成年哺乳动物海马齿状回神经发生的研究进展

近年来研究发现,成年哺乳动物海马齿状回仍然保持着神经发生的能力,其增殖水平在正常生理条件下较低,但在特殊环境或某些病理条件下可以增强,其发生的过程和机制十分复杂,受众多因素的影响和调节,这些因素在神经元增殖、存活和分化的不同阶段起重要作用。     

成年哺乳动物海马齿状回神经发生的研究进展

<正> 神经发生指神经干细胞增殖、存活和分化的过程,传统的观点认为成年哺乳动物中枢神经系统不存在神经发生。近年大量研究证实成年哺乳动物海马齿状回终身存在着神经发生,这为脑损伤和神经系统变性疾病如老年性痴呆的治疗带来希望,通过刺激机体自身的神经发生使中枢神经系统实现自我修复,有望为神经系统疾病的治疗开拓新领域。     

成年哺乳动物海马齿状回神经发生的研究进展

近年来研究发现，成年哺乳动物海马齿状回仍然保持着神经发生的能力。其增殖水平在正常生理条件下较低。但在特殊环境或某些病理条件下可以增强，其发生的过程和机制十分复杂，受众多因素的影响和调节，这些因素在神经元增殖，存活和分化的不同阶段起重要作用。     

成年哺乳动物海马齿状回神经发生的研究进展

神经干细胞（NSCs）在一定条件下可增殖分化成神经元和神经胶质细胞，参与神经功能的修复过程，称之为神经发生。传统观念认为，神经发生主要存在于胚胎期。近年研究发现，成年哺乳动物的中枢神经系统也存在神经发生，生理状态下神经发生较少，而病理状态下神经发生较多。这为临床上神经损伤的修复提供了理论依据。现将成年哺乳动物海马齿状回神经发生的研究进展综述如下。     

亚麻醉浓度的七氟烷对成年大鼠认知功能及海马齿状回神经发生的影响

目的探讨亚麻醉浓度的七氟烷对成年大鼠认知功能及海马齿状回神经发生的影响。方法将18只SD大鼠经过Moms水迷宫训练2d后,随机分为空白组（未经任何处理）、氧气组（吸氧2h）和七氟烷组（1-5％七氟烷吸入麻醉2h）,给予相应的处理后,连续5d用Moms水迷宫行学习记忆测试。测试完毕后处死大鼠,取脑组织用免疫组化方法观察海马齿状回的神经发生。结果与空白组相比,七氟烷组元认知功能障碍,海马齿状回神经发生明显增加（P〈0．05）。结论亚麻醉浓度的七氟烷不影响成年大鼠的认知功能,且能诱发成年大鼠海马齿状回的神经发生。     

胰岛素样生长因子与糖尿病脑病

胰岛素样生长因子是一类结构上与胰岛素部分同源并具有胰岛素样活性的多肽,广泛分布于中枢和外周神经系统,具有神经营养作用。近年来研究发现,胰岛素样生长因子与糖尿病脑病密切相关,胰岛素样生因子水平下降可引起糖尿病脑病患者认知功能受损,补充胰岛素样生长因子可能对糖尿病脑病认知功能的改善有治疗作用。     

