Comparison of fiber tract low frequency stimulation to focal and ANT stimulation in an acute rat model of focal cortical seizures

BackgroundCurrent implementations of direct brain stimulation for epilepsy in patients involve high-frequency (HFS) electrical current and targeting of grey matter. Studies have shown that low-frequency (LFS) fiber-tract stimulation may also prove effective. To compare the efficacy of high-frequency grey matter stimulation to the low-frequency fiber tract stimulation technique a well-controlled set of experiments using a single animal model of epilepsy is needed.ObjectiveThe goal of this study was to determine the relative efficacy of different direct brain stimulation techniques for suppressing seizures using an acute rat model of focal cortical seizures.Methods4-AP was injected into the S1 region of cortex in rodents over 3 h. LFPs were recorded from the seizure focus and mirror focus to monitor seizure frequency during the experiments. CC-LFS, HFS-ANT, Focal-HFS, or a transection of the CC was applied.ResultsStimulation of the CC yielded a 65% ±14% (p = 0.0014) reduction of seizures in the focus and a 97% ±15% (p = 0.0026) reduction in the mirror focus (n = 7). By comparison transection of the CC produced a 65% ±18% reduction in the focus and a non-statistically significant reduction of 57% ±18% (p = 0.1381) in the mirror focus (n = 5). All other methods of stimulation failed to have a statistically significant effect on seizure suppression.ConclusionsLFS of the CC is the only method of stimulation to significantly reduce seizure frequency in this model of focal cortical seizures. These results support the hypothesis that LFSof fiber tracts has significant potential for seizure control.     

The voltage-gated calcium channel CaV1.2 promotes adult oligodendrocyte progenitor cell survival in the mouse corpus callosum but not motor cortex

Throughout life, oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes. OPCs express cell surface receptors and channels that allow them to detect and respond to neuronal activity, including voltage-gated calcium channel (VGCC)s. The major L-type VGCC expressed by developmental OPCs, CaV1.2, regulates their differentiation. However, it is unclear whether CaV1.2 similarly influences OPC behavior in the healthy adult central nervous system (CNS). To examine the role of CaV1.2 in adulthood, we conditionally deleted this channel from OPCs by administering tamoxifen to P60 Cacna1c ^fl/fl (control) and Pdgfrα-CreER:: Cacna1c ^fl/fl (CaV1.2-deleted) mice. Whole cell patch clamp analysis revealed that CaV1.2 deletion reduced L-type voltage-gated calcium entry into adult OPCs by ~60%, confirming that it remains the major L-type VGCC expressed by OPCs in adulthood. The conditional deletion of CaV1.2 from adult OPCs significantly increased their proliferation but did not affect the number of new oligodendrocytes produced or influence the length or number of internodes they elaborated. Unexpectedly, CaV1.2 deletion resulted in the dramatic loss of OPCs from the corpus callosum, such that 7 days after tamoxifen administration CaV1.2-deleted mice had an OPC density ~42% that of control mice. OPC density recovered within 2 weeks of CaV1.2 deletion, as the lost OPCs were replaced by surviving CaV1.2-deleted OPCs. As OPC density was not affected in the motor cortex or spinal cord, we conclude that calcium entry through CaV1.2 is a critical survival signal for a subpopulation of callosal OPCs but not for all OPCs in the mature CNS.     

Effect of stromal cell-derived factor-1/CXCR4 axis in neural stem cell transplantation for Parkinson’s disease

Previous studies have shown that neural stem cell transplantation has the potential to treat Parkinson’s disease,but its specific mechanism of action is still unclear.Stromal cell-derived factor-1 and its receptor,chemokine receptor 4(CXCR4),are important regulators of cell migration.We speculated that the CXCR4/stromal cell-derived factor 1 axis may be involved in the therapeutic effect of neural stem cell transplantation in the treatment of Parkinson’s disease.A Parkinson’s disease rat model was injected with 6-hydroxydopamine via the right ascending nigrostriatal dopaminergic pathway,and then treated with 5μL of neural stem cell suspension(1.5×104/L)in the right substantia nigra.Rats were intraperitoneally injected once daily for 3 days with 1.25 mL/kg of the CXCR4 antagonist AMD3100 to observe changes after neural stem cell transplantation.Parkinson-like behavior in rats was detected using apomorphine-induced rotation.Immunofluorescence staining was used to determine the immunoreactivity of tyrosine hydroxylase,CXCR4,and stromal cell-derived factor-1 in the brain.Using quantitative real-time polymerase chain reaction,the mRNA expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra were measured.In addition,western blot assays were performed to analyze the protein expression of stromal cell-derived factor-1 and CXCR4.Our results demonstrated that neural stem cell transplantation noticeably reduced apomorphine-induced rotation,increased the mRNA and protein expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra,and enhanced the immunoreactivity of tyrosine hydroxylase,CXCR4,and stromal cell-derived factor-1 in the brain.Injection of AMD3100 inhibited the aforementioned effects.These findings suggest that the stromal cell-derived factor-1/CXCR4 axis may play a significant role in the therapeutic effect of neural stem cell transplantation in a rat model of Parkinson’s disease.This study was approved by the Animal Care and Use Committee of Kunming Medical University,China(approval No.SYXKK2015-0002)on April 1,2014.     

