Modeling of a Developing Planar Network of Cortical Neurons for Studying the Effects of Pharmacologically Modified Synaptic Connectivity on Cell Rhythmogenesis

A software tool for studying neural networks grown on planar substrates is described. The tool provides: (i) modeling the neuritic fields of individual neurons and their dynamic connectivity, (ii) creation of templates, cloning and connecting multiple instances of the neurons, (iii) computing the cellular electrical activity and Ca²⁺ dynamics, and (iv) estimating synchronization of the networked cells. Examples are shown of employing this tool for the study of synchronization of burst discharges in a network of the cortical neurons, whose connectivity is modified by neuropsin.     

Integration of A Deep Learning Classifier with A Random Forest Approach for Predicting Malonylation Sites

As a newly-identified protein post-translational modification, malonylation is involved in a variety of biological functions. Recognizing malonylation sites in substrates represents an initial but crucial step in elucidating the molecular mechanisms underlying protein malonylation. In this study, we constructed a deep learning (DL) network classifier based on long short-term memory (LSTM) with word embedding (LSTM_WE) for the prediction of mammalian malonylation sites. LSTM_WE performs better than traditional classifiers developed with common pre-defined feature encodings or a DL classifier based on LSTM with a one-hot vector. The performance of LSTM_WE is sensitive to the size of the training set, but this limitation can be overcome by integration with a traditional machine learning (ML) classifier. Accordingly, an integrated approach called LEMP was developed, which includes LSTM_WE and the random forest classifier with a novel encoding of enhanced amino acid content. LEMP performs not only better than the individual classifiers but also superior to the currently-available malonylation predictors. Additionally, it demonstrates a promising performance with a low false positive rate, which is highly useful in the prediction application. Overall, LEMP is a useful tool for easily identifying malonylation sites with high confidence. LEMP is available at http://www.bioinfogo.org/lemp.     

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.     

Modulation of Hippocampus-Dependent Learning and Synaptic Plasticity by Nicotine

A long-standing relationship between nicotinic acetylcholine receptors (nAChRs) and cognition exists. Drugs that act at nAChRs can have cognitive-enhancing effects and diseases that disrupt cognition such as Alzheimer's disease and schizophrenia are associated with altered nAChR function. Specifically, hippocampus-dependent learning is particularly sensitive to the effects of nicotine. However, the effects of nicotine on hippocampus-dependent learning vary not only with the doses of nicotine used and whether nicotine is administered acutely, chronically, or withdrawn after chronic nicotine treatment but also vary across different hippocampus-dependent tasks such as the Morris water maze, the radial arm maze, and contextual fear conditioning. In addition, nicotine has variable effects across different types of hippocampal long-term potentiation (LTP). Because different types of hippocampus-dependent learning and LTP involve different neural and molecular substrates, comparing the effects of nicotine across these paradigms can yield insights into the mechanisms that may underlie the effects of nicotine on learning and memory and aid in understanding the variable effects of nicotine on cognitive processes. This review compares and contrasts the effects of nicotine on hippocampus-dependent learning and LTP and briefly discusses how the effects of nicotine on learning could contribute to nicotine addiction.     

A Biophysical Model of Synaptic Delay Learning and Temporal Pattern Recognition in a Cerebellar Purkinje Cell

It has been suggested that information in the brain is encoded in temporal spike patterns which are decoded by a combination of time delays and coincidence detection. Here, we show how a multi-compartmental model of a cerebellar Purkinje cell can learn to recognise temporal parallel fibre activity patterns by adapting latencies of calcium responses after activation of metabotropic glutamate receptors (mGluRs). In each compartment of our model, the mGluR signalling cascade is represented by a set of differential equations that reflect the underlying biochemistry. Phosphorylation of the mGluRs changes the concentration of receptors which are available for activation by glutamate and thereby adjusts the time delay between mGluR stimulation and voltage response. The adaptation of a synaptic delay as opposed to a weight represents a novel non-Hebbian learning mechanism that can also implement the adaptive timing of the classically conditioned eye-blink response.     

