Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex

During brain maturation, the occurrence of the extracellular matrix (ECM) terminates juvenile plasticity by mediating structural stability. Interestingly, enzymatic removal of the ECM restores juvenile forms of plasticity, as for instance demonstrated by topographical reconnectivity in sensory pathways. However, to which degree the mature ECM is a compromise between stability and flexibility in the adult brain impacting synaptic plasticity as a fundamental basis for learning, lifelong memory formation, and higher cognitive functions is largely unknown. In this study, we removed the ECM in the auditory cortex of adult Mongolian gerbils during specific phases of cortex-dependent auditory relearning, which was induced by the contingency reversal of a frequency-modulated tone discrimination, a task requiring high behavioral flexibility. We found that ECM removal promoted a significant increase in relearning performance, without erasing already established—that is, learned—capacities when continuing discrimination training. The cognitive flexibility required for reversal learning of previously acquired behavioral habits, commonly understood to mainly rely on frontostriatal circuits, was enhanced by promoting synaptic plasticity via ECM removal within the sensory cortex. Our findings further suggest experimental modulation of the cortical ECM as a tool to open short-term windows of enhanced activity-dependent reorganization allowing for guided neuroplasticity.Structural remodeling and stabilization of synaptic networks are key mechanisms underlying learning in the adult brain. During early life, high structural and functional plasticity is required for the experience-shaped development of basic neuronal circuits (1). With brain maturation, juvenile plasticity of so-called critical or sensitive periods is decreased and is accompanied by the appearance of the brain’s extracellular matrix (ECM) and its specialized compact form named “perineuronal net” (PNN) enwrappping cell bodies and synaptic contacts (2, 3). Enzymatic degradation of the ECM in adult animals has been demonstrated to restore such forms of developmental (juvenile) plasticity with respect to topographical map plasticity in the visual cortex (4), fear-response–mediating circuits in the amygdala (5), spinal cord injuries (6, 7), and song learning circuits of zebra finches (8). In addition, enzymatic ECM removal altered several forms of synaptic plasticity in vitro and in vivo (9–12). However, even though structural stability of networks acquired during developmental phases is essential for neuronal efficiency, mechanisms allowing synaptic remodeling are key events during learning and memory formation throughout life (13). We recently demonstrated that endogenous proteases moderately digesting specific components of the ECM are regulated in an activity-dependent manner (2, 14) and ECM removal modulates synaptic short-term plasticity by synaptic exchange of postsynaptic glutamate receptors (10, 15). Further, ECM modulation enhances synaptic short-term plasticity by affecting voltage-dependent calcium channels (9). These findings challenge the view of the purely stabilizing role of ECM in the brain and indicate a potential regulatory switch for plastic network adaptations within the adult brain at the level of individual synapses by modulating the extracellular space (16). However, it remains open to what extent ECM modulations influence learning-related plasticity in the adult brain and its specific effects on behavior during a cognitive task.In the present study, we aimed at evaluating the potential role of experimental ECM removal within the auditory cortex (ACx) of Mongolian gerbils, which has been found to be particularly rich in ECM (17), during a cognitively demanding auditory go/no go shuttle-box task. We selected discrimination and reversal learning of frequency-modulated (FM) tones as a cognitive task, which necessarily requires ACx plasticity (18, 19). Injections of the ECM-degrading enzyme hyaluronidase (HYase) into the ACx after the first acquisition phase significantly enhanced subsequent reversal learning compared with sham-treated animals (injection of 0.9% saline). Particularly, after ECM degradation, animals abandoned the inappropriate discrimination strategy from the initial acquisition phase faster and thus promoted successful discrimination performance of the new contingency during reversal learning. ECM removal did not further influence the initial acquisition learning or interfere with already established—that is, learned—capacities in later learning stages, suggesting an enhanced activity-dependent neuroplastic reorganization of established synaptic networks in ACx during reversal learning.Our findings suggest that experimental degradation of the ECM in sensory cortex, although not affecting general sensory learning, does, however, enhance the cognitive flexibility that can build on the learned behaviors. Thereby, ECM degradation could be used as a tool for guided neuroplasticity, which might also bear therapeutic potential.     

