Morphological characteristics of eosinophilic neuronal death after transient unilateral forebrain ischemia in Mongolian gerbils

Various types of eosinophilic neurons (ENs) are found in the post‐ischemic brain. The aim of the present study was to elucidate the temporal and spatial profile of ENs, the expression of TUNEL staining and ultrastructural characteristics in the core and peripheral regions of the cortex post‐ischemia. Unilateral forebrain ischemia was induced in Mongolian gerbils by transient common carotid artery occlusions, and the brains from 3 h to 2 weeks post‐ischemia were prepared for morphometric, electron microscopy (EM) and TUNEL staining of the ENs. Light microscopy showed that ENs with minimally abnormal nuclei and swollen cell bodies appeared at 3 h in the ischemic core and at 12 h in the periphery. Thereafter, ENs with pyknosis and irregular atrophic cytoplasm peaked at 12 h, pyknosis with scant cytoplasm peaked at 4 days, and TUNEL‐positive staining was observed in the ischemic core. In the ischemic periphery, ENs had slightly atrophic cytoplasm and sequentially developed pyknosis, karyorrhexis and karyolysis over 1 week. These cells were also positive for TUNEL. In EM, severe organelle dilation and vacuolization preceded chromatin fragmentation in the ischemic core, while chromatin fragmentation and homogenization were the vital characteristics in the ischemic periphery. There might be two region‐dependent pathways for EN changes in the post‐ischemic brain: pyknosis with cytoplasmic shrinkage in the core and nuclear disintegration with slightly atrophic cytoplasm in the periphery. These pathways were comparable to necrosis and proceeded from non‐classical apoptosis to necrosis, respectively.     

Atorvastatin enhances kainate‐induced gamma oscillations in rat hippocampal slices

Atorvastatin has been shown to affect cognitive functions in rodents and humans. However, the underlying mechanism is not fully understood. Because hippocampal gamma oscillations (γ, 20–80 Hz) are associated with cognitive functions, we studied the effect of atorvastatin on persistent kainate‐induced γ oscillation in the CA3 area of rat hippocampal slices. The involvement of NMDA receptors and multiple kinases was tested before and after administration of atorvastatin. Whole‐cell current‐clamp and voltage‐clamp recordings were made from CA3 pyramidal neurons and interneurons before and after atorvastatin application. Atorvastatin increased γ power by ~ 50% in a concentration‐dependent manner, without affecting dominant frequency. Whereas atorvastatin did not affect intrinsic properties of both pyramidal neurons and interneurons, it increased the firing frequency of interneurons but not that of pyramidal neurons. Furthermore, whereas atorvastatin did not affect synaptic current amplitude, it increased the frequency of spontaneous inhibitory post‐synaptic currents, but did not affect the frequency of spontaneous excitatory post‐synaptic currents. The atorvastatin‐induced enhancement of γ oscillations was prevented by pretreatment with the PKA inhibitor H89, the ERK inhibitor U0126, or the PI3K inhibitor wortmanin, but not by the NMDA receptor antagonist D‐AP5. Taken together, these results demonstrate that atorvastatin enhanced the kainate‐induced γ oscillation by increasing interneuron excitability, with an involvement of multiple intracellular kinase pathways. Our study suggests that the classical cholesterol‐lowering agent atorvastatin may improve cognitive functions compromised in disease, via the enhancement of hippocampal γ oscillations.     

Previous Midlife Oestradiol Treatment Results in Long‐Term Maintenance of Hippocampal Oestrogen Receptor α Levels in Ovariectomised Rats: Mechanisms and Implications for Memory

Ovariectomised rats that have received previous administration of oestradiol in midlife display enhanced cognition and increased hippocampal levels of oestrogen receptor (ER)α months after oestradiol treatment ended compared to ovariectomised controls. The present study aimed to investigate the mechanisms by which ERα levels are maintained following midlife oestradiol exposure and the role of ERα in memory in ageing females in the absence of circulating oestrogens. Unliganded ERα has increased interaction with the ubiquitin ligase, C‐terminus of Hsc‐70 interacting protein (CHIP), leading to increased degradation of the receptor. In our first experiment, we tested the hypothesis that midlife oestradiol exposure in ovariectomised rats results in decreased interaction between CHIP and hippocampal ERα, leading to increased levels of ERα. Middle‐aged rats were ovariectomised and received oestradiol or vehicle implants. After 40 days, implants were removed. One month later, rats were killed and hippocampi were processed for whole protein western blotting and co‐immunoprecipitation, in which ERα was immunoprecipitated from lysate. As expected, ERα protein expression was increased in rats previously treated with oestradiol compared to vehicle‐treated rats. In rats treated with oestradiol, there was a decrease in CHIP–ERα interaction, suggesting that previous oestradiol treatment reduces interaction, slowing the degradation of ERα. In a second experiment, we determined the impact on memory of antagonism of ER in the absence of circulating oestrogens. Rats were ovariectomised and implanted with oestradiol capsules. Capsules were removed after 40 days. Rats received chronic i.c.v. infusion of ER antagonist, ICI 182 780, or artificial cerebrospinal fluid vehicle and were tested on a spatial memory radial‐maze task. Rats treated with ICI 182 780 had significantly worse performance (more errors). These experiments provide evidence that previous midlife oestradiol treatment maintains hippocampal ERα by decreasing its interaction with CHIP and that activation of these receptors provides cognitive benefits in the absence of circulating oestrogens.     