Reinforcement Learning Recruits Somata and Apical Dendrites across Layers of Primary Sensory Cortex

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Development of electrical excitability in embryonic neurons: Mechanisms and roles

Xenopus spinal neurons serve as a nearly ideal population of excitable cells for study of developmental regulation of electrical excitability. On the one hand, the firing properties of these neurons can be directly examined at early stages of differentiation and membrane excitability changes as neurons mature. Underlying changes in voltage-dependent ion channels have been characterized and the mechanisms that bring about these changes are being defined. On the other hand, these neurons have been shown to be spontaneously active at stages when action potentials provide significant calcium entry. Calcium entry provokes further elevation of intracellular calcium via release from intracellular stores. The resultant transient elevations of intracellular calcium encode differentiation in their frequency. Recent studies have shown that different neuronal subpopulations enlist distinct mechanisms for regulation of excitability and recruit specific programs of differentiation by particular patterns of activity. © 1998 John Wiley & Sons, Inc. J Neurobiol 37: 190–197, 1998     

DeepNitro: Prediction of Protein Nitration and Nitrosylation Sites by Deep Learning

Protein nitration and nitrosylation are essential post-translational modifications(PTMs)involved in many fundamental cellular processes. Recent studies have revealed that excessive levels of nitration and nitrosylation in some critical proteins are linked to numerous chronic diseases.Therefore, the identification of substrates that undergo such modifications in a site-specific manner is an important research topic in the community and will provide candidates for targeted therapy. In this study, we aimed to develop a computational tool for predicting nitration and nitrosylation sites in proteins. We first constructed four types of encoding features, including positional amino acid distributions, sequence contextual dependencies, physicochemical properties, and position-specificscoring features, to represent the modified residues. Based on these encoding features, we established a predictor called DeepNitro using deep learning methods for predicting protein nitration and nitrosylation. Using n-fold cross-validation, our evaluation shows great AUC values for DeepNitro, 0.65 for tyrosine nitration, 0.80 for tryptophan nitration, and 0.70 for cysteine nitrosylation, respectively,demonstrating the robustness and reliability of our tool. Also, when tested in the independent dataset, DeepNitro is substantially superior to other similar tools with a 7%à42% improvement in the prediction performance. Taken together, the application of deep learning method and novel encoding schemes, especially the position-specific scoring feature, greatly improves the accuracy of nitration and nitrosylation site prediction and may facilitate the prediction of other PTM sites. DeepNitro is implemented in JAVA and PHP and is freely available for academic research at http://deepnitro.renlab.org.     

Learning and coding of concepts in neural networks

Our environment consists of virtually an infinite number of scenarios in which we have to function. In order to respond properly to an incoming stimulus, the brain has first to analyze it, and to find out the basic familiar elements that are part of it. In other words, by using a library which contains a relatively small number of basic concepts, the brain analyzes the multitude of incoming events. Some of those basic concepts are innate, but many of them must be learned, in order to accommodate for the arbitrary environment around us. A classifying box is defined as the neural network that finds out the familiar concepts that are present in an incoming stimulus. Models for classifying boxes are introduced, and possible mechanisms by which they may establish their libraries of concepts are suggested, and then compared and evaluated by computer simulations.     

Type IIE and IIF Restriction Endonucleases Interacting with Two Recognition Sites on DNA

Recent studies have shown that restriction endonucleases (REs), which are broadly used in genetic engineering and molecular biology, vary not only in nucleotide sequence of the recognition site, but also in the mechanism of their interaction with DNA. This review focuses on type IIF and IIE REs, which require simultaneous interaction with two nucleotide sequences for efficient DNA cleavage. Crystal structures of these REs and their complexes with DNA, stepwise interactions with DNA, catalytic mechanisms of DNA hydrolysis, and DNA looping are considered. Type IIE REs have provided an example of a new type of DNA–protein recognition: two copies of one recognition sequence interact specifically with two different amino acid sequences and two different structural motifs of one polypeptide chain.     