The Impact of Endogenous Breast Cancer Resistance Protein on Human P-Glycoprotein-Mediated Transport Assays Using LLC-PK1 Cells Transfected With Human P-Glycoprotein

Lilly Laboratories cell porcine kidney 1 (LLC-PK1) cells transfected with human P-glycoprotein (LLC-PK1-P-gp) are widely used in transport assays to identify drug candidates that function as substrates of this efflux transporter. Endogenous transporters expressed in LLC-PK1 cells may complicate the interpretation of findings from P-gp-mediated transport assays. We investigated the impact of porcine breast cancer resistance protein (Bcrp) in P-gp-mediated transport assays in LLC-PK1 cells. Porcine Bcrp mRNA was detected in both LLC-PK1 wildtype (WT) and LLC-PK1-P-gp cells by quantitative RT-PCR. To investigate the activity and impact of porcine Bcrp, we conducted transport assays using 6 typical BCRP substrates in LLC-PK1 cells. Efflux ratios (ER) of the 6 BCRP substrates in LLC-PK1 WT cells were >2, and were reduced in the presence of the BCRP inhibitor Ko143. The efflux activities of the 6 BCRP substrates were confirmed using MDCKII cells transfected with human BCRP. Net ERs of prazosin and fluvastatin, dual substrates of P-gp and BCRP, determined by dividing ERs in LLC-PK1-P-gp cells by those in LLC-PK1 WT cells, were <2, but increased to >2 in the presence of Ko143. These results indicated that endogenous Bcrp in LLC-PK1 cells was involved in the transport of BCRP substrates and may interfere with the identification of P-gp substrates.     

Analysis of Plasma Albumin,Vitamin D,and Apolipoproteins A and B as Predictive Coronary Risk Biomarkers in the REGICOR Study

Introduction and objectives

New biomarkers could improve the predictive capacity of classic risk functions. The aims of this study were to determine the association between circulating levels of apolipoprotein A1 (apoA1), apolipoprotein B (apoB), albumin, and 25-OH-vitamin D and coronary events and to analyze whether these biomarkers improve the predictive capacity of the Framingham-REGICOR risk function.

Feature-Tracking Global Longitudinal Strain Predicts Death in a Multicenter Population of Patients With Ischemic and Nonischemic Dilated Cardiomyopathy Incremental to Ejection Fraction and Late Gadolinium Enhancement

Objectives

The aim of this study was to evaluate the prognostic value of cardiac magnetic resonance (CMR) feature-tracking–derived global longitudinal strain (GLS) in a large multicenter population of patients with ischemic and nonischemic dilated cardiomyopathy.

套索回归模型在中医临床研究数据的统计应用与R语言实践

目的：构建简洁且易于解释的模型,为同类研究提高模型预测的准确率提供参考。方法：从国家自然科学基金项目在研课题(81673904)中选取200例肺纤维化合并心力衰竭患者心力衰竭分级与其可能的相关因素,运用套索回归从患者的“性别”“年龄”“体质量指数”“收缩压”“舒张压”“血清总胆固醇”“空腹血糖”“舌质颜色”“舌苔颜色”“中医体质”等自变量中筛选特征变量,构建回归模型以探讨其与心力衰竭严重程度之间的关系。结果：剔除高维数据中的混杂因素,筛选特征变量,模型中包含6个特征变量,体质量指数=0.006 357 091,收缩压=0.219 695 622,血清总胆固醇=0.229 324 833,舌色红=0.004 216 705,苔色薄白=-0.825 660 057,苔色黄厚=0.356 499 153。肺纤维化合并心力衰竭出现严重心力衰竭的概率为P=-33.632+0.006×BMI+0.220×SBP+0.229×TC+0.004×是否红舌-0.826×是否薄白苔+0.356×是否黄厚苔。结论：得到的模型可用以解释严重心力衰竭发病的相关因素并推广到总体中进行预测。套索回归模型适用于中医临...     

基于纹理特征的神经网络分类器用于肝硬化核磁共振图像分类识别

目的 研究基于纹理特征的神经网络分类器用于肝硬化核磁共振图像(MRI)分类诊断方法.方法 选取经大连医科大学附属第二医院临床和实验室检查确诊的18例患者的肝脏MR图像,其中肝硬化10例,正常肝脏8例,通过手工分割共获取MR图像感兴趣区(ROI)170个(肝硬化组88个,正常肝脏组82个).通过灰度共生矩阵提取了2组170个ROI0°、45°、90°、135°4个方向的纹理特征参数(共计56个),采用盒状图评估56个纹理特征参数区分肝硬化和正常肝脏的性能,获得2组间可分性好的纹理特征参数24个.分别采用全部的56个纹理特征参数(特征组A)、完全随机选择24个纹理特征参数(特征组B)及两组间可分性好的24个纹理特征参数(特征组C)训练反向传播(BP)神经网络,其中用于网络训练的ROI为110个,而测试BP神经网络的ROI为60个.结果 盒状图评价显示0°,45°,90°,135°4个方向上的能量、对比度、相关性、逆差矩、和方差以及差平均共计24个特征参数在肝硬化组和正常肝脏组间可分性较好.特征组C的正确识别率最高(95.00%,57/60),高于特征组A和特征组B(78.33%,47/60;88.33%,53/60;P＜0.05).结论 基于纹理特征的BP神经网络分类器适于肝硬化和正常肝脏MR图像的分类识别.     

