Melatonin alters neuronal architecture and increases cysteine-rich protein 1 signaling in the male mouse hippocampus

Neuronal plasticity describes changes in structure, function, and connections of neurons. The hippocampus, in particular, has been shown to exhibit considerable plasticity regarding both physiological and morphological functions. Melatonin, a hormone released by the pineal gland, promotes cell survival and dendrite maturation of neurons in the newborn brain and protects against neurological disorders. In this study, we investigated the effect of exogenous melatonin on neuronal architecture and its possible mechanism in the hippocampus of adult male C57BL/6 mice. Melatonin treatment significantly increased the total length and complexity of dendrites in the apical and basal cornu ammonis (CA) 1 and in the dentate gyrus in mouse hippocampi. Spine density in CA1 apical dendrites was increased, but no significant differences in other subregions were observed. In primary cultured hippocampal neurons, the length and arborization of neurites were significantly augmented by melatonin treatment. Additionally, western blot and immunohistochemical analyses in both in vivo and in vitro systems revealed significant increases in the level of cysteine-rich protein 1 (crp-1) protein, which is known to be involved in dendritic branching in mouse hippocampal neurons after melatonin treatment. Our results suggest that exogenous melatonin leads to significant alterations of neuronal micromorphometry in the adult hippocampus, possibly via crp-1 signaling.     

Central motor conduction time reveals upper motor neuron involvement masked by lower motor neuron impairment in a significant portion of patients with amyotrophic lateral sclerosis

ObjectiveWe retrospectively investigated the utility of the central motor conduction time (CMCT) in detecting upper motor neuron (UMN) involvements in patients with amyotrophic lateral sclerosis (ALS).MethodsFifty-two ALS patients and 12 disease control patients participated in this study. Surface electromyograms were recorded from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles. We stimulated the motor cortex, brainstem, and spinal nerve using transcranial magnetic stimulation (TMS) in order to measure the cortical, brainstem, and spinal latencies. We divided the ALS patients into 2 subgroups (with UMN impairment vs. without UMN impairment) and calculated the rates of abnormal CMCT prolongation judged by their comparison with the normal ranges obtained by the measurement in the control patients.ResultsThe CMCTs in the FDI and TA were abnormally prolonged in over 40% of the ALS patients with UMN impairment and in nearly 30% of those without UMN impairment.ConclusionsCMCT shows UMN dysfunction in ALS patients without clinical UMN impairment.SignificanceTMS still has diagnostic utility in a significant portion of ALS patients.     

Denervation findings on EMG in amyotrophic lateral sclerosis and correlation with prognostic milestones: Data from a retrospective study

ObjectiveTo verify whether the finding of denervation activity on EMG at the time of diagnosis has a prognostic value in amyotrophic lateral sclerosis (ALS).MethodsWe retrospectively studied all the patients discharged with a diagnosis of ALS between January 2009 and January 2017. 92 patients met the inclusion criteria. We mainly verified three prognostic targets:

• (1)Time to non-invasive ventilation (NIV) or tracheostomy.
• (2)Time to percutaneous endoscopic gastrostomy or parental nutrition.
• (3)Survival.

All EMG examinations were reviewed and a denervation score (DS) was calculated.The association of DS with clinical milestones was analysed, adjusting for disease duration, age , sex, and clinical phenotype.ResultsWe found a significant association between bulbar DS and time to NIV/tracheostomy (HR: 3.34, 95% CI: 1.49 to 7.48, p = 0.002) and with survival (HR 3.633, 95% CI 1.681–7.848, p = 0.001), regardless of the clinical phenotype. Furthermore, we found a significant influence of a general DS on survival (HR: 2.62, 95% CI 1.335–5.160, p = 0.005).ConclusionEMG assessment could be of value not just for ALS diagnosis but also for its intrinsic prognostic value.SignificanceEMG could provide additional information about the rate of progression of ALS as early as the diagnosis is made.     