心室不同部位起搏对正常犬和扩张型心肌病心力衰竭犬模型在体心肌跨室壁复极离散的影响

实验以正常犬和扩张型心肌病心力衰竭犬(dilated cardiomyopathy congestive heart failure,DCM-CHF)模型为对象、以心肌跨室壁复极离散的相关参数为指标,研究左心室心外膜起搏、双心室起搏(模拟临床上心室再同步治疗的方法)后的心肌电生理特性变化。实验以快速右心室起搏的方法制备DCM-CHF犬模型;正常犬和DCM-CHF犬均经射频消融希氏束制备三度房室传导阻滞模型;采用同步记录犬体表心电图和内膜下、中层、外膜下三层心肌单相动作电位(monophasic action potentials,MAP)的方法,测定不同部位起搏时的QT间期、Tpeak-Tend(Tp-Te)间期和三层心肌的单相动作电位时程(MAP duration,MAPD)、跨室壁复极离散度(transmural dispersion of repolaization,TDR)。结果显示:在正常犬,左室心外膜与双心室起搏后三层心肌的MAPD均延长,同时TDR增大(左室心外膜起搏47.16 ms、双心室起搏37.54 ms、右室心内膜起搏26.75 ms,P<0.001),体表心电图Tp-Te间期的变化与之平行;在DCM-CHF犬较正常犬已表现出中层心肌MAPD延长(276.30 ms vs 257.35 ms,P<0.0001)和TDR(33.8 ms vs 27.58 ms,P=0.002)增大的基础上,左室心外膜参与起搏后仍进一步使三层心肌的MAPD延长和TDR增大。研究结果提示,左室心外膜起搏和双心室起搏后使内膜下、中层     

The incidence of giant spike bursts and repetitive bursts of action potentials in the ovine small bowel before and after cholecystokinin administration

Giant spike bursts (GSBs) or giant contractions (GCs) and repetitive bursts of action potentials (RBAPs) are less common motility patterns as compared to the migrating motor complex (MMC), fed pattern or minute rhythm. They are present in small and large intestines in various animal species. Their occurrence in ruminants has not been satisfactorily evidenced. Thus, the aim of this study was to present the incidence of these patterns in the ovine small bowel before and after different doses of cholecystokinin octapeptide (CCK-OP) and cerulein as well as to demonstrate the motor correlates of RBAPs.Six sheep equipped with electrodes in the antrum and entire small intestine and with duodenal strain gauge force transducer were used. In fasted and non-fasted animals, continuous myoelectrical and motor recordings were performed before and after the slow injection of cholecystokinin octapeptide (20, 200 and 2000 ng/kg i.v.) and cerulein (1, 10 and 100 ng/kg i.v.) during phase 2 MMC. The incidence of GSBs and RBAPs was assessed and these patterns arrived before and after Cholecystokinin (CCK). During the control period RBAPs were most frequently observed in the ileum. GSBs and RBAPs were induced by the highest dose of the hormones. RBAPs exhibited the motor correlates and their tonic component was more pronounced following CCK-OP and cerulein injection.It is concluded that GSBs and RBAPs occur in the small intestine and the administration of CCK peptides further increases their incidence.     

