Computing along the axon

A special form of spiking neural P systems, called axon P systems, corresponding to the activity of Ranvier nodes of neuron axon, is considered and a class of SN-like P systems where the computation is done along the axon is introduced and their language generative power is investigated.     

Semaphorin 7A promotes axon outgrowth through integrins and MAPKs

Striking parallels exist between immune and nervous system cellular signalling mechanisms. Molecules originally shown to be critical for immune responses also serve neuronal functions, and similarly neural guidance cues can modulate immune function. We show here that semaphorin 7A (Sema7A), a membrane-anchored member of the semaphorin family of guidance proteins previously known for its immunomodulatory effects, can also mediate neuronal functions. Unlike many other semaphorins, which act as repulsive guidance cues, Sema7A enhances central and peripheral axon growth and is required for proper axon tract formation during embryonic development. Unexpectedly, Sema7A enhancement of axon outgrowth requires integrin receptors and activation of MAPK signalling pathways. These findings define a previously unknown biological function for semaphorins, identify an unexpected role for integrins and integrin-dependent intracellular signalling in mediating semaphorin responses, and provide a framework for understanding and interfering with Sema7A function in both immune and nervous systems.     

Axon guidance in cultured epithelial fragments of Drosophila wing

Growing axons can be guided by a number of different cues: adhesive substrates, diffusible factors, electrical fields and even factors intrinsic to the neurone itself have all been shown to affect axon orientation and outgrowth in vitro. However, in most intact systems it has proved difficult to test directly the role played by these putative guidance cues. Here, we describe a system, the developing wing of the fruitfly, in which we have tested simultaneously two putative guidance mechanisms, physical constraints to axon growth (channels) and the position of neuronal somata (guideposts), using surgical techniques. We show that pioneer sensory axons can navigate correctly and form their normal stereotyped pattern of axon bundles in wing fragments that apparently lack both physical and neural cues. This technique allows access to the surface along which neuronal pathfinding takes place, making possible a wide range of experimental manipulations on the developing system.     

Common mechanisms of nerve and blood vessel wiring

Blood vessels and nerve fibres course throughout the body in an orderly pattern, often alongside one another. Although superficially distinct, the mechanisms involved in wiring neural and vascular networks seem to share some deep similarities. The discovery of key axon guidance molecules over the past decade has shown that axons are guided to their targets by finely tuned codes of attractive and repulsive cues, and recent studies reveal that these cues also help blood vessels to navigate to their targets. Parallels have also emerged between the actions of growth factors that direct angiogenic sprouting and those that regulate axon terminal arborization.     

Turnover of fluorescently labelled tubulin and actin in the axon.

The cytoskeleton has an important role in the generation and maintenance of the structure of the axon. Microtubules, neurofilaments and actin, together with various kinds of associated proteins, form highly organized dynamic cytoskeletal structures. Because tubulin and actin molecules are essential cytoskeletal components and are transported down the axon, it is important to understand their dynamic behaviour within the axon. Although previous pulse-labelling studies have indicated that the axonal cytoskeleton is a static complex travelling down the axon, this view has been challenged by the results of several recent experiments. We have now addressed this question by analysing the recovery of fluorescence after photobleaching fluorescent analogues of tubulin and actin in the axons of cultured neurons. We did not observe movement or spreading of bleached zones along the axon, both in neurons injected with fluorescein-labelled tubulin and actin. All bleached zones recovered their fluorescence gradually, however, indicating that microtubules and actin filaments are not static polymers moving forward within the axon, but are dynamic structures that continue to assemble along the length of the axon.     

Target size regulates calibre and myelination of sympathetic axons

Axons in vertebrate peripheral nerves are ensheathed by Schwann cells. For some axons, this sheath consists of a single layer of glial cell cytoplasm and plasma membranes; for other axons, Schwann cells form multilayered myelin. Whether or not a Schwann cell makes myelin is determined by a signal from the axon, but the nature of this signal is not known. Here I show that sympathetic postganglionic axons, which are normally not myelinated, become myelinated when their calibre is increased as a result of increasing the size of the peripheral target they innervate. This result implies that axon calibre, which is known to be correlated with myelination, is in fact the crucial determinant of whether an axon becomes myelinated. Furthermore, the finding that increasing or decreasing target size causes corresponding increases or decreases in axon size indicates that axon calibre is itself regulated by retrograde signals from peripheral target tissues.     