别孕烯醇酮对6-羟基多巴胺损伤的细胞系SH-SY5Y的保护作用

目的 明确别孕烯醇酮（APα）对6-羟多巴胺（6-OHDA）损伤的SH-SY5Y细胞系的保护作用，并阐明可能的分子机制。方法 向体外培养的SH-SY5Y细胞系中分别加入6-OHDA、APα、γ-氨基丁酸A受体（GABAAR）拮抗剂荷包牡丹碱（Bic）和电压门控L型Ca²⁺通道拮抗剂硝苯地平（nifedipine），采用免疫荧光细胞化学染色方法观察不同组别酪氨酸羟化酶（TH）阳性细胞的变化，Western blotting检测胞质钙调蛋白（CaM）、钙离子 钙调蛋白依赖性蛋白激酶Ⅱ δ3（CaMKⅡδ3），胞核CaMKⅡδ3、脑源性神经营养因子（BDNF）和细胞周期蛋白依赖性激酶（CDK1）表达的变化，采用蛋白质免疫共沉淀验证CaMKⅡδ3与CDK1/BDNF的相互作用。 结果 APα作用后，6-OHDA损伤的SH-SY5Y细胞TH和5-溴脱氧尿嘧啶核苷（BrdU）阳性细胞数目均明显增加，而TH/BrdU双阳性细胞数目无显著变化；同时Western blotting结果表明，SH-SY5Y细胞胞质和胞核上述蛋白的表达与单纯 6-OHDA 组相比也明显上升，经Bic处理后各蛋白增加更为明显。免疫共沉淀结果表明，CaMKⅡδ3与CDK1/BDNF存在相互作用。 结论 APα对6-OHDA损伤的SH-SY5Y细胞的保护中，GABAAR发挥负性调控作用，通过稳定细胞的内环境达到增加TH阳性神经元数量的目的，其中Ca²⁺ -CaM-CaMKⅡδ3信号通路和BDNF与CDK1发挥了关键作用。     

Lycium barbarum polysaccharide-glycoprotein preventative treatment ameliorates aversive stimuli-induced depression

Previous studies have shown that Lycium barbarum polysaccharide,the main active component of Lycium barbarum,exhibits antiinflammatory and antioxidant effects in treating neurological diseases.However,the therapeutic action of Lycium barbarum polysaccharide on depression has not been studied.In this investigation,we established mouse models of depression using aversive stimuli including exposure to fox urine,air puff and foot shock and physical restraint.Concurrently,we administered 5 mg/kg per day Lycium barbarum polysaccharide-glycoprotein to each mouse intragastrically for the 28 days.Our results showed that long-term exposure to aversive stimuli significantly enhanced depressive-like behavior evaluated by the sucrose preference test and the forced swimming test and increased anxietylike behaviors evaluated using the open field test.In addition,aversive stimuli-induced depressed mice exhibited aberrant neuronal activity in the lateral habenula.Importantly,concurrent Lycium barbarum polysaccharide-glycoprotein treatment significantly reduced these changes.These findings suggest that Lycium barbarum polysaccharide-glycoprotein is a potential preventative intervention for depression and may act by preventing aberrant neuronal activity and microglial activation in the lateral habenula.The study was approved by the Jinan University Institutional Animal Care and Use Committee(approval No.20170301003) on March 1,2017.     

经颅磁刺激的多尺度建模仿真研究

经颅磁刺激是一种无创无痛的电磁刺激手段，被广泛应用于神经调控，在临床上对多种精神疾病和神经类疾病有明显的治疗效果。本文从电磁场建模仿真，细胞跨膜电位建模仿真，以及神经元响应建模仿真3个方面对经颅磁刺激多尺度建模仿真研究进行了详细的综述，并提出现阶段存在的问题以及对未来的展望。经颅磁刺激的多尺度建模仿真对磁刺激仪的设计开发具有指导意义，对磁刺激的导航系统提供重要的理论基础，有助于我们更好的理解电磁刺激的神经调控机制。     

Endocytosis and Transport of Growth Factor Receptors in Peripheral Axon Regeneration: Novel Lessons from Neurons Expressing Lysine-Deficient FGF Receptor Type 1 in vitro

In the course of peripheral nerve regeneration, axons encounter different extracellular growth factors secreted by non-neuronal cells at the injury site and retrogradely transported after binding to neuronal membrane receptor tyrosine kinases. The present study reviews the role of receptor transport in peripheral axon outgrowth and provides novel data on trafficking of fibroblast growth factor receptor type 1 (FGFR1). Differences in receptor transport are determined by different numbers of lysine residues acting as ubiquitination sites in the intracellular receptor domain. We previously demonstrated that overexpression of mutant FGFR1-25R (25 out of 29 intracellular lysines replaced with arginine) results in enhanced receptor recycling as compared to wild-type FGFR1 followed by strong stimulation of elongative axon growth in vitro. Here, the effects of lysine-deficient FGFR1 (FGFR1-29R lacking all 29 cytoplasmic lysine residues) or of only 15 lysine mutations (FGFR1-15R) on axon outgrowth and concomitant changes in signal pathway activation were investigated by immunocytochemistry and morphometry of cultured primary neurons. Overexpression of FGFR1-15R in adult sensory neurons resulted in enhanced receptor recycling, which was accompanied by increased axon elongation without stimulating axon branching. By contrast, FGFR1-29R was neither endocytosed nor axon outgrowth affected. Although overexpression of FGFR1-15R or FGFR1-25Ra strongly promoted elongation, we did not detect increased signal pathway activation (ERK, AKT, PLC, or STAT3) in neurons expressing mutant FGFR1 as compared with wild-type neurons raising the possibility that other signaling pathways or signaling independent mechanisms may be involved in the axon outgrowth effects of recycled FGF receptors. Anat Rec, 302:1268–1275, 2019. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.