How is information transmitted in a nerve?

In the last 15 years, a debate has emerged about the validity of the famous Hodgkin-Huxley model for nerve impulse. Mechanical models have been proposed. This note reviews the experimental properties of the nerve impulse and discusses the proposed alternatives. The experimental data, which rule out some of the alternative suggestions, show that while the Hodgkin-Huxley model may not be complete, it nevertheless includes essential features that should not be overlooked in the attempts made to improve, or supersede, it.     

An analysis of the reliability phenomenon in the FitzHugh-Nagumo model

The reliability of single neurons on realistic stimuli has been experimentally confirmed in a wide variety of animal preparations. We present a theoretical study of the reliability phenomenon in the FitzHugh-Nagumo model on white Gaussian stimulation. The analysis of the model's dynamics is performed in three regimes—the excitable, bistable, and oscillatory ones. We use tools from the random dynamical systems theory, such as the pullbacks and the estimation of the Lyapunov exponents and rotation number. The results show that for most stimulus intensities, trajectories converge to a single stochastic equilibrium point, and the leading Lyapunov exponent is negative. Consequently, in these regimes the discharge times are reliable in the sense that repeated presentation of the same aperiodic input segment evokes similar firing times after some transient time. Surprisingly, for a certain range of stimulus intensities, unreliable firing is observed due to the onset of stochastic chaos, as indicated by the estimated positive leading Lyapunov exponents. For this range of stimulus intensities, stochastic chaos occurs in the bistable regime and also expands in adjacent parts of the excitable and oscillating regimes. The obtained results are valuable in the explanation of experimental observations concerning the reliability of neurons stimulated with broad-band Gaussian inputs. They reveal two distinct neuronal response types. In the regime where the first Lyapunov has negative values, such inputs eventually lead neurons to reliable firing, and this suggests that any observed variance of firing times in reliability experiments is mainly due to internal noise. In the regime with positive Lyapunov exponents, the source of unreliable firing is stochastic chaos, a novel phenomenon in the reliability literature, whose origin and function need further investigation.     

Reinforcement learning links spontaneous cortical dopamine impulses to reward

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PRP-1 Protective Effect against Central and Peripheral Neurodegeneration following n. ischiadicus Transection

We investigated the action of the new hypothalamic proline-rich peptide (PRP-1), normally produced by neurosecretory cells of hypothalamic nuclei (NPV and NSO), 3 and 4 weeks following rat sciatic nerve transection. The impulse activity flow of interneurons (IN) and motoneurons (MN) on stimulation of mixed (n. ischiadicus), flexor (n. gastrocnemius – G) and extensor (n. peroneus communis – P) nerves of both injured and symmetric intact sides of spinal cord (SC) was recorded in rats with daily administration of PRP-1 (for a period of 3 weeks) and without it (control). On the injured side of SC in control, there were no responses of IN and MN on ipsilateral G and P stimulation, while responses were elicited on contralateral nerve stimulation. The neuron responses on the intact side of SC were revealed in a reverse ratio. Thus, there were no effects upon stimulation of the injured nerve distal stump in the control because of the absence of fusion between transected nerve stumps. This was also testified by the atrophy of the distal stump and the absence of motor activity of the affected limb. In PRP-1-treated animals, the responses of SC IN and MN in postaxotomy 3 weeks on the injured side of SC at ipsilateral nerve stimulation and on the intact side at contralateral nerve stimulation were recorded because of the obvious fusion of the severed nerve stumps. The histochemical data confirmed the electrophysiological findings. Complete coalescence of transected fibers together with restoration of the motor activity of the affected limb provided evidence for reinnervation on the injured side. Thus, it may be concluded that PRP-1 promotes nerve regeneration and may be used clinically to improve the outcome of peripheral nerve primary repair.     

Cyclin-dependent Kinases Participate in Death of Neurons Evoked by DNA-damaging Agents

Previous reports have indicated that DNA-damaging treatments including certain anticancer therapeutics cause death of postmitotic nerve cells both in vitro and in vivo. Accordingly, it has become important to understand the signaling events that control this process. We recently hypothesized that certain cell cycle molecules may play an important role in neuronal death signaling evoked by DNA damage. Consequently, we examined whether cyclin-dependent kinase inhibitors (CKIs) and dominant-negative (DN) cyclin-dependent kinases (CDK) protect sympathetic and cortical neurons against DNA-damaging conditions. We show that Sindbis virus–induced expression of CKIs p16^ink4, p21^waf/cip1, and p27^kip1, as well as DN-Cdk4 and 6, but not DN-Cdk2 or 3, protect sympathetic neurons against UV irradiation– and AraC-induced death. We also demonstrate that the CKIs p16 and p27 as well as DN-Cdk4 and 6 but not DN-Cdk2 or 3 protect cortical neurons from the DNA damaging agent camptothecin. Finally, in consonance with our hypothesis and these results, cyclin D1–associated kinase activity is rapidly and highly elevated in cortical neurons upon camptothecin treatment. These results suggest that postmitotic neurons may utilize Cdk4 and 6, signals that normally control proliferation, to mediate death signaling resulting from DNA-damaging conditions.     