神经元轴突电刺激响应的有限元数值模拟

为了研究神经元轴突的微观生理电传导特性,建立了神经元轴突的三维有限元模型,通过数值计算模拟神经元轴突对电刺激的动态响应.建立海马神经元轴突的三维几何模型并指定其生物物理参数,根据Hodgkin-Huxley方程和Maxwell方程,建立偏微分方程组,对神经元轴突有限元模型施加不同持续时间和不同脉冲幅度的电流脉冲并求解,获得神经元轴突的三维电势分布和动作电位曲线.数值模拟结果显示,该神经元轴突的静息电位约为-65 mV;对模型施加持续时间为2 ms,强度0.01 A/m2的电流脉冲刺激未产生动作电位,施以(2 ms、0.2 A/m2),(20ms、0.01 A/m2),(20ms、0.2 A/m2)脉冲刺激均产生动作电位,峰值分别出现在0.012 s、0.017 s和0.012 s,动作电位幅度约为100mV,持续时间约为2 ms.神经元轴突电刺激响应的有限元模拟结果与实验结果吻合,表明所建立的神经元轴突有限元模型及数值模拟方法合理、可靠,为深入研究神经电生理特性提供了基础模型和仿真分析方法.     

Novel pathway connecting the outer and inner vertebrate retina

In many fish retinas, thin axons from the external horizontal cells extend through the inner nuclear layer and expand into large terminal processes that lie along the border of the inner nuclear and inner plexiform layers. Although the horizontal-cell axon terminals are structurally very prominent, their function is unknown. Here we report morphological and functional evidence that signals from catfish (Ictalurus punctatus) horizontal-cell axon terminals can be transmitted directly to amacrine cells. Current injected into horizontal-cell axon terminals produces responses from both transient and sustained amacrine cells very similar to those elicited by light stimuli. Electron microscope observations show chemical synapses from the axon terminals onto amacrine cell perikarya and processes. These data suggest that amacrine cells in the catfish retina receive two inputs, one from bipolar cells and the other from horizontal-cell axon terminals.     

Threshold channels--a novel type of sodium channel in squid giant axon

Sodium channels in nerve and muscle cells are functionally similar across wide phylogenetic boundaries and are usually thought to represent a single, homogeneous population that initiates the action potential at threshold and unerringly transmits it along the surface membrane. In marked contrast, many cell types are known to have several distinct potassium permeability systems. Distinguishable populations of Na channels have been reported in a few cell types, however, including denervated skeletal muscle, embryonic cardiac muscle, Purkinje cell somata and non-myelinated axons at low temperature. We report here that in squid giant axon, in standard experimental conditions, there are two functionally distinct populations of Na channels. The newly discovered population accounts for only a few per cent of the total Na permeability. The channels are selectively activated by small depolarizations and have very slow closing kinetics. Because these channels activate at voltages near the resting potential and tend to stay open for long times, they must dominate behaviour of the axon membrane in the threshold region for action potential initiation.     

P物质--甲醛急性刺激效应的分子生物标志物

分别用0 mg/m3、1 mg/m3、2 mg/m3、3 mg/m3的甲醛对10名受试者进行眼部控制暴露,暴露时间5 min,测定暴露前后鼻腔灌洗液中P物质含量. 结果表明,甲醛暴露后鼻腔灌洗液中P物质含量增加,尤其是3 mg/m3甲醛暴露组P物质含量增加尤为显著(p<0.05). 这说明甲醛刺激眼部三叉神经末梢后,会通过局部轴突反射,引起鼻腔内的三叉神经末梢释放P物质. 因此P物质可作为评价甲醛急性刺激效应的分子生物标志物.     

Oligodendroglia metabolically support axons and contribute to neurodegeneration

Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.     

