An electromagnetic view of relay time in propagation of neural signals

We review the experimental and computational data about the propagation of neural signals in myelinated axons in mice,cats,rabbits,and frogs published in the past five decades.In contrast to the natural assumption that neural signals occur one by one in time and in space,we figure out that neural signals are highly overlapped in time between neighboring nodes.This phenomenon was occasionally illustrated in some early reports,but seemed to have been overlooked for some time.The shift in time between two successive neural signals from neighboring nodes,defined as relay timeτ,was calculated to be only 16.3μs-87.0μs,i.e.,0.8%-4.4%of the average duration of an action potential peak(roughly 2 ms).We present a clearer picture of the exact physical process about how the information transmits along a myelinated axon,rather than a whole action potential peak,what is transmitted is only a rising electric field caused by transmembrane ion flows.Here in the paper,τrepresents the waiting time until the neighboring node senses an attenuated electric field reaching the threshold to trigger the open state.The mechanisms addressed in this work have the potential to be universal,and may hold clues to revealing the exact triggering processes of voltage-gated ion channels and various brain functions.

Neural Wiskott-Aldrich syndrome protein(N-WASP)promotes distant metastasis in pancreatic ductal adenocarcinoma via activation of LOXL2

Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.

Simulation of the physical process of neural electromagnetic signal generation based on a simple but functional bionic Na^(+)channel

The physical processes occurring at open Na^(+) channels in neural fibers are essential for the understanding of the nature of neural signals and the mechanism by which the signals are generated and transmitted along nerves.However,there is a less generally accepted description of these physical processes.We studied changes in the transmembrane ionic flux and the resulting two types of electromagnetic signals by simulating the Na^(+) transport across a bionic nanochannel model simplified from voltage-gated Na^(+) channels.The results show that the Na^(+) flux can reach a steady state in approximately 10 ns due to the dynamic equilibrium of the Na^(+) ion concentration difference between both sides of the membrane.After characterizing the spectrum and transmission of these two electromagnetic signals,the low-frequency transmembrane electric field is regarded as the physical quantity transmitting in the waveguide-like lipid dielectric layer and triggering the neighboring voltage-gated channels.Factors influencing the Na^(+) flux transport are also studied.The impact of the Na^(+) concentration gradient is found to be higher than that of the initial transmembrane potential on the Na^(+) transport rate,and introducing the surface-negative charge in the upper third channel could increase the transmembrane Na^(+) current.This work can be further studied by improving the simulation model;however,the current work helps to better understand the electrical functions of voltage-gated ion channels in neural systems.

Correlation between receptor-interacting protein 140 expression and directed differentiation of human embryonic stem cells into neural stem cells

Overexpression of receptor-interacting protein 140（RIP140） promotes neuronal differentiation of N2 a cells via extracellular regulated kinase 1/2（ERK1/2） signaling.However,involvement of RIP140 in human neural differentiation remains unclear.We found both RIP140 and ERK1/2 expression increased during neural differentiation of H1 human embryonic stem cells.Moreover,RIP140 negatively correlated with stem cell markers Oct4 and Sox2 during early stages of neural differentiation,and positively correlated with the neural stem cell marker Nestin during later stages.Thus,ERK1/2 signaling may provide the molecular mechanism by which RIP140 takes part in neural differentiation to eventually affect the number of neurons produced.

Regenerative potential of targeting glycogen synthase kinase-3 signaling in neural tissues

Multiple roles of glycogen synthase kinase-3（GSK-3）in neural tissues：GSK-3 is a serine/threonine kinase that has two isoforms encoded by two different genes,GSK-3αand GSK-3β,in mammals.GSK-3 has several sites of serine and tyrosine phosphorylation.

Houshiheisan and its components promote axon regeneration after ischemic brain injury