Orexin-A对癫痫大鼠学习记忆能力及海马齿状回神经细胞增殖的影响

目的探讨Orexin-A(OXA)对癫痫大鼠学习记忆能力及海马齿状回神经细胞增殖的影响。方法选取健康成年SD大鼠50只,随机分为对照组、PTZ+NS组、PTZ+OXA组、PTZ+U0126组、PTZ+U0126+OXA组,每组10只。选用PTZ(30 mg/kg)腹腔注射造模。对照组和PTZ+NS组注射8μl生理盐水,PTZ+OXA组注射等量1.5 nmol/μl的OXA,PTZ+U0126组注射等量的U0126,PTZ+U0126+OXA组分别注射等量U0126和OXA;注射后恢复饲养7 d后进行水迷宫试验。观察各组大鼠学习记忆能力,并采用免疫荧光染色法检测海马齿状回神经细胞增殖情况。结果与对照组相比,其余四组大鼠的逃避潜伏期明显变长(P0.01)。PTZ+U0126组逃避潜伏期明显长于PTZ+NS组(P0.01);PTZ+NS组、PTZ+U0126组、PTZ+U0126+OXA组逃避潜伏期明显长于PTZ+OXA组(P0.05)。与对照组相比,其余四组大鼠穿越平台的次数、穿越平台所处象限的时间均明显减少(P0.01);PTZ+OXA组、PTZ+U0126+OXA组大鼠穿越平台象限的次数、穿越平台所处象限的时间均明显多于PTZ+NS组(P0.01)。PTZ+U0126+OXA组大鼠穿越平台象限的次数、穿越平台所处象限的时间明显少于PTZ+OXA组(P0.01)。PTZ+U0126组海马齿状回区Brdu+/DCX+细胞数明显低于PTZ+NS组(P0.01);PTZ+NS组、PTZ+U0126组、PTZ+U0126+OXA组海马齿状回区Brdu+/DCX+细胞数明显低于PTZ+OXA组(P0.05)。结论 OXA能够通过促进齿状回颗粒细胞的再生改善癫痫大鼠的学习记忆能力,其可能与ERK1/2激活有关。     

丰富环境对老龄大鼠学习记忆功能与海马齿状回神经发生及DNA甲基化水平的影响

目的 探讨丰富环境对老龄大鼠的学习记忆功能与海马齿状回神经发生的影响以及DNA甲基化在这个过程中的调控作用.方法 将月龄为18个月的雄性Wistar大鼠随机分为丰富环境组和对照组,分别对两组进行水迷宫试验测试,标记、检测海马齿状回的神经干细胞并测定脑组织的5-甲基脱氧胞苷含量.结果 丰富环境组大鼠的海马齿状回5-溴脱氧尿核苷(BrdU)阳性细胞数目[(650±87)个/mm2]显著高于对照组[(420±58)个/mm2](P＜0.05).丰富环境组大鼠海马组织的5-甲基脱氧胞苷含量(5.4%±0.25%)明显高于对照组(4.2%±0.36%)(P＜0.05).与对照组相比,丰富环境组大鼠到达平台所需的时间明显缩短(P＜0.05).结论 DNA甲基化可能参与了丰富环境促进老龄大鼠学习记忆功能与海马齿状回神经发生的调控.     

海马齿状回GABAB受体在血管性痴呆大鼠空间学习记忆中的作用

目的探讨海马齿状回(DG)的GABAB受体是否参与血管性痴呆(VD)大鼠空间学习记忆损害。方法 SD雄性大鼠24只,随机分为假手术组、VD组及GABAB受体阻断剂沙克洛芬组,双侧颈总动脉永久性结扎法制备VD大鼠模型。利用Morris水迷宫检测大鼠的空间学习记忆能力;脑部微量透析法和高效液相色谱法测定DG区γ-氨基丁酸(GABA)含量;免疫组织化学法观察DG区GABAB受体表达;用脑部微量注射法往DG区注射GABAB受体阻断剂沙克洛芬,观察其对VD模型大鼠空间学习记忆的影响。结果 VD大鼠海马DG区GABA含量明显增加,而GABAB受体表达减少(均为P0.05)。VD大鼠的空间学习记忆能力显著下降,而训练前向DG区微量注射GABAB受体阻断剂可改善VD大鼠的空间学习记忆损害。结论 VD模型大鼠海马DG内增加的GABA通过GABAB受体参与其空间学习记忆的损害。     