基于CUDA并行平台实现核膜系统求解可满足性问题的研究

膜系统能以空间换时间的方式在多项式时间内求解NP难问题,作为膜系统中的一个新类型,核膜系统不仅包含了不同类型膜系统的特征,而且能提供一种统一性的描述．因此基于核膜系统构建系统模型,并以此求解一个典型的NP难问题：可满足性问题．为了加速对核膜系统的仿真过程,程序将在CUDA并行方式下仿真实现,通过与传统的串行方式比较,使用CUDA能减少95％的仿真时间,这也表明使用CUDA并行方式非常适合仿真核膜系统．     

Axonal site of spike initiation enhances auditory coincidence detection

Neurons initiate spikes in the axon initial segment or at the first node in the axon. However, it is not yet understood how the site of spike initiation affects neuronal activity and function. In nucleus laminaris of birds, neurons behave as coincidence detectors for sound source localization and encode interaural time differences (ITDs) separately at each characteristic frequency (CF). Here we show, in nucleus laminaris of the chick, that the site of spike initiation in the axon is arranged at a distance from the soma, so as to achieve the highest ITD sensitivity at each CF. Na+ channels were not found in the soma of high-CF (2.5-3.3 kHz) and middle-CF (1.0-2.5 kHz) neurons but were clustered within a short segment of the axon separated by 20-50 microm from the soma; in low-CF (0.4-1.0 kHz) neurons they were clustered in a longer stretch of the axon closer to the soma. Thus, neurons initiate spikes at a more remote site as the CF of neurons increases. Consequently, the somatic amplitudes of both orthodromic and antidromic spikes were small in high-CF and middle-CF neurons and were large in low-CF neurons. Computer simulation showed that the geometry of the initiation site was optimized to reduce the threshold of spike generation and to increase the ITD sensitivity at each CF. Especially in high-CF neurons, a distant localization of the spike initiation site improved the ITD sensitivity because of electrical isolation of the initiation site from the soma and dendrites, and because of reduction of Na+-channel inactivation by attenuating the temporal summation of synaptic potentials through the low-pass filtering along the axon.     

UNC-6/netrin and its receptor UNC-5 locally exclude presynaptic components from dendrites

Polarity is an essential feature of many cell types, including neurons that receive information from local inputs within their dendrites and propagate nerve impulses to distant targets through a single axon. It is generally believed that intrinsic structural differences between axons and dendrites dictate the polarized localization of axonal and dendritic proteins. However, whether extracellular cues also instruct this process in vivo has not been explored. Here we show that the axon guidance cue UNC-6/netrin and its receptor UNC-5 act throughout development to exclude synaptic vesicle and active zone proteins from the dendrite of the Caenorhabditis elegans motor neuron DA9, which is proximal to a source of UNC-6/netrin. In unc-6/netrin and unc-5 loss-of-function mutants, presynaptic components mislocalize to the DA9 dendrite. In addition, ectopically expressed UNC-6/netrin, acting through UNC-5, is sufficient to exclude endogenous synapses from adjacent subcellular domains within the DA9 axon. Furthermore, this anti-synaptogenic activity is interchangeable with that of LIN-44/Wnt despite being transduced through different receptors, suggesting that extracellular cues such as netrin and Wnts not only guide axon navigation but also regulate the polarized accumulation of presynaptic components through local exclusion.     

Long-term regenerated nerve fibres retain sensitivity to potassium channel blocking agents

Mammalian myelinated peripheral nerve fibres display a remarkable degree of regeneration following a discrete nerve crush. Nerve crush disrupts the axon cylinder, but leaves the basement membrane of the Schwann cell intact. These intact endoneurial tubes provide pathways to guide the regenerating axon sprouts. After contact with the periphery is established, the regenerating fibres enlarge and myelinate. Conduction velocity recovers to nearly normal and functional recovery is, in many cases, nearly complete. A distinct feature of normal mature myelinated axons is the insensitivity of these fibres to potassium channel blocking agents. In contrast, immature myelinated axons are exquisitely sensitive to the K channel blocking agent 4-aminopyridine (4-AP). Application of 4-AP to immature myelinated fibres leads to a delayed membrane depolarization with action potential burst activity in response to a single stimulus. This sensitivity to 4-AP is attenuated as the fibres mature. Previous studies have demonstrated a sensitivity to 4-AP in regenerating nerve fibres; this sensitivity differentiates the regenerating axon segments from their normal parent axon segments. Such studies have not, however, examined the question of whether regenerated fibres, which have re-established peripheral connections and are functionally active, fully recapitulate the functional organization of normal mature myelinated fibres. We demonstrate here that while sensitivity to the potassium channel blocking agents 4-AP and 3, 4-diaminopyridine (3, 4-DAP) is lost in the normal course of myelinated axon maturation, this property is present in long-term regenerated axons. This suggests that long-term regenerated mammalian axons are characterized by a functional organization that bears a closer resemblance to that of immature myelinated fibres than to that of adult myelinated fibres.     

