Summation of Spatiotemporal Input Patterns in Leaky Integrate-and-Fire Neurons: Application to Neurons in the Cochlear Nucleus Receiving Converging Auditory Nerve Fiber Input

The response of leaky integrate-and-fire neurons is analyzed for periodic inputs whose phases vary with their spatial location. The model gives the relationship between the spatial summation distance and the degree of phase locking of the output spikes (i.e., locking to the periodic stochastic inputs, measured by the synchronization index). The synaptic inputs are modeled as an inhomogeneous Poisson process, and the analysis is carried out in the Gaussian approximation. The model has been applied to globular bushy cells of the cochlear nucleus, which receive converging inputs from auditory nerve fibers that originate at neighboring sites in the cochlea. The model elucidates the roles played by spatial summation and coincidence detection, showing how synchronization decreases with an increase in both frequency and spatial spread of inputs. It also shows under what conditions an enhancement of synchronization of the output relative to the input takes place.     

Unsupervised Learning and Adaptation in a Model of Adult Neurogenesis

Adult neurogenesis has long been documented in the vertebrate brain and recently even in humans. Although it has been conjectured for many years that its functional role is related to the renewing of memories, no clear mechanism as to how this can be achieved has been proposed. Using the mammalian olfactory bulb as a paradigm, we present a scheme in which incorporation of new neurons proceeds at a constant rate, while their survival is activity-dependent and thus contingent on new neurons establishing suitable connections. We show that a simple mathematical model following these rules organizes its activity so as to maximize the difference between its responses and can adapt to changing environmental conditions in unsupervised fashion, in agreement with current neurophysiological data.     

Robust Identification of Local Adaptation from Allele Frequencies

Comparing allele frequencies among populations that differ in environment has long been a tool for detecting loci involved in local adaptation. However, such analyses are complicated by an imperfect knowledge of population allele frequencies and neutral correlations of allele frequencies among populations due to shared population history and gene flow. Here we develop a set of methods to robustly test for unusual allele frequency patterns and correlations between environmental variables and allele frequencies while accounting for these complications based on a Bayesian model previously implemented in the software Bayenv. Using this model, we calculate a set of “standardized allele frequencies” that allows investigators to apply tests of their choice to multiple populations while accounting for sampling and covariance due to population history. We illustrate this first by showing that these standardized frequencies can be used to detect nonparametric correlations with environmental variables; these correlations are also less prone to spurious results due to outlier populations. We then demonstrate how these standardized allele frequencies can be used to construct a test to detect SNPs that deviate strongly from neutral population structure. This test is conceptually related to F_ST and is shown to be more powerful, as we account for population history. We also extend the model to next-generation sequencing of population pools—a cost-efficient way to estimate population allele frequencies, but one that introduces an additional level of sampling noise. The utility of these methods is demonstrated in simulations and by reanalyzing human SNP data from the Human Genome Diversity Panel populations and pooled next-generation sequencing data from Atlantic herring. An implementation of our method is available from http://gcbias.org.     

Transient information flow in a network of excitatory and inhibitory model neurons: Role of noise and signal autocorrelation

We investigate the performance of sparsely-connected networks of integrate-and-fire neurons for ultra-short term information processing. We exploit the fact that the population activity of networks with balanced excitation and inhibition can switch from an oscillatory firing regime to a state of asynchronous irregular firing or quiescence depending on the rate of external background spikes. We find that in terms of information buffering the network performs best for a moderate, non-zero, amount of noise. Analogous to the phenomenon of stochastic resonance the performance decreases for higher and lower noise levels. The optimal amount of noise corresponds to the transition zone between a quiescent state and a regime of stochastic dynamics. This provides a potential explanation of the role of non-oscillatory population activity in a simplified model of cortical micro-circuits.     