Transdifferentiation of mesenchymal stem cells into Schwann cell-like myelinating cells

Bone marrow stromal cells (MSC) are multipotent stem cells that differentiate into cells of the mesodermal lineage. Although adult, their differentiation potential is remarkable, and they are able to transdifferentiate. Transdifferentiated cultivated rat MSC (tMSC) changed morphologically into cells resembling typical spindle-shaped Schwann cells (SC) with enhanced expression of LNGF receptor, Krox-20, CD104 and S100beta protein and decreased expression of bone morphogenetic protein receptor-1A compared to untreated rat MSC (rMSC). Transdifferentiation was reversible and repeatable. To evaluate the myelinating capacity, rMSC, tMSC, or SC cultured from male rats were grafted into an autologous muscle conduit bridging a 2-cm gap in the female rat sciatic nerve. The presence of the male-specific SRY gene (as revealed by PCR analysis) and S100 immunoreactivity of pre-labeled tMSC confirmed the presence of the implanted cells in the grafts. Three weeks after grafting, an appropriate regeneration was noted in the SC and in the tMSC groups, while regeneration in the rMSC group and in the control group without any cells was impaired. In contrast to SC, in some cases, single tMSC were able to myelinate more than one axon. Our findings demonstrate that it may be possible to differentiate MSC into therapeutically useful cells for clinical applications.     

毛囊来源的神经嵴干细胞修复大鼠坐骨神经缺损

毛囊来源的神经嵴干细胞(Epidermal Neural Crest Stem Cell,EPI-NCSC)由于取材方便,具有多种分化潜能,是一种具有良好应用前景的组织工程种子细胞。目前,在神经损伤修复领域中,EPI-NCSC主要被应用于脊髓损伤的修复。为了探讨EPI-NCSC对周围神经缺损的修复作用,对原代培养的GFP-SD大鼠来源的EPI-NCSC的体外性质进行了考察,并以其为种子细胞,将其等量与细胞外基质(Extracellular matrix,ECM)混合后,预置入聚乳酸-聚羟基乙酸共聚物(Poly lactic acid co glycolic acid copolymer,PLGA)导管中,同时,以等量的达尔伯克(氏)改良伊格尔(氏)培养基(Dulbecco's Modified Eagle's medium,DMEM)代替EPI-NCSC作为对照,以用于修复大鼠坐骨神经10 mm距离的缺失。噻唑蓝(Methyl thiazolyl tetrazolium,MTT)比色分析结果显示,EPI-NCSC在PLGA膜上的初期粘附率为89.7%。在第1、3、5、7天细胞相对增殖率分别为89.3%、87.6%、85.6%和96.6%。细胞周期与DNA倍体分析表明,与PLGA共培养的EPI-NCSC与单独培养的EPI-NCSC相比较,二者的细胞周期变化趋势相同,增殖指数变化趋势也相同。在神经导管移植4周,术部实现了组织学水平的修复。大鼠手术一侧后肢感觉功能有所恢复,坐骨神经指数有所提高。研究结果表明,在PLGA导管中预置EPI-NCSC,有望实现较好的周围神经缺损的修复效果。     

Stability of delayed memristive neural networks with time-varying impulses

This paper addresses the stability problem on the memristive neural networks with time-varying impulses. Based on the memristor theory and neural network theory, the model of the memristor-based neural network is established. Different from the most publications on memristive networks with fixed-time impulse effects, we consider the case of time-varying impulses. Both the destabilizing and stabilizing impulses exist in the model simultaneously. Through controlling the time intervals of the stabilizing and destabilizing impulses, we ensure the effect of the impulses is stabilizing. Several sufficient conditions for the globally exponentially stability of memristive neural networks with time-varying impulses are proposed. The simulation results demonstrate the effectiveness of the theoretical results.     

Recognition molecules and neural repair

Neural recognition molecules were discovered and characterized initially for their functional roles in cell adhesion as regulators of affinity between cells and the extracellular matrix in vitro. They were then recognized as mediators or co-receptors which trigger signal transduction mechanisms affecting cell adhesion and de-adhesion. Their involvement in contact attraction and repulsion relies on cell-intrinsic properties that are modulated by the spatial contexts of their expression at particular stages of ontogenetic development, in synaptic plasticity and during regeneration after injury. The functional roles of recognition molecules in cell proliferation and migration, determination of developmental fate, growth cone guidance, and synapse formation, stabilization and modulation have been well documented not only by in vitro, but also by in vivo studies that have been greatly aided by generation of genetically altered mice. More recently, the functions of recognition molecules have been investigated under conditions of neural repair and manipulated using a broad range of genetic and pharmacological approaches to achieve a beneficial outcome. The principal aim of most therapeutically oriented approaches has been to neutralize inhibitory factors. However, less attention has been paid to enhancing repair by stimulating the stimulatory factors. When considering potential therapeutic strategies, it is worth considering that a single recognition molecule can possess domains that are conducive or repellent and that the spatial distribution of recognition molecules can determine the overall function: Recognition molecules may be repellent for neurite outgrowth when presented as barriers or steep-concentration gradients and conducive when presented as uniform substrates. The focus of this review will be on the more recent attempts to study the conducive mechanisms with the expectation that they may be able to tip the balance from a regeneration inhospitable to a hospitable environment. It is likely that a combination of the two principles, as multifactorial as each principle may be in itself, will be of therapeutic value in humans.     