Wnt-mediated axon guidance via the Drosophila Derailed receptor

In nervous systems with bilateral symmetry, many neurons project axons across the midline to the opposite side. In each segment of the Drosophila embryonic nervous system, axons that display this projection pattern choose one of two distinct tracts: the anterior or posterior commissure. Commissure choice is controlled by Derailed, an atypical receptor tyrosine kinase expressed on axons projecting in the anterior commissure. Here we show that Derailed keeps these axons out of the posterior commissure by acting as a receptor for Wnt5, a member of the Wnt family of secreted signalling molecules. Our results reveal an unexpected role in axon guidance for a Wnt family member, and show that the Derailed receptor is an essential component of Wnt signalling in these guidance events.     

Rac GTPases control axon growth, guidance and branching

Growth, guidance and branching of axons are all essential processes for the precise wiring of the nervous system. Rho family GTPases transduce extracellular signals to regulate the actin cytoskeleton. In particular, Rac has been implicated in axon growth and guidance. Here we analyse the loss-of-function phenotypes of three Rac GTPases in Drosophila mushroom body neurons. We show that progressive loss of combined Rac1, Rac2 and Mtl activity leads first to defects in axon branching, then guidance, and finally growth. Expression of a Rac1 effector domain mutant that does not bind Pak rescues growth, partially rescues guidance, but does not rescue branching defects of Rac mutant neurons. Mosaic analysis reveals both cell autonomous and non-autonomous functions for Rac GTPases, the latter manifesting itself as a strong community effect in axon guidance and branching. These results demonstrate the central role of Rac GTPases in multiple aspects of axon development in vivo, and suggest that axon growth, guidance and branching could be controlled by differential activation of Rac signalling pathways.     

Assembly of microtubules at the tip of growing axons

The growth of axons in the developing nervous system depends on the elongation of the microtubules that form their principal longitudinal structural element. It is not known whether individual microtubules in the axon elongate at their proximal ends, close to the cell body, and then move forward into the lengthening axon, or whether tubulin subunits are transported to the tip of the axon and assembled there onto the free ends of microtubules. The former possibility is supported by studies of slow axonal transport in mature nerves from which it has been deduced that microtubule assembly occurs principally at the neuronal cell body. By contrast, the polarity of microtubules in axons, which have their 'plus' or 'fast-growing' ends distal to the cell body, suggests that assembly occurs at the growing tip, or growth cone, of the axon. We have addressed this question by topically applying Colcemid (N-desacetyl-N-methylcolchicine), and other drugs which alter microtubule stability, to different regions of isolated nerve cells growing in tissue culture. We find that the sensitivity to these drugs is greatest at the growth cone by at least two orders of magnitude, suggesting that this is a major site of microtubule assembly during axonal growth.     

基于蚁群算法的P2P网络路由

对等计算是目前分布计算领域的一个研究热点。对于对等网络系统来说,路由效率是一个关键问题。在此应用蚁群算法到对等网路由中,解决P2P网络的路由问题。仿真实验证实该方法是有效、可行的。     

Regulation of axon growth in vivo by activity-based competition

The formation of functional neural networks requires precise regulation of the growth and branching of the terminal arbors of axons, processes known to be influenced by early network electrical activity. Here we show that a rule of activity-based competition between neighbouring axons appears to govern the growth and branching of retinal ganglion cell (RGC) axon arbors in the developing optic tectum of zebrafish. Mosaic expression of an exogenous potassium channel or a dominant-negative SNARE protein was used to suppress electrical or neurosecretory activity in subsets of RGC axons. Imaging in vivo showed that these forms of activity suppression strongly inhibit both net growth and the formation of new branches by individually transfected RGC axon arbors. The inhibition is relieved when the activity of nearby 'competing' RGC axons is also suppressed. These results therefore identify a new form of activity-based competition rule that might be a key regulator of axon growth and branch initiation.