Expression of a rapid,low-voltage threshold K current in insulin-secreting cells is dependent on intracellular calcium buffering

Summary Depolarization-activated outward currents ranging in amplitude from 100–1000 pA were studied in cultured, insulinsecreting HIT cells and mouse B-cells using the whole-cell patch clamp. Outward current was identified as a K current since it was blocked by K channel blockers and its tail current reversed nearE _K. The K currents of HIT cells dialyzed with internal solutions containing 0.1–10mm EGTA with no added calcium (Ca), or 10mm EGTA with 2mm added Ca, activated rapidly with depolarization. However, the stronger Ca buffer BAPTA (5mm; no added Ca) blocked the rapidly activating current to reveal an underlying more slowly activating K current. With intracellular EGTA, application of the Ca channel blocker cadmium mimicked the effect of intracellular BAPTA. These data suggest that the rapid K current was mediated by low-voltage threshold, Ca-activated K channels while the slower K current was mediated by high threshold delayed rectifier K channels. Mouse B-cells also had both K current components. Dialyzing these cells with either BAPTA (5mm, no added Ca) or high EGTA (10mm with 2mm Ca) blocked the rapid Ca-activated K current observed when cells were filled with 0.1 to 1mm EGTA. It is concluded that the extent of Ca-activated K current activation in either HIT or adult mouse B-cells depends on the degree of intracellular Ca buffering.     

成年蜜蜂脑神经细胞的培养和电生理特征

为了研究杀虫剂等对蜜蜂毒性作用的神经机制,需在体外建立成年蜜蜂脑神经细胞的分离培养和电生理记录技术并研究其正常电生理特征,而对成年蜜蜂脑神经细胞的分离培养和电生理特性的研究报道甚少。我们采用酶解和机械吹打相结合的方法获得了数量较多且活力较好的成年意大利蜜蜂Apis mellifera脑神经细胞,并用全细胞膜片钳技术研究了成年意大利蜜蜂脑神经细胞对电流和电压刺激的反应,获得了成年意蜂脑神经细胞的基本电生理特征以及钠电流和钾电流的特性。全细胞电流钳的记录结果表明,在体外培养条件下,细胞无自发放电发生,注射电流后仅引起细胞单次放电,引起细胞放电的阈电流平均为60.8±63 pA; 细胞动作电位产生的阈电位平均为−27.4±2.3 mV。用全细胞电压钳记录了神经细胞的钠电流和钾电流。钠电流的分离是在电压刺激下通过阻断钾通道和钙通道实现。细胞的内向钠电流在指令电压为−40～−30 mV左右激活,−10 mV达峰值,钠通道的稳态失活电压V_1/2为−58.4 mV; 外向钾电流成份至少包括较小的快速失活钾电流和和较大的缓慢失活钾电流（占总钾电流的80%）,其半激活膜电位V_1/2为3.86 mV,无明显的稳态失活。结果提示缓慢失活钾电流的特征可能是细胞单次放电的机制之一。     

低功率2 450 MHz射频磁场对神经元延迟整流钾通道的抑制作用

由于电子设备的广泛使用,人类已经越来越多地暴露在射频磁场的辐射下,但射频磁场的辐射效应却一直不明确．采用全细胞膜片钳技术,记录2 450 MHz射频磁场辐射对小鼠脑皮层神经元延迟整流钾电流IK的影响．利用Ansoft HFSS软件对6 dB全向天线建模仿真,验证距天线2~3 cm处磁场分布均匀,使用Agilent E5070B网络分析仪经该天线发射出2 450 MHz输出功率为39.81 mW电磁场,对细胞进行刺激．实验发现,2 450 MHz低功率射频磁场暴露5、10和15 min对IK均有明显的抑制作用;显著影响IK激活特性,对照组与磁场暴露组半数激活电压分别为（－1.13±2.32）mV和（19.52±1.03）mV(n=10, P <0.05);斜率因子分别为（23.21±3.29）mV和（13.95±1.27）mV(n=10, P <0.05)．结果表明,低功率射频磁场通过减小延迟整流钾通道电流,影响神经元的生理功能,为进一步研究电磁辐射所引发的生物学效应提供了一种新的方法．     

