经颅直流电刺激促进小鼠脑缺血后海马神经发生涉及NMDA受体上调

目的探讨经颅直流电刺激(transcranial direct current stimulation,tDCS)促进脑缺血小鼠内源性海马神经发生的作用及其可能机制。方法采用双侧颈总动脉夹闭法建立小鼠急性脑缺血模型,HE染色检测小鼠海马病理形态学改变;Morris水迷宫以检测小鼠学习记忆功能;免疫荧光染色观察海马区BrdU、DCX以及BrdU/NeuN阳性细胞表达以检测小鼠海马神经发生;以qRT-PCR和Western blot法分别检测小鼠海马NMDAR亚基NR2a、NR2b的mRNA及蛋白表达。结果脑缺血小鼠海马CA1区神经元损伤明显(P<0.01),学习记忆功能显著下降(P<0.01),提示脑缺血模型成功建立。同时,海马BrdU,DCX和BrdU/NeuN阳性细胞表达明显增加(P<0.01),表明脑缺血后海马出现神经发生。tDCS治疗后可显著改善CA1区病理损害,提高学习记忆能力,并促进神经发生。同时,海马NR2a、NR2b的mRNA及蛋白表达水平也上调(P<0.05或P<0.01)。结论tDCS可促进脑缺血后小鼠海马神经发生,改善学习记忆功能,其机制可能与上调NR2a、NR2b表达相关。     

生长激素在神经系统疾病治疗中的作用

生长激素的生理作用主要是促进物质代谢与生长发育。研究表明,生长激素对机体各器官和各组织均有影响,在神经系统疾病的神经再生和神经保护过程中,生长激素也起到了一定的作用。本文总结生长激素治疗常见神经系统疾时所起的作用以及可能的机制。     

Valproic acid,a histone deacetylase inhibitor,regulates cell proliferation in the adult zebrafish optic tectum

Background: Valproic acid (VPA) has been used to treat epilepsy and bipolar disorder. Several reports have demonstrated that VPA functions as a histone deacetylase (HDAC) inhibitor. While VPA is known to cause teratogenic changes in the embryonic zebrafish brain, its effects on neural stem cells (NSCs) in both the embryonic and adult zebrafish are not well understood. Results: In this study, we observed a proliferative effect of VPA on NSCs in the embryonic hindbrain. In contrast, VPA reduced cell proliferation in the adult zebrafish optic tectum. Treatment with HDAC inhibitors showed a similar inhibitory effect on cell proliferation in the adult zebrafish optic tectum, suggesting that VPA reduces cell proliferation through HDAC inhibition. Cell cycle progression was also suppressed in the optic tectum of the adult zebrafish brain because of HDAC inhibition. Recent studies have demonstrated that HDAC inhibits the Notch signaling pathway; hence, adult zebrafish were treated with a Notch inhibitor. This increased the number of proliferating cells in the adult zebrafish optic tectum with down‐regulated expression of her4, a target of Notch signaling. Conclusions: These results suggest that VPA inhibits HDAC activity and upregulates Notch signaling to reduce cell proliferation in the optic tectum of adult zebrafish. Developmental Dynamics 243:1401–1415, 2014. © 2014 Wiley Periodicals, Inc.     

成年海马神经发生与阿尔茨海默病的关系

阿尔茨海默病(Alzheimer’s disease,AD)是老年期常见的神经退行性疾病,被 WHO 公布为目前人 类面临的最大全球公共卫生事项之一。临床主要症状是学习记忆能力渐进性减退。其神经病理学改变包括 β- 样淀粉蛋白(amyloid β protein,Aβ)聚集在神经细胞外形成的老年斑(senile plaque,SP)、Tau 蛋白过度磷酸化 聚集在神经细胞内形成的神经纤维缠结(neurofibrillary tangle,NFT)、神经元丢失变性和突触减少等,特别是神经 发生异常改变,也是 AD 神经病理改变的主要特征。神经发生是成年哺乳动物海马齿状回神经干细胞产生新生神 经细胞的过程,增加成年神经发生对补偿神经元和改善学习记忆障碍有促进等作用,维持了脑内的可塑性和相关 性功能。因此,促进成年海马神经发生可能有利于 AD 的治疗。该文就成年海马神经发生与 AD 的关系予以总结。     

Modeling local and cross-species neuron number variations in the cerebral cortex as arising from a common mechanism