兔左室壁三层心肌细胞的分离及动作电位、钙和钾电流分布的异质性

探讨兔左室壁三层心肌单个细胞的分离方法以及电生理特征,实验以胶原酶按二步消化法分离兔心肌细胞,其中用剃须刀分离左室游离壁内,中,外三层心肌,采用全细胞膜片钳记录AP和离子电流,结果显示：（1）中层细胞上的动作电位时程明显长于内膜下心肌和外膜下心肌,且存在显著的1相切迹和2相驼峰;（2）中层细胞的Ica,L和Lto较内,外膜下的大,IK,s相反,可见三层心肌细胞上多种电流存在显著差异。     

Synaptic Vesicle Ultrastructural Changes in the Rat Hippocampus Induced by a Combination of α-Linolenate Deficiency and a Learning Task

Abstract: Rats fed either a safflower oil (α-linolenate-deficient) or a perilla oil (α-linolenate-sufficient) diet through two generations (F1) showed significant differences in the brightness-discrimination learning task. In this task, correct responses were lever-pressing responses, which were reinforced with dietary pellets, and incorrect responses were those with no reinforcement. The inferior learning performance in the safflower oil group was caused mainly by the inferior ability to rectify the incorrect responses through the learning sessions. In the safflower oil group after the learning task, the average densities of synaptic vesicles in the terminals of the hippocampus CA1 region were decreased by nearly 30% as compared with those in the perilla oil group, and it is notable that this difference was not detected without the learning task. These results suggest that dietary oil-induced morphological changes in synapses in the hippocampus of rats are related to the differential learning performance and that the turnover rate of synaptic vesicles in the hippocampus may be an important factor affecting learning performance.     

Properties of a Protein Kinase C Activity in Synaptic Plasma Membrane and Postsynaptic Density Fractions Isolated from Canine Cerebral Cortex

Protein kinase C (PKC) activity (phosphorylation increased by addition of Ca2+/phosphatidylserine or Ca2+/phosphatidylserine/phorbol ester) was found in both a synaptic plasma membrane (SPM) and a postsynaptic density (PSD) fraction. The SPM fraction had as endogenous substrates 87K-, 60K-, 50K-, and 20K-Mr proteins, whereas the PSD fraction had only the 20K-Mr protein. The PKC activity was also detected using histone III-S as a substrate, in SPM but much less in PSD. Phosphorylations of histone and the endogenous substrates of PKC, assayed in the absence of Ca2+, were enhanced in the SPM prepared after treatment of brain homogenate with phorbol 12-myristate 13-acetate (TPA), but very little enhancement was found in PSD after such treatment. The SPM PKC activity (both for endogenous substrate proteins and for histone), which was enhanced by TPA treatment of brain homogenate, was inhibited by calcium (IC50, 3 x 10(-7) M). The phosphorylations of the 20K-Mr protein in PSD, and in SPM prepared with and without TPA treatment, were all inhibited by H-7. The 20K-Mr protein in the PSD fraction is also phosphorylated by a PSD Ca2+/calmodulin-dependent protein kinase II. The evidence indicates that both SPM and PSD fractions contain a PKC activity. Detergent treatment of SPM, to produce a purified PSD fraction, results in a PSD fraction that has lost most of the endogenous substrates, lost the TPA-induced enhanced activity assayed in the absence of Ca2+, and lost the inhibitory effect of low Ca2+ concentration.     

Seasonal variation in hydrochloric acid, malic acid, and calciumions secreted by the trichomes of chickpea (Cicer arietinum)

A novel experimental set-up and method of recording of electrical potential differences in plants have been developed which enable continuous, 8-channel monitoring of electrical activity over extended periods of time using inserted, extracellular electrodes. The investigations were carried out on 21- to 23-day-old Helianthus annuus plants, and spontaneously-generated action potentials were recorded during monitoring sessions lasting for 3 days and nights. Characteristics of these spontaneous action potentials were elaborated, adopting as parameters their typical form, amplitude, duration, velocity, direction, and distance of propagation and frequency of occurrence in morphologically different parts of the plant, Variability, similarities, and interdependence of the above parameters in individual plants and in a group of 15 plants were determined. A hypothesis concerning propagation of action potentials in plants along specific impulse-propagating 'columns' is discussed. The frequency of generated impulses is highest at night and lowest in the day and also displays an apparent 24-h rhythm. Presumably this mechanism is under both endogenous and exogenous control and may be partly dependent on a biological clock.     

