effects of physical training on the expression of neurotrophic factors and their receptors in the brain, we used a rat strain (spontaneously hypertensive rat, SHR), known to spontaneously run up to 20 km/night. We show that such long-distance running affects the brain-derived neurotrophic factor (BDNF) and TrkB system in hippocampus, and in particular that abrupt deprivation of habitual running leads to long-lasting decreases of BDNF/TrkB expression in hippocampus. Quantitative in situ hybridization demonstrates that running increases the expression of mRNA coding for BDNF and its high affinity receptor TrkB in hippocampus in a running length dependent manner. In addition, we show that an abrupt interruption of prolonged spontaneous exercise decrease expression of mRNA encoding BDNF and TrkB in certain hippocampal areas and that this decrease lasts at least 10 days. This down-regulation was most prominent in medial cornu ammonis 3 (CA3M). Several other trophic factors and receptors were investigated, including NGF, NT3, GDNF, trkC and p75. For these other probes investigated, no robust changes in mRNA expression were noted. Areas examined included sensorimotor cortex and hippocampus. For RET, p75, NT3, TrkB and BDNF we also examined the spinal cord without detecting any robust changes. We conclude that spontaneous running as well as its abrupt termination, leads to area-specific and trophic factor-specific changes in hippocampus.     

Distinct regulation of brain-derived neurotrophic factor and noradrenaline in S100B knockout mice

The mainly glia-derived protein S100B has been shown to be involved in the pathophysiology of diseases such as neurodegenerative diseases, schizophrenia or depression. These diseases go along with distinct changes of cerebral neurotransmitters and neurotrophic factors. Few and partly inconsistent data exist on the influence of cerebral S100B protein levels on different neurotransmitters. Therefore we investigated levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), dopamine (DA), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus, frontal cortex and residual neocortex in S100B knock out (S100B KO) mice compared to wildtype controls. There was a significant increase of hippocampal BDNF (+53%) and a decrease of hippocampal (-12%) and residual neocortical (-15%) NA in 10-month-old S100B KO mice compared to wildtype mice whereas the other mediators investigated did not show genotype-dependent changes. The increased hippocampal BDNF may represent an endogenous attempt to compensate trophic effects of S100B protein especially on serotonergic neurons, which have been shown to be unaffected in S100B KO mice previously. As referred to changes in NA levels functional studies are warranted to elucidate the link between S100B protein and the noradrenergic metabolism.     

Curcumin reverses corticosterone-induced depressive-like behavior and decrease in brain BDNF levels in rats

A rat model of depression has been recently developed using exogenous corticosterone (CORT) administration. This study aimed to examine the antidepressant-like effect and the possible mechanisms of curcumin in a CORT-induced depression model in rats. The results showed that 3-week CORT injections caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. Repeated CORT injections also significantly decreased brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus and frontal cortex of the rats. Treatment of the rats with curcumin significantly suppressed the depression-like behavior and the decrease in brain BDNF levels induced by the repeated CORT injections. The results suggest that curcumin produces an antidepressant-like effect in CORT-treated rats, which is possibly mediated by increasing BDNF expression in the hippocampus and frontal cortex.     

小鼠慢性酒精中毒及戒断过程中抑郁样行为的改变及其共病机制

 目的: 研究小鼠慢性酒精中毒及戒断过程中抑郁样行为的改变,进一步探讨酒精中毒与抑郁症的共病机制。方法: 构建新型慢性酒精中毒小鼠模型;实验分为正常对照组及慢性酒精7 d、14 d、21 d和28 d组。在第6、13、20和27天分别进行酒精偏好度测试,测试后戒断酒精1 d,随后次日进行抑郁行为学测试,测试结束后处死小鼠取海马与额叶皮层,采用高效液相色谱法测定5-羟色胺(5-HT)及去甲肾上腺素(NE)含量,采用免疫印迹法测定cAMP反应元件结合蛋白(CREB)和脑源性神经营养因子(BDNF)的含量。结果: 随着酒精饮酒天数及戒断次数的增加,小鼠表现出明显嗜酒现象,并且在强迫游泳和悬尾测试中,表现出明显的不动时间增加。7 d组小鼠额叶皮层内5-HT水平升高(P < 0.05),海马与额叶5-HT水平在21 d与28 d组降低(P < 0.01);7 d和14 d组小鼠海马与额叶NE水平无明显变化,21 d和28 d组NE水平降低(P < 0.05)。21 d和28 d组小鼠海马与额叶内p-CREB/CREB比值及BDNF表达水平明显下降(P < 0.05),7 d与14 d组无明显变化。结论: 酒精中毒、戒断阶段与抑郁的共病机制涉及5-HT。5-HT-cAMP-CREB-BDNF信号转导通路可能为酒精中毒与抑郁症的共病机制。     