D-半乳糖致衰老小鼠学习记忆行为改变及对海马神经发生的影响

目的 探讨D-半乳糖衰老模型小鼠学习记忆行为变化及对海马齿状回细胞增殖的影响.方法 采用连续皮下注射D-半乳糖构建亚急性衰老小鼠模型,用Y-电迷宫检测衰老小鼠的学习记忆情况,并于造模完成前7 d腹腔内注射5-溴脱氧尿嘧啶核苷(BrdU),行为检测完成后,取海马脑块行常规石蜡包埋,冠状连续切片,采用免疫组化法检测齿状回BrdU阳性细胞并计数.结果 衰老模型小鼠呈现明显的学习记忆减退,其齿状回增殖细胞数量与正常衰老相近.结论 采用连续皮下注射D-半乳糖可成功构建衰老模型,其学习记忆障碍可能与齿状回细胞增殖抑制有关.     

Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus

Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.     

Space radiation-induced inhibition of neurogenesis in the hippocampal dentate gyrus and memory impairment in mice: ameliorative potential of the melatonin metabolite, AFMK

Evaluation of potential health effects from high energy charged particle radiation exposure during long duration space travel is important for the future of manned missions. Cognitive health of an organism is considered to be maintained by the capacity of hippocampal precursors to proliferate and differentiate. Environmental stressors including irradiation have been shown to inhibit neurogenesis and are associated with the onset of cognitive impairments. The present study reports on the protective effects of N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK), a melatonin metabolite, against high energy charged particle radiation-induced oxidative damage to the brain. We observed that radiation exposure (2.0 Gy of 500 MeV/nucleon (56)Fe beams, a ground-based model of space radiation) impaired the spatial memory of mice at later intervals without affecting the motor activities. AFMK pretreatment significantly ameliorated these neurobehavioral ailments. Radiation-induced changes in the population of immature and proliferating neurons in the dentate gyrus were localized using anti-doublecortin (Dcx) and anti-Ki-67 expression. AFMK pretreatment significantly inhibited the loss of Dcx and Ki-67 positive cells. Moreover, AFMK pretreatment ameliorated the radiation-induced augmentation of protein carbonyls and 4-hydroxyalkenal + malondialdehyde (MDA + HAE) in the brain and maintained the total antioxidant capacity of plasma and nonprotein sulfhydryl contents in brain.     

Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum

Childhood maltreatment or abuse is a major risk factor for mood, anxiety, substance abuse, psychotic, and personality disorders, and it is associated with reduced adult hippocampal volume, particularly on the left side. Translational studies show that the key consequences of stress exposure on the hippocampus are suppression of neurogenesis in the dentate gyrus (DG) and dendritic remodeling in the cornu ammonis (CA), particularly the CA3 subfield. The hypothesis that maltreatment is associated with volume reductions in 3-T MRI subfields containing the DG and CA3 was assessed and made practical by newly released automatic segmentation routines for FreeSurfer. The sample consisted of 193 unmedicated right-handed subjects (38% male, 21.9 ± 2.1 y of age) selected from the community. Maltreatment was quantified using the Adverse Childhood Experience study and Childhood Trauma Questionnaire scores. The strongest associations between maltreatment and volume were observed in the left CA2-CA3 and CA4-DG subfields, and were not mediated by histories of major depression or posttraumatic stress disorder. Comparing subjects with high vs. low scores on the Childhood Trauma Questionnaire and Adverse Childhood Experience study showed an average volume reduction of 6.3% and 6.1% in the left CA2-CA3 and CA4-DG, respectively. Volume reductions in the CA1 and fimbria were 44% and 60% smaller than in the CA2-CA3. Interestingly, maltreatment was associated with 4.2% and 4.3% reductions in the left presubiculum and subiculum, respectively. These findings support the hypothesis that exposure to early stress in humans, as in other animals, affects hippocampal subfield development.     