磁场作用对小鼠学习记忆的影响

目的 :探讨磁场作用对小鼠学习记忆能力的影响。方法 :应用水迷宫学习模型测定并对比 30分钟磁场处理组、1 5分钟磁场处理组和非磁场处理的正常对照组动物的空间学习记忆能力。结果 :水迷宫学习训练的实验表明 30分钟磁场处理组与正常对照组比较 ,动物到达水下平台的时间延长 ;游程增加 ;平均游速减慢 ,且均具有显著性差异 (p <0 .0 5)。 1 5分钟磁场处理组与正常对照组比较 ,动物到达水下平台的时间延长 ,且具有显著性差异 (p <0 .0 5) ;游程和平均速度与正常对照组相比无显著性差异 (p >0 .0 5)。结论 :磁场处理 30分钟或 1 5分钟损伤小鼠的空间学习记忆能力 ,且以 30分钟的磁场处理作用较强     

Two mechanistically distinct forms of endocytosis in adrenal chromaffin cells: Differential effects of SH3 domains and amphiphysin antagonism

We previously identified two forms of endocytosis using capacitance measurements in chromaffin cells: rapid endocytosis (RE), dynamin-1 dependent but clathrin-independent and slow endocytosis (SE), dynamin-2 and clathrin-dependent. Various recombinant SH3 domains that interact with the proline-rich domain of dynamin were introduced into single cells via the patch pipette. GST-SH3 domains of amphiphysin-1, intersectin-IC, and endophilin-I inhibited SE but had no effect on RE. Grb2-SH3 (N-terminal) or a mutant of amphiphysin-1-SH3 was inactive on either process. These data confirm that dynamin-1 dependent RE is independent of clathrin and show that amphiphysin is exclusively associated with clathrin and dynamin-2-dependent SE.     

Foraging Behavior in Two Species of Ectatomma (Formicidae: Ponerinae): Individual Learning of Orientation and Timing

The foraging behavior of marked individuals of Ectatomma ruidum and E. tuberculatum (Formicidae: Ponerinae) was observed on Barro Colorado Island, Panama, in order to determine whether learning of orientation and timing is involved when foraging on patchy resources on the forest floor. Foraging experiments under seminatural conditions were designed to control for the spatiotemporal distribution of resources at one or two preying sites. Using both single- and multi–event past experience, individual foragers of E. ruidum and (although less significantly) E. tuberculatum made directional and temporal adjustments to their behavior in response to previous differential foraging success. In spite of considerable individual variation in foraging efficiency, it is hypothesized that the observed differences in cognitive abilities can be invoked to explain ecological differences among both species.     

Modulatory effects of Gs-coupled excitatory opioid receptor functions on opioid analgesia,tolerance, and dependence

Electrophysiologic studies of opioid effects on nociceptive types of dorsal root ganglion (DRG) neurons in organotypic cultures have shown that morphine and mostμ, δ, and κ opioid agonists can elicit bimodal excitatory as well as inhibitory modulation of the action potential duration (APD) of these cells. Excitatory opioid effects have been shown to be mediated by opioid receptors that are coupled via Gs to cyclic AMP-dependent ionic conductances that prolong the APD, whereas inhibitory opioid effects are mediated by opioid receptors coupled via Gi/Go to ionic conductuances that shorten the APD. Selective blockade of excitatory opioid receptor functions by low (ca. pM) concentrations of naloxone, naltrexone, etorphine and other specific agents markedly increases the inhibitory potency of morphine or other bimodally acting agonists and attenuates development of tolerance/dependence. These in vitro studies have been confirmed by tail-flick assays showin that acute co-treatment of mice with morphine plus ultra-low-dose naltrexone or etorphine remarkably enhances the antinociceptive potency of morphine whereas chronic co-treatment attenuates development of tolerance and naloxone-precipitated withdrawal-jumping symptoms. Special issue dedicated to Dr. Eric J. Simon.