Expression of mRNA of neurotrophic factors and their receptors are significantly altered after subchronic ketamine treatment

The neurotrophic factors play an important role in the maintenance of neurone viability and neuronal communication which are considered to be altered in schizophrenia. Subchronic application of ketamine (Ket) was found to be a useful model in schizophrenia research. To further validate this model the mRNA levels of neurotrophic factors NGF, NT-3, and BDNF and their receptors TrkA, TrkB, and TrkC, respectively, were measured in different brain areas in Ket-pretreated rats subchronically dosed with the atypical antipsychotic drug risperidone (Ris). With the exception of NGF in the frontal cortex, Ket pretreatment did change NGF, NT-3, and BDNF mRNA levels in the frontal cortex, the hippocampus, the striatum, the thalamus/hypothalamus region, and in the cerebellum. These changes correspond with changes at their tyrosine kinase receptors. Ris treatment normalised altered NT-3 levels in the hippocampus and balanced BDNF levels in the same structure. It was concluded that the Ket model might reflect distinct alterations in neurotrophic factor activity as found in schizophrenic patients and, moreover, that Ris treatment rebalances disturbed neurotrophic factor activity.     

精神分裂症患者血清BDNF、GDNF水平与认知功能的改变及抗精神药物和物理治疗对其的影响

目的:探讨精神分裂症患者血清脑源性神经营养因子(brain-derived neurotrophic factors,BDNF)、胶质源性神经营养因子(glial-derived neurotrophic factors,GDNF)水平、认知功能的改变及抗精神药物和物理治疗对其的影响。方法:以2013年2月-2015年6月我院收治的60例慢性精神分裂症患者(研究组)及同期于我院体检的30例健康志愿者(健康组)为研究对象,比较两组BDNF、GDNF、认知功能,将研究组患者依据治疗方式不同分为干预组(抗精神药物和物理治疗,28例)及基础组(基础药物治疗,32例),比较治疗后两组BDNF、GDNF水平、认知功能。结果:研究组BDNF、GDNF表达水平及Stroop测验、符号编码、言语记忆、工作记忆评分较健康组显著低,而连线测试评分较健康组明显高(t=-11.504,-3.613,-8.649,-5.155,-3.982,-3.260,4.701;P0.05);治疗后干预组及基础组BDNF、GDNF水平、认知功能总评分较治疗前明显升高,PANSS阳性、阴性、一般精神病理评分明显降低,且治疗后干预组的升高、降低程度较基础组显著(t=-3.908,-2.141,-5.008,-3.423,-3.064,-3.166;P0.05);受试患者血清BDNF水平与PANSS阳性评分呈负相关(r=-0.310,P0.05),而血清GDNF水平与Stroop色词干扰测验评分呈正相关(r=0.542,P0.05)。结论:精神分裂症患者血清BDNF、GDNF水平、认知功能较健康人群显著低,BDNF、GDNF在本病发生、进展及预后中发挥重要作用,而抗精神药物和物理治疗可作为精神分裂症患者首选治疗方案。     

Activation of basal forebrain cholinergic neurons differentially regulates brain-derived neurotrophic factor mRNA expression in different projection areas.

Afferent cholinergic pathways from the basal forebrain were activated by injections of the glutamate analog quisqualate either into the nucleus basalis or into the medial septal nucleus. Nucleus basalis injections had no effect on the expression of brain-derived neurotrophic factor (BDNF) mRNA in its neocortical projection areas as measured by in situ hybridization. In contrast, 7 h after an injection into the septum the level of BDNF mRNA increased 3- to 5-fold in the dentate gyrus, throughout CA1 to CA3 in the hippocampus and in the piriform cortex.     