A familial Sonic Hedgehog (SHH) stop-gain mutation associated with agenesis of the corpus callosum,mild intellectual disability and facial dysmorphism

BackgroundAgenesis of the corpus callosum (ACC) is a relatively common brain malformation in children with developmental disabilities, caused by mutations in many genes. These genetic causes are characterized by their extreme heterogeneity with more than 300 causative genes identified to date.Case reportWe describe two new cases from a three-generation family with ACC and a de novo mutation of the sonic hedgehog (SHH) gene. The affected family members had mild intellectual disability, broad forehead, and widely spaced eyes. A next-generation sequencing (NGS) approach revealed a stop-gain mutation (NM_000193.2:c.1300_1301insA p.Trp434Ter) of the SHH gene; it is the first family to report ACC associated with a single SHH gene mutation.ConclusionACC with mild intellectual disability and facial dysmorphism may be caused by a mutation in SHH, but further research investigating the genotype-phenotype correlation of SHH mutations is required.     

胼胝体病变-肝豆状核变性的少见脑部影像学表现

目的研究肝豆状核变性患者胼胝体病变及其临床价值。方法收集3例肝豆状核变性患者的临床及影像资料,参照2001年第八届莱比锡肝豆状核变性国际会议制定的诊断评分系统评分。利用磁共振成像(MRI)技术检查胼胝体压部病变。结果 3例患者均存在胼胝体压部病变,但均无胼胝体病变所致的失连接综合征表现。头颅MRI技术提示3例患者胼胝体病变主要为长T2异常信号、FLAIR像稍高信号,其中1例DWI呈高信号。出现胼胝体病变的3例肝豆状核变性患者均病情较重、脑部损伤弥漫(尾状核、壳核、苍白球、丘脑、中脑及桥脑)。结论胼胝体病变为肝豆状核变性患者少见的影像学表现,若在有典型基底节病变的同时还伴有胼胝体病变则高度支持肝豆状核变性的诊断。胼胝体病变也提示患者病情较重、脑部损伤弥漫,预后相对较差。     

中药益坎胶囊对动脉性勃起功能障碍大鼠阴茎海绵体平滑肌细胞表型转化的影响

目的:探讨中药益坎胶囊对动脉性勃起功能障碍(ED)大鼠阴茎海绵体平滑肌细胞表型转化的影响,以揭示益坎胶囊治疗ED的机制。方法:选取SD大鼠50只,其中10只设为正常组,另40只通过结扎双髂内动脉造成动脉性ED模型。造模后将其中10只设为模型对照组,其余30只灌胃给予ED治疗中药益坎胶囊,浓度分别为1.88、0.94、0.47 g/kg。给药1个月后,经腹腔注射阿朴吗啡,观察大鼠呵欠次数和阴茎勃起次数;切取大鼠的阴茎组织标本,通过免疫组化法观测海绵体平滑肌细胞收缩型性标志物碱性调宁蛋白(calponin 1)和合成型标志物骨桥蛋白(OPN)的表达,实验组结果与正常组和对照组进行比较。结果:注射阿朴吗啡后,正常组大鼠勃起次数为(4.48±1.25)次,模型对照组为(1.63±0.22)次,两组比较,差异有统计学意义(P0.01);给药后,中药益坎胶囊高、中、低剂量组大鼠勃起次数有明显改善[高剂量:(3.05±1.37)次;中剂量:(2.98±0.16)次;低剂量:(1.75±0.40)次]。免疫组化结果显示,模型对照组大鼠海绵体平滑肌细胞calponin 1表达减少,而OPN表达增多,与正常组相比差异有统计学意义(P0.05);与模型对照组相比,给药后,中药益坎胶囊高、中、低剂量组大鼠海绵体平滑肌细胞calponin 1表达增多,OPN表达减少。结论:中药益坎胶囊能改善动脉性ED大鼠的勃起功能,抑制海绵体平滑肌细胞表型由收缩型向合成型转化。     

Different patterns of cerebellar abnormality and hypomyelination between POLR3A and POLR3B mutations

Background

Mutations of POLR3A and POLR3B have been reported to cause several allelic hypomyelinating disorders, including hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome). Patients and methods: To clarify the difference in MRI between the two genotypes, we reviewed MRI in three patients with POLR3B mutations, and three with POLR3A mutations. Results: Though small cerebellar hemispheres and vermis are common MRI findings with both types of mutations, MRI in patients with POLR3B mutations revealed smaller cerebellar structures, especially vermis, than those in POLR3A mutations. MRI also showed milder hypomyelination in patients with POLR3B mutations than those with POLR3A mutations, which might explain milder clinical manifestations. Conclusions: MRI findings are distinct between patients with POLR3A and 3B mutations, and can provide important clues for the diagnosis, as these patients sometimes have no clinical symptoms suggesting 4H syndrome.