Light-intensity exercise improves memory dysfunction with the restoration of hippocampal MCT2 and miRNAs in type 2 diabetic mice

Cognitive decline associated with type 2 diabetes mellitus (T2DM) is a risk factor to impair human health. Although light-intensity exercise prevents hippocampal memory dysfunction in pre-symptomatic T2DM animals by altering hippocampal lactate transport and neurotrophic factors, the effects of light-intensity exercise in an advanced stage of T2DM animals remain unclear. Here, ob/ob mice, an animal model of T2DM, were subjected to light-intensity exercise (5.0 m/min) for 30 min/day, five days/week for four weeks. The effects of light-intensity exercise on hippocampal complications, mRNA expressions of monocarboxylate transporter (MCT), and miRNA levels were assessed. The light-intensity exercise improved hippocampal memory retention in ob/ob mice. Downregulated hippocampal Mct2 mRNA levels in T2DM were improved with light-intensity exercise. Hippocampal mRNA levels of Mct1 and Mct4 were unchanged within groups. Based on miRNA sequencing, sedentary ob/ob mice exhibited that 71 miRNAs were upregulated, and 77 miRNAs were downregulated in the hippocampus. In addition, the exercise significantly increased 24 miRNAs and decreased 4 miRNAs in the T2DM hippocampus. The exercise reversed T2DM-induced alterations of hippocampal 9 miRNAs, including miR-200a-3p. Our findings imply that miR-200a-3p/Mct2 in the hippocampus would be a possible clinical target for treating T2DM-induced memory dysfunction.

     

1型糖尿病患者血清HCMV DNA与T细胞亚群和胰岛功能的关系研究

目的 研究1型糖尿病患者血清人类巨细胞病毒（HCMV）DNA与外周血T细胞亚群和胰岛功能的相关性。方法 采用定量PCR技术测量20例1型糖尿病患者和40例对照组血清中HCMV DNA含量，并与外周血T细胞亚群、血糖（BG）、胰岛素（Ins)和C肽（C－P）水平进行比较和相关分析。结果 1型糖尿病患者HCMV DNA阳性率及含量明显高于对照组。HCMV DNA阳性患者CD8、空腹及2h BG明显高于对照组，CD4、CD4／CD8比值、空腹及2h Ins和2h C-P明显低于对照组，HCMV DNA含量与CD8、空腹BG呈直线正相关，与CD4／CD8比值、空腹Ins及C－P呈直线负相关。而HCMV DNA阴性患者上述指标与对照组比较差异显著性不及阳性者。结论 1型糖尿病患者HCMV感染与T细胞免疫和胰岛功能异常有关。     

Hippocampal M1 receptor function associated with spatial learning and memory in aged female rhesus macaques

Of the acetylcholine muscarinic receptors, the type 1 (M1) and type 2 (M2) receptors are expressed at the highest levels in the prefrontal cortex (PFC) and hippocampus, brain regions important for cognition. As equivocal findings of age-related changes of M1 and M2 in the nonhuman primate brain have been reported, we first assessed age-related changes in M1 and M2 in the PFC and hippocampus using saturation binding assays. Maximum M1 receptor binding, but not affinity of M1 receptor binding, decreased with age. In contrast, the affinity of M2 receptor binding, but not maximum M2 receptor binding, increased with age. To determine if in the elderly cognitive performance is associated with M1 or M2 function, we assessed muscarinic function in elderly female rhesus macaques in vivo using a scopolamine challenge pharmacological magnetic resonance imaging and in vitro using saturation binding assays. Based on their performance in a spatial maze, the animals were classified as good spatial performers (GSP) or poor spatial performers (PSP). In the hippocampus, but not PFC, the GSP group showed a greater change in T₂*-weighted signal intensity after scopolamine challenge than the PSP group. The maximum M1 receptor binding and receptor binding affinity was greater in the GSP than the PSP group, but no group difference was found in M2 receptor binding. Parameters of circadian activity positively correlated with the difference in T₂*-weighted signal intensity before and after the challenge, the maximum M1 receptor binding, and the M1 receptor binding affinity. Thus, while in rhesus macaques, there are age-related decreases in M1 and M2 receptor binding, in aged females, hippocampal M1, but not M2, receptor function is associated with spatial learning and memory and circadian activity.     