Houshiheisan,a classic prescription in traditional Chinese medicine,contains Flos Chrysanthemi,Radix Saposhnikoviae,Ramulus Cinnamomi,Rhizoma Chuanxiong,Radix et Rhizoma Asari,Radix Platycodonis,Rhizoma Atractylodis macrocephalae,Poria,Rhizoma Zingiberis,Radix Angelicae sinensis,Radix et Rhizoma Ginseng,Radix Scutellariae and Concha Ostreae.According to traditional Chinese medicine theory,Flos Chrysanthemi,Radix Saposhnikoviae,Ramulus Cinnamomi,Rhizoma Chuanxiong,Radix et Rhizoma Asari and Radix Platycodonis are wind-dispelling drugs;Rhizoma Atractylodis macrocephalae,Poria,Rhizoma Zingiberis,Radix Angelicae sinensis and Radix et Rhizoma Ginseng are deficiency-nourishing drugs.A large number of randomized controlled trials have shown that Houshiheisan is effective in treating stroke,but its mechanism of action is unknown.Axonal remodeling is an important mechanism in neural protection and regeneration.Therefore,this study explored the effect and mechanism of action of Houshiheisan on the repair of axons after cerebral ischemia.Rat models of focal cerebral ischemia were established by ligating the right middle cerebral artery.At 6 hours after model establishment,rats were intragastrically administered 10.5 g/kg Houshiheisan or 7.7 g/kg wind-dispelling drug or 2.59 g/kg deficiency-nourishing drug.These medicines were intragastrically administered as above every 24 hours for 7 consecutive days.Houshiheisan,and its wind-dispelling and deficiency-nourishing components reduced the neurological deficit score and ameliorated axon and neuron lesions after cerebral ischemia.Furthermore,Houshiheisan,and its wind-dispelling and deficiency-nourishing components decreased the expression of proteins that inhibit axonal remodeling：amyloid precursor protein,neurite outgrowth inhibitor protein A（Nogo-A）,Rho family small GTPase A（Rho A） and Rho-associated kinase 2（Rock2）,and increased the expression of growth associated protein-43,microtubule-associated protein-2,netrin-1,Ras-related C3 botulinum toxin substrate 1（Rac1） and cell division cycle 42（Cdc42）.The effect of Houshiheisan was stronger than wind-dispelling drugs or deficiency-nourishing drugs alone.In conclusion,Houshiheisan,and wind-dispelling and deficiency-nourishing drugs promote the repair of axons and nerve regeneration after cerebral ischemia through Nogo-A/Rho A/Rock2 and Netrin-1/Rac1/Cdc42 signaling pathways.These effects are strongest with Houshiheisan.

Effects of cytokines and chemokines on migration of mesenchymal stem cells following spinal cord injury

We investigated the effects of cytokines and chemokines and their associated signaling pathways on mesenchymal stem cell migration after spinal cord injury, to determine their roles in the curative effects of mesenchymal stem cells. This study reviewed the effects of tumor necrosis factor-α, vascular endothelial growth factor, hepatocyte growth factor, platelet-derived growth factor, basic fibroblast growth factor, insulin like growth factor-I, stromal cell-derived factor and monocyte chemoattractant protein-1, 3 during mesenchymal stem cell migration to damaged sites, and analyzed the signal transduction pathways involved in their effects on mesenchymal stem cell migration. The results confirmed that phosphatidylinositol 3-kinase/serine/threonine protein kinases and nuclear factor-KB play crucial roles in the migration of mesenchymal stem cells induced by cytokines and chemokines.

Axonal remodeling in the corticospinal tract after stroke： how does rehabilitative training modulate it？

Stroke causes long-term disability, and rehabilitative training is commonly used to improve the consecutive functional recovery. Following brain damage, surviving neurons undergo morphological alterations to reconstruct the remaining neural network. In the motor system, such neural network remodeling is observed as a motor map reorganization. Because of its significant correlation with functional recovery, motor map reorganization has been regarded as a key phenomenon for functional recovery after stroke. Although the mechanism underlying motor map reorganization remains unclear, increasing evidence has shown a critical role for axonal remodeling in the corticospinal tract. In this study, we review previous studies investigating axonal remodeling in the corticospinal tract after stroke and discuss which mechanisms may underlie the stimulatory effect of rehabilitative training. Axonal remodeling in the corticospinal tract can be classified into three types based on the location and the original targets of corticospinal neurons, and it seems that all the surviving corticospinal neurons in both ipsilesional and contralesional hemisphere can participate in axonal remodeling and motor map reorganization. Through axonal remodeling, corticospinal neurons alter their output selectivity from a single to multiple areas to compensate for the lost function. The remodeling of the corticospinal axon is influenced by the extent of tissue destruction and promoted by various therapeutic interventions, including rehabilitative training. Although the precise molecular mechanism underlying rehabilitation-promoted axonal remodeling remains elusive, previous data suggest that rehabilitative training promotes axonal remodeling by upregulating growth-promoting and downregulating growth-inhibiting signals.

Buyang Huanwu decoction up-regulates Notch1 gene expression in injured spinal cord

Expression of genes in the Notch signaling pathway is altered in the injured spinal cord, which indicates that Notch participates in repair after spinal cord injury. Buyang Huanwu decoction, a traditional Chinese herbal preparation, can promote the growth of nerve cells and nerve fibers; however, it is unclear whether Buyang Huanwu decoction affects the Notch signaling pathway in injured spinal cord. In this study, a rat model was established by injuring the T10 spinal cord. At 2 days after injury, rats were intragastrically administered 2 m L of 0.8 g/m L Buyang Huanwu decoction daily until sacrifice. Real-time reverse transcription polymerase chain reaction analysis demonstrated that at 7, 14 and 28 days after injury, the expression of Notch1 was increased in the Buyang Huanwu decoction group compared with controls. These findings confirm that Buyang Huanwu decoction can promote the expression of Notch1 in rats with incomplete spinal cord injury, and may indicate a mechanism to promote the repair of spinal cord injury.