Calmodulin mediates Ca2+-dependent modulation of M-type K+ channels

To quantify the modulation of KCNQ2/3 current by [Ca2+]i and to test if calmodulin (CaM) mediates this action, simultaneous whole-cell recording and Ca2+ imaging was performed on CHO cells expressing KCNQ2/3 channels, either alone, or together with wild-type (wt) CaM, or dominant-negative (DN) CaM. We varied [Ca2+]i from <10 to >400 nM with ionomycin (5 microM) added to either a 2 mM Ca2+, or EGTA-buffered Ca2+-free, solution. Coexpression of wt CaM made KCNQ2/3 currents highly sensitive to [Ca2+]i (IC50 70 +/- 20 nM, max inhibition 73%, n = 10). However, coexpression of DN CaM rendered KCNQ2/3 currents largely [Ca2+]i insensitive (max inhibition 8 +/- 3%, n = 10). In cells without cotransfected CaM, the Ca2+ sensitivity was variable but generally weak. [Ca2+]i modulation of M current in superior cervical ganglion (SCG) neurons followed the same pattern as in CHO cells expressed with KCNQ2/3 and wt CaM, suggesting that endogenous M current is also highly sensitive to [Ca2+]i. Coimmunoprecipitations showed binding of CaM to KCNQ2-5 that was similar in the presence of 5 mM Ca2+ or 5 mM EGTA. Gel-shift analyses suggested Ca2+-dependent CaM binding to an "IQ-like" motif present in the carboxy terminus of KCNQ2-5. We tested whether bradykinin modulation of M current in SCG neurons uses CaM. Wt or DN CaM was exogenously expressed in SCG cells using pseudovirions or the biolistic "gene gun." Using both methods, expression of both wt CaM and DN CaM strongly reduced bradykinin inhibition of M current, but for all groups muscarinic inhibition was unaffected. Cells expressed with wt CaM had strongly reduced tonic current amplitudes as well. We observed similar [Ca2+]i rises by bradykinin in all the groups of cells, indicating that CaM did not affect Ca2+ release from stores. We conclude that M-type currents are highly sensitive to [Ca2+]i and that calmodulin acts as their Ca2+ sensor.     

无噪声Hodgkin-Huxley神经元对正弦信号的响应

研究了无噪声影响下的Hcdgkin-Huxley神经元在正弦信号刺激下的动力学行为,并利用“魔梯”图和峰峰间期分布图来分别描述。数值模拟结果表明,当信号振幅一定时,神经元的发放情况随频率而改变;当信号的频率一定时,峰峰间期分布随振幅而改变,相应地,峰峰间期序列也具有不同的特点。     

Mutant TDP-43 Causes Early-Stage Dose-Dependent Motor Neuron Degeneration in a TARDBP Knockin Mouse Model of ALS

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线粒体大麻素受体1在大鼠海马神经元缺氧复氧损伤中对线粒体分裂的影响

目的:探讨线粒体CB1受体(mitochondrial cannabinoid receptor1,mtCB1)在大鼠海马神经元缺氧复氧损伤中对线粒体分裂的影响。方法:原代培养新生的Wistar大鼠海马神经元,将培养至第8天的海马神经元采用随机数字表分为5组(n=60):正常组(N组):正常培养,不做任何处理;缺氧复氧组(H/R组):采用氧糖剥夺法构建海马神经元缺氧复氧损伤模型,缺氧6h,复氧20 h;缺氧复氧组+ACEA+AM251组(H/R+ACEA+AM251组):缺氧6 h结束后立即加入ACEA和AM251,终浓度分别为1μmol/L、10μmol/L,复氧20 h;缺氧复氧+ACEA+Hemopressin(H/R+ACEA+Hemo组):缺氧6h结束后立即加入ACEA和Hemopressin,终浓度分别为1μmol/L、10μmol/L,复氧20 h;缺氧复氧+赋形剂组(H/R+V组):同样于缺氧6h结束后立即加入二甲基亚砜(DMSO),终浓度0.1%,复氧20 h。使用激光共聚焦显微镜检测细胞内Ca~(2+)的浓度,流式细胞仪检测细胞凋亡率,Western blot检测凋亡诱导因子(AIF)、线粒体分裂相关蛋白Drp1、Fis1,细胞凋亡相关蛋白细胞色素C(Cytc)和Rho相关的卷曲蛋白激酶1(ROCK1)的表达。结果:与N组相比,H/R组、H/R+ACEA+AM251组、H/R+ACEA+Hemo组和H/R+V组的细胞内Ca~(2+)浓度、细胞凋亡率、以及AIF、Drp1、Fis1、Cytc、ROCK1蛋白的表达水平均明显增加(P0.05);与H/R组相比,H/R+ACEA+Hem组上述各检测指标明显降低(P0.05),H/R+ACEA+AM251组和H/R+V组各指标比较差异无统计学意义(P0.05)。结论:线粒体CB1受体(mtCB1受体)可能通过降低细胞内ROS的含量来减少细胞内Ca~(2+)浓度和ROCK1的表达,进而抑制线粒体分裂,并最终减轻海马神经元缺氧复氧损伤。     