Enhanced nerve growth factor efficiency in neural cell culture by immobilization on the culture substrate

Nerve growth factor (NGF) immobilization on a culture substrate may dramatically reduce the amount of NGF required for pheochromocytoma (PC12) cell culture. Coverslips on which NGF had been immobilized, or with NGF added to the culture medium daily, were used to culture PC12 cells. We examined the effects of adding 5, 10, or 100 ng of NGF to cultures daily, and compared them to the effects of immobilizing 5, 10, or 100 ng of NGF on culture substrates in a single dose. Cultures with 10 or 5 ng NGF added daily showed dramatically decreased cell viability, mitochondrial metabolic activity, and neuronal differentiation compared to cultures with 100 ng NGF added daily, while also exhibiting increased apoptosis. In contrast, a single dose of 100 ng immobilized NGF yielded results similar to 100 ng NGF added daily (total: 300 ng over 3 days), and 10 or 5 ng immobilized NGF showed far better results than 10 or 5 ng NGF added daily. These results demonstrate that NGF immobilization can dramatically reduce the amount of NGF required in neuronal cell culture.     

Small amplitude periodic waves for the FitzHugh-Nagumo equations

Periodic waves of small amplitude are shown to exist for a simplified version of the FitzHugh-Nagumo equations and their stability is analyzed.UDDM Report DE 81:2     

Neuroglobin involvement in visual pathways through the optic nerve

Neuroglobin is a member of the globin superfamily proposed to be only expressed in neurons and involved in neuronal protection from hypoxia or oxidative stress. A significant fraction of the protein localizes within the mitochondria and is directly associated with mitochondrial metabolism and integrity. The retina is the site of the highest concentration for neuroglobin and has been reported to be up to 100-fold higher than in the brain. Since neuroglobin was especially abundant in retinal ganglion cell layer, we investigated its abundance in optic nerves. Remarkably in optic nerves, neuroglobin is observed, as expected, in retinal ganglion cell axon profiles but also astrocyte processes, in physiological conditions, possess high levels of the protein. Neuroglobin mRNA and protein levels are ~ 10-fold higher in optic nerves than in retinas, indicating an important accumulation of neuroglobin in these support cells. Additionally, neuroglobin levels increase in Müller cells during reactive gliosis in response to eye injury. This suggests the pivotal role of neuroglobin in retinal glia involved in neuronal support and/or healing. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.     

Clb5-associated Kinase Activity is Required Early in the Spindle Pathway for Correct Preanaphase Nuclear Positioning in Saccharomyces cerevisiae

In Saccharomyces cerevisiae, a single cyclin-dependent kinase, Cdc28, regulates both G1/S and G2/M phase transitions by associating with stage-specific cyclins. During progression through S phase and G2/M, Cdc28 is activated by the B-type cyclins Clb1–6. Because of functional redundancy, specific roles for individual Clbs have been difficult to assign. To help genetically define such roles, strains carrying a cdc28^ts allele, combined with single CLB deletions were studied. We assumed that by limiting the activity of the kinase, these strains would be rendered more sensitive to loss of individual Clbs.     

Aspirin inhibits proliferation and promotes differentiation of neuroblastoma cells via p21Waf1 protein up‐regulation and Rb1 pathway modulation

Several clinical and experimental studies have demonstrated that regular use of aspirin (acetylsalicylic acid, ASA) correlates with a reduced risk of cancer and that the drug exerts direct anti‐tumour effects. We have previously reported that ASA inhibits proliferation of human glioblastoma multiforme‐derived cancer stem cells. In the present study, we analysed the effects of ASA on nervous system‐derived cancer cells, using the SK‐N‐SH (N) human neuroblastoma cell line as an experimental model. ASA treatment of SK‐N‐SH (N) dramatically reduced cell proliferation and motility, and induced neuronal‐like differentiation, indicated by the appearance of the neuronal differentiation marker tyrosine hydroxylase (TH) after 5 days. ASA did not affect cell viability, but caused a time‐dependent accumulation of cells in the G₀/G₁ phase of the cell cycle, with a concomitant decrease in the percentage of cells in the G₂ phase. These effects appear to be mediated by a COX‐independent mechanism involving an increase in p21^Waf1 and underphosphorylated retinoblastoma (hypo‐pRb1) protein levels. These findings may support a potential role of ASA as adjunctive therapeutic agent in the clinical management of neuroblastoma.