A massive increase in the number of neurons in the cerebral cortex, driving its size to increase by five orders of magnitude, is a key feature of mammalian evolution. Not only are there systematic variations in cerebral cortical architecture across species, but also across spatial axes within a given cortex. In this article we present a computational model that accounts for both types of variation as arising from the same developmental mechanism. The model employs empirically measured parameters from over a dozen species to demonstrate that changes to the kinetics of neurogenesis (the cell-cycle rate, the progenitor death rate, and the “quit rate,” i.e., the ratio of terminal cell divisions) are sufficient to explain the great diversity in the number of cortical neurons across mammals. Moreover, spatiotemporal gradients in those same parameters in the embryonic cortex can account for cortex-wide, graded variations in the mature neural architecture. Consistent with emerging anatomical data in several species, the model predicts (i) a greater complement of neurons per cortical column in the later-developing, posterior regions of intermediate and large cortices, (ii) that the extent of variation across a cortex increases with cortex size, reaching fivefold or greater in primates, and (iii) that when the number of neurons per cortical column increases, whether across species or within a given cortex, it is the later-developing superficial layers of the cortex which accommodate those additional neurons. We posit that these graded features of the cortex have computational and functional significance, and so must be subject to evolutionary selection.Changes in brain structure follow a remarkably stable pattern over ∼450 My in the vertebrate lineage: it is always the same brain parts that become enlarged when overall brain size increases (1). Moreover, in studies of individual variation in humans and other mammals, when overall brain size is larger, those same divisions as would be predicted by looking at brain enlargement across taxa are also found to be preferentially enlarged (2, 3). Such regularities in brain scaling from the individual to the taxon level suggest that the developmental mechanisms which generate central nervous systems are strongly conserved across species (4).To tease apart the features of the isocortex contributed by the scaling of conserved developmental mechanisms from those features which might be specially selected for in a given niche or species, we have created an empirically informed, mathematical model of cortical neurogenesis. The model elucidates how the dials and levers made available by conserved developmental mechanisms allow selection to shape the basic landscape of the embryonic cortex. The extent to which any particular cortical area (e.g., a visual or language area) has been a special subject of selection can be better evaluated given the baselines provided by this evolutionary developmental or “evo-devo” model.The modeling approach presented here provides an explicit structure to assimilate known data and predict unknowns, both for developmental kinetic parameters and for the resultant time courses of neuronal and progenitor cell populations, for the entire range of mammalian brain sizes and across a spatial axis within the respective cortices. Our model incorporates important insights from several previously published mathematical models of cortical neurogenesis which focus on more limited sets of species or which consider spatial variations in a single species (5–10).     

Tadalafil: 15 years' journey in male erectile dysfunction and beyond

Tadalafil, Cialis, Eli Lilly & Co./ICOS, (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6] pyrido[3,4-b]indole-1,4-dione, was first discovered in 2003. It was reported to have high diastereospecificity for phosphodiesterase 5 (PDE5) inhibitions. The cis-(6R, 12aR) enantiomer is the most active enantiomer. Tadalafil showed PDE5 inhibition with IC₅₀ = 5 nM. It possesses high selectivity for PDE5 versus PDE1-4 and PDE6. Tadalafil is more selective to PDE5 against PDE6 whereas sildenafil, another commercially available PDE5 inhibitor shows similar potencies to inhibit PDE5 and PDE6. Tadalafil is used for the treatment of male erectile dysfunction (MED), prostatic benign hyperplasia (PBH) signs and symptoms, and pulmonary arterial hypertension (PAH). Adcirca, another name for tadalafil, is used to treat PAH and improve exercise capacity. Recent clinical studies suggest the use of tadalafil for nonurological applications, including circulatory disorders (ischemia injury, myocardial infarction, cardiac hypertrophy, cardiomyopathy, heart failure, and stroke), neurodegenerative disorders, and cognitive impairment conditions. This review discusses tadalafil and its analogues reported in the past 15 years. It discusses synthetic pathways, structural activity relationships, existing and future pharmacological indications of tadalafil and its analogues. This work can help medicinal chemists developing novel PDE5 inhibitors with wider therapeutic indications.     

Development of GABAergic inputs controls the contribution of maturing neurons to the adult hippocampal network

New neurons are continuously generated in the dentate gyrus (DG) in the adult hippocampus, and new granule cells (GCs) have been shown to be necessary for several aspects of learning and memory. Nonetheless, the limited information available regarding the anatomical and physiological development of synaptic inputs onto maturing neurons has restricted our understanding of how new GCs affect cognition. Here, we use photostimulation to demonstrate the time course by which anatomically isolated inhibitory inputs develop onto maturing GCs. We then show that the gradual development of inhibition is sufficient in a computational model to drive learning of novel information in young neurons. Finally, we validate this model observation by using slice physiology to show how inhibition regulates firing probability and plasticity in young GCs. Combined, these data demonstrate that the unique connectivity of immature GCs affords them a functional role that is different from mature neurons in the DG circuit, a distinction that potentially underlies many of the proposed functions of new neurons in the hippocampal network.     

Is neurogenesis relevant in depression and in the mechanism of antidepressant drug action? A critical review

Abstract

Objectives. Major depression is a complex disorder that involves genetic, epigenetic and environmental factors in its aetiology. Recent research has suggested that hippocampal neurogenesis may play a role in antidepressant action. However, careful examination of the literature suggests that the complex biological and psychological changes associated with depression cannot be attributed to disturbance in hippocampal neurogenesis alone. While antidepressants may induce hippocampal neurogenesis in non-human primates, there is a paucity of evidence that such effects are sufficient for full therapeutic action in humans. Methods. This review examines the literature on neurogenesis and discusses the stress-induced cortisol neurotoxicity and antidepressant-induced neurogenesis rescue model of depression. The disparity between a simple antidepressant-induced neurogenesis rescue model in the hippocampus and the complexity of clinical depression is analyzed through critical evaluation of recent research data. Results and conclusions. Major depression is a complex brain disorder with multiple symptoms and disturbances reflecting dysfunction in more than one single brain area. Initial research suggesting a model of hippocampal degeneration as basis of depression, and reversal by antidepressants through neurogenesis seems to be over-simplified given the emergence of new data. Synaptogenesis and re-organization or re-integration of new neurons rather than simple addition of new neurons may underlie the role of antidepressant drugs in the reversal of some but not all symptoms in depression. The importance of the neurogenesis hypothesis of depression and antidepressant action lies in stimulating further research into the possible roles played by the new neurons and synapses generated.