Brain‐derived neurotrophic factor prevents dendritic retraction of adult mouse retinal ganglion cells

We used cultured adult mouse retinae as a model system to follow and quantify the retraction of dendrites using diolistic labelling of retinal ganglion cells (RGCs) following explantation. Cell death was monitored in parallel by nuclear staining as ‘labelling’ with RGC and apoptotic markers was inconsistent and exceedingly difficult to quantify reliably. Nuclear staining allowed us to delineate a lengthy time window during which dendrite retraction can be monitored in the absence of RGC death. The addition of brain‐derived neurotrophic factor (BDNF) produced a marked reduction in dendritic degeneration, even when application was delayed for 3 days after retinal explantation. These results suggest that the delayed addition of trophic factors may be functionally beneficial before the loss of cell bodies in the course of conditions such as glaucoma.     

多巴胺系统功能在青春期前大鼠精神分裂症中的异常调节

目的探讨青春期前大鼠精神分裂症的多巴胺机制,为精神分裂症的早期预防及诊断提供重要依据。方法母鼠孕期17d时腹腔注射甲基氧化偶氮甲醇醋酸盐(methylazoxymethanol acetate,MAM)/盐水(25mg/kg),选取出生后35~40d龄的雄性子鼠作为模型实验动物,出生后10周作为成年动物。实验一:随机分为青春期前模型组和对照组,成年模型组和对照组,每组10只动物,于腹侧海马埋置刺激电极,通过自由运动行为法检测各组动物在接受阿朴吗啡刺激和腹侧海马电刺激后的行为变化;实验二:另有正常或MAM处理后的青春期前和成年大鼠各10只,记录腹侧被盖区(VTA)多巴胺能神经元放电活动,并于腹侧海马(vHipp)注射盐水/MK801,观察自发放电的变化。结果细胞外记录实验发现,MAM处理大鼠的子代VTA自发放电的多巴胺能神经元数目明显增多,且被vHipp注射MK801所翻转。成年精神分裂模型大鼠基础活动明显增加,对vHipp刺激后阿朴吗啡的刺激反应也明显增强;而青春期前和精神分裂模型组大鼠对vHipp电刺及对阿朴吗啡的刺激均无明显反应。结论精神分裂症大鼠的病理生理学改变在青春期前已经出现,但并未引发行为异常,青春期是多巴胺受体功能改变的关键期。     

CD200调控小胶质细胞KATP通道在抑制帕金森病发病中的作用

目的：探讨CD200减轻帕金森病（PD ）病变区域炎症反应的作用。方法制备1‐甲基‐4‐苯基‐1,2,3,6‐四氢吡啶（MPTP）小鼠PD模型,取脑组织。检测CD200及其受体CD200R的表达和ATP敏感性钾通道（KATP通道）不同亚基在小胶质细胞（MG）的表达;检测MG的细胞因子;分析外源性重组CD200对KATP通道释放的影响。结果 PD模型小鼠CD200及CD200R的表达下调, M G的IFN‐γ、T N F‐α和IL‐1β的释放增多。外源性重组CD200能够抑制M G中A T P的释放,M G中KATP通道的开放增加,1‐甲基‐4‐苯基‐吡啶离子（Mpp＋）引起的MG激活及炎症因子和氧化因子的释放受到抑制。结论CD200通过抑制MG内ATP的水平,促进MG中KATP通道的开放,抑制MG的活化及相关炎症因子的释放,减轻黑质纹状体区域的炎症反应,从而起到了保护多巴胺神经元的作用。     

Inhibition of microglial activity alters spinal wide dynamic range neuron discharge and reduces microglial Toll‐like receptor 4 expression in neuropathic rats