Time course of the expression of genes of brain-derived neurotrophic factor and nerve growth factor in the hippocampus and frontal cortex induced by semax in rats

Semax is a synthetic peptide consisting of the ACTH fragment (4–7) and the C-terminal Pro-Gly-Pro peptide. It promotes neuron survival during hypoxia and increases selcective attention and memory consolidation. It has been shown that semax influences the expression of some genes, particularly nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). In the present study, we performed an analysis of the time course of the expression of NGF and BDNF genes in the hippocampus and frontal cortex in rats after a single intranasal administration of semax at a dose of 50 μg/kg. We found that semax administration resulted in a rapid long-term activation of the NGF and BDNF genes expression, which was specific for different rat brain structures investigated.     

Spatial memory training modifies the expression of brain-derived neurotrophic factor tyrosine kinase receptors in young and aged rats

Aging leads to alterations in the function of the hippocampus, a brain structure largely involved in learning processes. This study aimed at examining the basal levels and the impact of a learning-associated task on brain-derived neurotrophic factor (BDNF), on BDNF full-length catalytic receptor (TrkB.FL) and on the truncated forms (TrkB.T1 and TrkB.T2) receptor expression (mRNA and protein) in the hippocampus of young (2-month-old) and aged (24-month-old) Wistar rats. Spatial memory was evaluated using a water-maze procedure involving visible and invisible platform location learning. Aged rats showed higher latencies during the first two training days but rapidly exhibited learning performances similar to patterns observed with young rats. Real-time PCR measurements showed that aged rats had significantly higher levels of trkB.FL mRNAs than young rats under basal conditions. In situ hybridization analysis indicated that the highest level of trkB.FL mRNA (mRNA encoding for TrkB.FL receptor) was noted in the dentate gyrus, and in the CA2 and CA3 hippocampal layers. In contrast, there was no marked difference in trkB.T1 signal in any hippocampal region. Training induced a significant reduction in trkB.FL mRNA levels solely in aged rats. In contrast, in young and aged rats, trkB.T2 mRNA levels were significantly increased after training. Measurements of proteins revealed that learning significantly increased TrkB.FL content in aged rats. Untrained aged rats presented higher levels of BDNF and brain-derived neurotrophic factor precursor (proBDNF) proteins than young rats. Training strongly increased precursor BDNF metabolism in young and aged rats, resulting in increased levels of proBDNF in the two groups but in old rats the mature BDNF level did not change. This study shows that Wistar rats present age-related differences in the levels of BDNF and TrkB isoforms and that spatial learning differentially modifies some of these parameters in the hippocampus.     

Brain-derived neurotrophic factor in patients with frontotemporal dementia

Brain-derived neurotrophic factor (BDNF) promotes survival and growth of various nerve cell populations during normal development and following different insults in the developing and adult brain. BDNF expression is reduced in Alzheimer disease, but little is known about BDNF expression in other types of dementia. Frontotemporal dementia (FTD) is a common cause of mental impairment in old age, which is characterized by neuron loss in the upper cortical layers mainly of the frontal and temporal cortex. BDNF protein expression has been examined by Western blotting and immunohistochemistry in the cerebral cortex of individuals affected by FTD. Examination of pathological samples (n = 8, mean age: 74.7 years; four men, four women) was conducted in parallel with corresponding samples from age-matched controls (n = 8; mean age: 72.6 years; three men, five women). Post-mortem delay was between 2 and 6 h. Preserved BDNF expression, as revealed by Western blotting, has been observed in the frontal and temporal cortices of patients with FTD. Furthermore, immunohistochemistry has disclosed maintained BDNF immunoreactivity in surviving neurons of the upper cellular layers, as well as in neurons of the inner cellular layers in FTD. These results show that FTD is not associated with a decay of BDNF in cortical neurons, and therefore, that BDNF is differentially regulated in diseases causing dementia.