Alterations of ionic currents after reoxygenation in isolated cardiocytes of guinea-pigs

Single myocytes were isolated from ventricles of adult guinea-pig hearts. The patch-clamp technique in the whole-cell configuration was used to study ionic currents. Experiments were performed in an experimental chamber that allowed the cells to be exposed to a sufficiently low O₂ pressure to cause metabolic inhibition after 4–35 min (mean 14.1 min, n=20), which was indicated by the appearance of a large time-independent K current. Reoxygenation about 1 min after the first extra outward current was observed caused this current to vanish completely within 2–6 s if the calcium inside the pipette was buffered to negligible values with 20 mmol/l EGTA. With only 10 M EGTA in the pipette, reoxygenation was followed by an arrhythmogenic period of 10–150 s duration, which was dominated by three types of event: (a) transient inward currents (I _ti) developed during the first 5–10 s (26 cells); (b) the net current was increased by a factor of 1.9±0.4 (mean±SD, n=17) yielding a reversal potential for the increased component of –77±4 mV (mean±SD, n=4); and (c) the Ca current decreased by 20%–100% within the first 5–10 s. At the end of the arrhythmogenic period, I _ti vanished, the net current recovered completely, and the Ca current recovered partially. At –45 mV, increasing preceding depolarization enlarged the amplitude of both the I _ti and the net current, I_ti being about four times more increased than the net current. The suppression of the Ca current was independent of the phase of the preceding I _ti. We conclude that in isolated cardiocytes, after the induction of an anoxia-induced K current, reoxygenation causes a period of up to 150 s of cytosolic Ca overload, during which I _ti is triggered, the net current is enhanced, and the Ca current is suppressed.This work was supported by the Deutsche Forschungsgemeinschaft, Hi 137/10-1     

髂腹部真皮下血管网皮瓣用于手部整复治疗的临床体会

目的：总结髂腹部真皮下血管网皮瓣用于手部整复治疗的方法和实用性。方法：应用髂腹部真皮下血管网皮瓣修复手部畸形与其他（同它共用）创面的方法,根据术后断蒂时间,成活状况以及术后手的外形和功能判断治疗效果。结果：112例患者除5例皮瓣局部坏死经换药痊愈外,其余均一期愈合,且断蒂时间短,手的外形和功能均良好。结论：髂腹部真皮下血管网皮瓣修复手部畸形及其他创面,手术方法操作简单易行,成功率高,有较强的实用性。     

激光近形制造钛合金试件力学性能的初步研究

目的 比较激光近形制造技术和铸造技术制作的钛合金试件的材料性能,探索激光快速成形此新工艺在口腔修复领域中的应用.方法 以-200～325目气雾化法制备的球形钛合金粉末为原料,应用激光近形制造技术制作钛合金试件,测试其在拉伸试验中的抗拉强度、屈服强度,三点弯曲试验中的弯曲弹性模量、抗弯强度,以及维氏显微硬度,并与铸造技术制作的钛合金试件进行对比;观察两种不同加工方法制作的钛合金试件的组织结构,以及拉伸断口的微观形貌特征.结果 激光近形制造技术制作钛合金试件,成形速度快,成形件无缺陷,其抗拉强度、屈服强度、弯曲弹性模量、抗弯强度、维氏显微硬度分别为(1 056.92±61.69)N/mm2、(62.65±61.91)N/mm2、(133 722.62±3 618.18)MPa、(2 313.42±129.16)MPa、376.24±14.88.激光近形制造试件的抗拉强度、屈服强度显著高于铸造钛合金试件.金相显微镜显示激光近形制造钛合金试件的组织为针状细枝晶的微晶结构,拉伸断口呈现均匀细致的韧窝形貌,发生韧性断裂.结论 激光近形制造技术可以满足口腔修复的加工要求,但需要进一步研究其成形性能及提高精度.     

钛网椎管成形植骨脊柱融合的实验研究

目的 观察以犬作为实验动物,进行钛合金网为支撑物的脊柱椎管重建及植骨融合情况,并探讨其临床可行性。方法对6只蒙古犬进行静脉全麻,暴露T_(10)～L_3椎板,行全椎板减压,用钛丝将“Ω”形钛合金网固定并覆盖于减压区,上填自体骨及异种脱蛋白松质骨,逐层闭合伤口。于术后,6周、12周分别摄手术部位X线正侧位片及CT扫描,对比观察骨质愈合情况,钛网位置及椎管成形情况。同时宰杀3只动物,对实验部位行大体观察。结果 所有伤口均一期愈合。12周X线提示异种骨与钛网融合成片,形成椎板样结构,椎板与异种骨相接处骨质融合。CT扫描示椎管成形良好,硬膜囊未见骨性压迫。结论 应用钛网支撑植骨脊柱后路融合,可以在保护脊髓,神经根免于受压,维持减压效果的同时,有效的进行脊柱后路融合,在临床上有广阔的应用前景。