It is believed that neuropathic pain results from aberrant neuronal discharges although some evidence suggests that the activation of glia cells contributes to pain after an injury to the nervous system. This study aimed to evaluate the role of microglial activation on the hyper‐responsiveness of wide dynamic range neurons (WDR) and Toll‐like receptor 4 (TLR4) expressions in a chronic constriction injury (CCI) model of neuropathic pain in rats. Adult male Wistar rats (230 ± 30 g) underwent surgery for induction of CCI neuropathy. Six days after surgery, administration of minocycline (10, 20, and 40 mg/kg, i.p.) was initiated and continued until day 14. After administration of the last dose of minocycline or saline, a behavioral test was conducted, then animals were sacrificed and lumbar segments of the spinal cord were collected for Western blot analysis of TLR4 expression. The electrophysiological properties of WDR neurons were investigated by single unit recordings in separate groups. The findings showed that after CCI, in parallel with thermal hyperalgesia, the expression of TLR4 in the spinal cord and the evoked response of the WDR neurons to electrical, mechanical, and thermal stimulation significantly increased. Post‐injury administration of minocycline effectively decreased thermal hyperalgesia, TLR4 expression, and hyper‐responsiveness of WDR neurons in CCI rats. The results of this study indicate that post‐injury, repeated administration of minocycline attenuated neuropathic pain by suppressing microglia activation and reducing WDR neuron hyper‐responsiveness. This study confirms that post‐injury modulation of microglial activity is a new strategy for treating neuropathic pain.     

Diet-Induced Cognitive Deficits: The Role of Fat and Sugar,Potential Mechanisms and Nutritional Interventions

It is of vital importance to understand how the foods which are making us fat also act to impair cognition. In this review, we compare the effects of acute and chronic exposure to high-energy diets on cognition and examine the relative contributions of fat (saturated and polyunsaturated) and sugar to these deficits. Hippocampal-dependent memory appears to be particularly vulnerable to the effects of high-energy diets and these deficits can occur rapidly and prior to weight gain. More chronic diet exposure seems necessary however to impair other sorts of memory. Many potential mechanisms have been proposed to underlie diet-induced cognitive decline and we will focus on inflammation and the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Finally, given supplementation of diets with omega-3 and curcumin has been shown to have positive effects on cognitive function in healthy ageing humans and in disease states, we will discuss how these nutritional interventions may attenuate diet-induced cognitive decline. We hope this approach will provide important insights into the causes of diet-induced cognitive deficits, and inform the development of novel therapeutics to prevent or ameliorate such memory impairments.     

初诊2型糖尿病患者胰岛素强化治疗前后海马区NAA/Cr、Cho/Cr的变化

目的研究初诊2型糖尿病患者胰岛素强化治疗前后海马区N-乙酰天门冬氨酸复合物( NAA)/肌酸( Cr)、胆碱复合物( Cho)/Cr的变化。方法氢质子磁共振波谱(1 H-MRS)检测30例初诊2型糖尿病患者双侧海马区NAA/Cr、Cho/Cr,同时检测空腹血糖(FPG)、餐后2 h血糖(2 hPG)、糖化血红蛋白( HbAlc)、三酰甘油( TG)、胆固醇( CHO)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、HOMA-β细胞功能指数( HOMA-β)和HOMA-胰岛素抵抗指数( HOMA-IR)。胰岛素泵强化降糖10~14 d,血糖达标后复查上述指标予以对比。结果胰岛素强化治疗后,患者 FPG、2 hPG、TG、CHO、LDL、HOMA-IR水平降低(P<0．05,P<0．01),HOMA-β水平升高( P <0．05);左右侧海马区 NAA/Cr 升高( P <0．05),右侧海马区 Cho/Cr 降低( P <0．05),左侧海马区
　　Cho/Cr呈下降趋势,但差异无统计学意义;NAA/Cr、Cho/Cr与血糖、HOMA-β、HOMA-IR有一定相关性。结论胰岛素强化治疗初诊2型糖尿病,可改善患者血糖、血脂,同时可升高双侧海马区NAA/Cr、降低右侧海马区Cho/Cr,其机制可能与血糖降低、胰岛素分泌增加、胰岛素抵抗改善有关。     

Hippocampal dendritic spines remodeling and fear memory are modulated by GABAergic signaling within the basolateral amygdala complex

GABAergic signaling in the basolateral amygdala complex (BLA) plays a crucial role on the modulation of the stress influence on fear memory. Moreover, accumulating evidence suggests that the dorsal hippocampus (DH) is a downstream target of BLA neurons in contextual fear. Given that hippocampal structural plasticity is proposed to provide a substrate for the storage of long‐term memories, the main aim of this study is to evaluate the modulation of GABA neurotransmission in the BLA on spine density in the DH following stress on contextual fear learning. The present findings show that prior stressful experience promoted contextual fear memory and enhanced spine density in the DH. Intra‐BLA infusion of midazolam, a positive modulator of GABAa sites, prevented the facilitating influence of stress on both fear retention and hippocampal dendritic spine remodeling. Similarly to the stress‐induced effects, the blockade of GABAa sites within the BLA ameliorated fear memory emergence and induced structural remodeling in the DH. These findings suggest that GABAergic transmission in BLA modulates the structural changes in DH associated to the influence of stress on fear memory. © 2015 Wiley Periodicals, Inc.