Regional differences in the manifestation of gastrointestinal motor disorders in type 1 diabetic patients with autonomic neuropathy

OBJECTIVE: The aim of this work was to establish the prevalence and severity of different gastrointestinal symptoms and their relationships to esophageal, gastric and recto-anal motor disturbances by manometry in patients with Type 1 diabetes mellitus and autonomic neuropathy. PATIENTS AND METHODS: Sixteen patients (mean age: 53.4 +/- 14.9 years) with long standing type 1 diabetes mellitus (mean diabetes duration: 22.1 +/- 14.7 years) and autonomic neuropathy (mean Ewing score: 5.73 +/- 2.34) were investigated. The gastrointestinal symptom scores were established by using the Talley dyspepsia questionnaire. The motor function of the digestive tract was tested in the esophagus, in the stomach, and in the ano-rectum by perfusion manometry. RESULTS: Manometric evaluation of the esophagus did not reveal significant abnormalities in the region of the upper sphincter in patients with diabetes mellitus. In contrast, diabetic patients had decreased peristaltic wave amplitude, prolonged duration, decreased wave propagation velocity, and increased number of simultaneous contractions in the esophageal body, and decreased lower esophageal sphincter pressures with prolonged relaxation compared to the age- and sex-matched controls. Symptom analysis showed correlations between reflux symptoms and LES relaxation times, and between dysphagia scores and esophageal body peristaltic wave duration, propagation velocity and the rate of simultaneous contractions. In the gastric antrum, frequent, and often severe, fasting motility disorders were observed, which had no correlation with dyspeptic symptoms. In the ano-rectal region the diabetic patients had a lower squeezing-resting pressure difference, and impaired fecal expulsive function. Motility disorders were simultaneously present at multiple parts of the gastrointestinal tract in 13/16 cases. CONCLUSIONS: In patients with type 1 diabetes mellitus and autonomic neuropathy gastrointestinal motility disorders were observed frequently, and in most of the cases simultaneously. While esophageal and ano-rectal symptoms correlated better with the manometric abnormalities, the lack of correlation between the impaired fasting gastric motility and dyspeptic symptoms shows that, on the basis of the clinical symptom analysis, the prevalence of such motor disorders could be underestimated. The early recognition of gastrointestinal motility disorders may be important for the better long-term management of patients with type 1 diabetes mellitus.     

Insulin pump therapy in type 1 pediatric patients: now and into the year 2000

There are a number of medical conditions such as growth failure in children, pregnancy, lipid abnormalities, and early complications that are improved by the meticulous glycemic control that can be achieved with insulin pump therapy (CSII). By using an insulin pump, many patients with severe hypoglycemia, the dawn phenomenon, extremes of glycemic excursion, recurrent diabetic ketoacidosis (DKA) and hypoglycemia unawareness have amelioration of these problems. However, pump therapy involves problems such as weight gain, recurrent ketosis due to pump failure, infections, and risk of hypoglycemia. Owing to many developmental issues, young children may not be able to wear the pump without parental supervision. We have used the pump at night time only in these patients. This has allowed children of 7-10 years of age to benefit from improved nocturnal glycemia without the risk of pump therapy when they are without an adult to help. We have also used the pump in subjects with recurrent DKA and in our general patient population (mean age 13.6+/-3.9 years). In our pump cohort, CSII led to improvement in quality of life, knowledge, adherence, and responsibility. A reduction in hypoglycemia, DKA rate and mean HbA(1c) was associated with pump usage. For this to occur, however, pump education must be geared to the pediatric subject and his/her family. Education materials and tools help in learning how to use the pump and how to deal with the intricacies of basal and bolus dosing, and the effect of exercise, food and illness on diabetes management. The pump has improved since it was first introduced and these modifications have made it easier, more painless and less hazardous. With the development of continuous glucose sensors and implantable pumps, the next century will see pump therapy lead to the artificial pancreas.