G蛋白Rab3a协同神经生长抑制因子(GIF)抑制神经元的生长

为了研究G蛋白Rab3a与神经生长抑制因子 (growthinhibitoryfactor,GIF ,原称金属硫蛋白 3,MT 3)相互作用对神经元细胞生长的影响 ,以嗜铬细胞瘤株 (pheochromocytoma)PC1 2充当神经元模型 .将hMT 3(humanMT 3)和Rab3a基因分别克隆至真核表达载体pFlag CMV 2和pSV HA中 ,质粒共同转染PC1 2细胞 ,观察转染后细胞的生长状态 .以共转染pFlag CMV 2 hMT 1和pSV HA Rab3a的细胞组作为对照 ,验证hMT 3与Rab3a相互作用对PC1 2影响的特异性 .结果发现 ,共转染pFlag CMV 2 hMT 3和pSV HA Rab3a的PC1 2细胞生长明显受到抑制 ,细胞生长抑制率与GIF在脑提取物存在F的神经元生长抑制作用接近 ,但转染两基因中的任何单个基因以及共转染pFlag CMV 2 hMT 1和pSV HA Rab3a对PC1 2细胞生长无影响 .进一步构建重组表达质粒pGEX 4T 1 Rab3a和pGEX 4T 1 hMT 3,转化大肠杆菌BL2 1 ,经谷胱甘肽 Sepharose 4B亲和层析、凝血酶酶切和SephacrylS 1 0 0纯化 ,得到纯度 95 %以上的Rab3a和hMT 3蛋白 .体外细胞生物学活性检测表明 ,表达的Rab3a蛋白与重组hMT 3蛋白共培养PC1 2 ,对细胞的生长产生了明显的特异性协同抑制作用 ,抑制曲线与GIF在脑提取物存在下的神经元生长抑制曲线极为相似     

A Model of Information Carried over a Neuron Soma

A series of cellular automata models of amino acid side chains on a neuron soma membrane have been created to simulate their hydropathic influences on adjacent water molecules. The presence of pathways, referred to as water wires, is identified. These pathways are invoked as passage ways across a neuron soma of proton hopping carrying the information from dendrites to the axon hillock.     

Adaptation of Drosophila to a novel laboratory environment reveals temporally heterogeneous trajectories of selected alleles

The genomic basis of adaptation to novel environments is a fundamental problem in evolutionary biology that has gained additional importance in the light of the recent global change discussion. Here, we combined laboratory natural selection (experimental evolution) in Drosophila melanogaster with genome‐wide next generation sequencing of DNA pools (Pool‐Seq) to identify alleles that are favourable in a novel laboratory environment and traced their trajectories during the adaptive process. Already after 15 generations, we identified a pronounced genomic response to selection, with almost 5000 single nucleotide polymorphisms (SNP; genome‐wide false discovery rates < 0.005%) deviating from neutral expectation. Importantly, the evolutionary trajectories of the selected alleles were heterogeneous, with the alleles falling into two distinct classes: (i) alleles that continuously rise in frequency; and (ii) alleles that at first increase rapidly but whose frequencies then reach a plateau. Our data thus suggest that the genomic response to selection can involve a large number of selected SNPs that show unexpectedly complex evolutionary trajectories, possibly due to nonadditive effects.     

Synaptosomal Glutamate Uptake Declines Progressively in the Spinal Cord of a Mutant Mouse with Motor Neuron Disease

Abstract: It has been suggested that the degeneration of motor neurons in amyotrophic lateral sclerosis is a consequence of excitotoxicity resulting from a loss of synaptosomal glutamate uptake. The role of synaptosomal glutamate uptake in the pathogenesis of motor neuron disease was studied in the Mnd mouse. Glutamate uptake in spinal-cord synaptosomes declined in parallel with the onset of behavioral deficits in Mnd mice but lagged considerably behind the appearance of pathology in motor neurons. Glutamate uptake did not decline significantly in corpus striatum, and GABA uptake did not change significantly in either spinal cord or striatum. The presence of pronounced histopathological changes before the loss of glutamate uptake suggests that the decline of glutamate uptake is a consequence rather than the primary cause of motor neuron disease in the Mnd mouse.