Axon regeneration impediment: the role of paired immunoglobulin-like receptor B

Regenerative capacity is weak after central nervous system injury because of the absence of an enhancing microenvironment and presence of an inhibitory microenvironment for neuronal and axonal repair. In addition to the Nogo receptor（Ng R）, the paired immunoglobulin-like receptor B（Pir B） is a recently discovered coreceptor of Nogo, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein. Concurrent blocking of Ng R and Pir B almost completely eliminates the inhibitory effect of myelin-associated inhibitory molecules on axonal regeneration. Pir B participates in a key pathological process of the nervous system, specifically axonal regeneration inhibition. Pir B is an inhibitory receptor similar to Ng R, but their effects are not identical. This study summarizes the structure, distribution, relationship with common nervous system diseases, and known mechanisms of Pir B, and concludes that Pir B is also distributed in cells of the immune and hematopoietic systems. Further investigations are needed to determine if immunomodulation and blood cell migration involve inhibition of axonal regeneration.

Baicalin protects neonatal rat brains against hypoxicischemic injury by upregulating glutamate transporter 1 via the phosphoinositide 3-kinase/protein kinase B signaling pathway

Baicalin is a flavonoid compound extracted from Scutellaria baicalensis root.Recent evidence indicates that baicalin is neuroprotective in models of ischemic stroke.Here,we investigate the neuroprotective effect of baicalin in a neonatal rat model of hypoxic-ischemic encephalopathy.Seven-day-old pups underwent left common carotid artery ligation followed by hypoxia（8% oxygen at 37°C） for 2 hours,before being injected with baicalin（120 mg/kg intraperitoneally） and examined 24 hours later.Baicalin effectively reduced cerebral infarct volume and neuronal loss,inhibited apoptosis,and upregulated the expression of p-Akt and glutamate transporter 1.Intracerebroventricular injection of the phosphoinositide 3-kinase/protein kinase B（PI3 K/Akt） inhibitor LY294002 30 minutes before injury blocked the effect of baicalin on p-Akt and glutamate transporter 1,and weakened the associated neuroprotective effect.Our findings provide the first evidence,to our knowledge that baicalin can protect neonatal rat brains against hypoxic-ischemic injury by upregulating glutamate transporter 1 via the PI3 K/Akt signaling pathway.

Low power CMOS preamplifier for neural recording applications

A fully-differential bandpass CMOS （complementary metal oxide semiconductor） preamplifier for extra- cellular neural recording is presented. The capacitive-coupled and capacitive-feedback topology is adopted. The preamplifier has a midband gain of 20.4 dB and a DC gain of 0. The -3 dB upper cut-off frequency of the preamplifier is 6.7 kHz. The lower cut-off frequency can be adjusted for amplifying the field or action potentials located in different bands. It has an input-referred noise of 8.2 μVrms integrated from 0.15 Hz to 6.7 kHz for recording the local field potentials and the mixed neural spikes with a power dissipation of 23.1μW from a 3.3 V supply. A bandgap reference circuitry is also designed for providing the biasing voltage and current. The 0.22 mm2 prototype chip, including the preamplifier and its biasing circuitry, is fabricated in the 0.35-μm N-well CMOS 2P4M process.

Up-regulation of Ras/Raf/ERK1/2 signaling in the spinal cord impairs neural cell migration, neurogenesis, synapse formation, and dendritic spine development

Background The Ras/Raf/ERK1/2 signaling pathway controls many cellular responses such as cell proliferation, migration, differentiation, and death. In the nervous system, emerging evidence also points to a death-promoting role for ERK1/2 in both in vitro and in vivo models of neuronal death. To further investigate how Ras/Raf/ERK1/2 up-regulation may lead to the development of spinal cord injury, we developed a cellular model of Raf/ERK up-regulation by over- expressing c-Raf in cultured spinal cord neurons （SCNs） and dorsal root ganglions （DRGs）.

A multi-channel analog IC for in vitro neural recording

Recent work in the field ofneurophysiology has demonstrated that, by observing the firing characteristic of action potentials （AP） and the exchange pattern of signals between neurons, it is possible to reveal the nature of ＂memory＂ and ＂thinking＂ and help humans to understand how the brain works. To address these needs, we developed a prototype fully integrated circuit （IC） with micro-electrode array （MEA） for neural recording. In this scheme, the microelectrode array is composed by 64 detection electrodes and 2 reference electrodes. The proposed IC consists of 8 recording channels with an area of 5 x 5 mm2. Each channel can operate independently to process the neural signal by amplifying, filtering, etc. The chip is fabricated in 0.5-#m CMOS technology. The simulated and measured results show the system provides an effective device for recording feeble signal such as neural signals.

Intrafascicular Vagal Activity Recording and Analysis Based on Carbon Nanotube Yarn Electrodes

The vagus nerve carries sensory information from multiple organs in the body.The recording of its activity and further processing is a key step for neuromodulation treatments.This paper presents a specific algorithm for the processing and discrimination of intrafascicular recordings from the vagus nerve using the novel carbon nanotube yarn electrodes.Up to four different neural waveforms were found,whose occurrence corresponded to distinct levels of anesthesia depth.