Neuron Model Research Articles

Dendritic cells under allergic condition enhance the activation of pruritogen-responsive neurons via inducing itch receptors in a co-culture study

BackgroundItch sensitization has been reported in patients with chronic allergic skin diseases and observed in a mouse model of allergic contact dermatitis (ACD). There is evidence suggesting that neuroimmune interactions may contribute to itch sensitization, as an increase in dendritic cells (DCs) within ganglia has been observed during allergic conditions. However, how DCs interact with sensory neurons in ganglia during allergic conditions is still not known. This study aims to investigate the role of DCs in dorsal root ganglion (DRG) under ACD conditions, specifically focusing on itch sensitization within the DRG. The tolylene-2,4-diisocyanate (TDI) mouse model for ACD and the co-culture model of DCs and DRG neurons was employed in this study.ResultsWe successfully induced ACD by TDI, as evidenced by the development of edema, elevated total serum IgE levels, and an observed itch reaction in TDI-sensitized mice. Calcium imaging and RT-qPCR analysis revealed that TDI-sensitized mice exhibited signs of peripheral sensitization, including a higher percentage of neurons responding to pruritogens and increased activation and expression of itch receptors in excised DRG of TDI-sensitized mice. Immunofluorescence and flow cytometric analysis displayed an increase of MHCII+ cells, which serves as a marker for DCs, within DRG during ACD. The co-culture study revealed that when DRG neurons were cultured with DCs, there was an increase in the number of neurons responsive to pruritogens and activation of itch receptors such as TRPA1, TRPV1, H1R, and TRPV4. In addition, the immunofluorescence and RT-qPCR study confirmed an upregulation of TRPV4.ConclusionsOur findings indicate that there is an increase of MHCII+ cells and itch peripheral sensitization in DRG under TDI-induced ACD condition. It has been found that MHCII+ cells in DRG might contribute to the itch peripheral sensitization by activating itch receptors, as shown through co-culture studies between DRG neurons and DCs. Further studies are required to identify the specific mediator(s) responsible for peripheral sensitization induced by activated DCs.

Excitatory action of low frequency depolarizing GABA/glycine synaptic inputs is prevalent in prenatal spinal SOD1G93A motoneurons.

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onsetneurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. Recent evidence suggests the dysfunction of inhibitory signalling in ALS motor neurons. We have shown that embryonic day (E)17.5spinal motoneurons (MNs) of the SOD1G93A mouse model of ALS exhibit an altered chloride homeostasis. At this prenatal stage, inhibition of spinal motoneurons (MNs) is mediated by depolarizing GABAergic/glycinergic postsynaptic potentials (dGPSPs). Here, using an ex vivo preparation and patch clamp recording from MNs with a chloride equilibrium set below spike threshold, we report that low input resistance (Rin ) E17.5 MNs from the SOD1G93A ALS mouse model do not correctly integrate dGPSPs evoked by electrical stimulations of GABA/glycine inputs at different frequencies. Indeed, firing activity of most wild-type (WT) MNs with low Rin was inhibited by incoming dGPSPs, whereas low Rin SOD1G93A MNs were excited or exhibited a dual response (excited by low frequency dGPSPs and inhibited by high frequency dGPSPs). Simulation highlighted the importance of the GABA/glycine input density and showed that pure excitation could be obtained in SOD-like MNs by moving GABA/glycine input away from the cell body to dendrites. This was in agreement with confocal imaging showing a lack of peri-somatic inhibitory terminals in SOD1G93A MNs compared to WT littermates. Putative fast ALS-vulnerable MNs with low Rin are therefore lacking functional inhibition at the near-term prenatal stage. KEY POINTS: We analysed the integration of GABAergic/glycinergic synaptic events by embryonic spinal motoneurons (MNs) in a mouse model of the amyotrophic lateral sclerosis (ALS) neurodegenerative disease. We found that GABAergic/glycinergic synaptic events do not properly inhibit ALS MNs with low input resistance, most probably corresponding to future vulnerable MNs. We used a neuron model to highlight the importance of the GABA/glycine terminal location and density in the integration of the GABAergic/glycinergic synaptic events. Confocal imaging showed a lack of GABA/glycine terminals on the cell body of ALS MNs. The present study suggests that putative ALS vulnerable MNs with low Rin lack functional inhibition at the near-term stage.

A model for an electronic spiking neuron built with a memristive voltage-gated element

This study introduces a mathematical model for an electronic circuit capable of emulating both spiking and bursting neurons. The circuit incorporates a memristor as the nonlinear element essential for generating excitable dynamics. Our demonstrations illustrate that the model's solutions effectively capture the qualitative features of circuit voltages and currents. Additionally, we provide interpretations of these qualitative characteristics in the context of the underlying dynamics of the system.

Rab11a Controls Cell Shape via C9orf72 Protein: Possible Relationships to Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTDALS) Type 1.

Abnormal nucleotide insertions of C9orf72, which forms a complex with Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) protein and WD repeat-containing protein 41 (WDR41) protein, are associated with an autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 1 (FTDALS1). The differentially expressed in normal and neoplastic cells (DENN) domain-containing C9orf72 and its complex with SMCR8 and WDR41 function as a guanine-nucleotide exchange factor for Rab GTP/GDP-binding proteins (Rab GEF, also called Rab activator). Among Rab proteins serving as major effectors, there exists Rab11a. However, it remains to be established which Rab protein is related to promoting or sustaining neuronal morphogenesis or homeostasis. In this study, we describe that the knockdown of Rab11a decreases the expression levels of neuronal differentiation marker proteins, as well as the elongation of neurite-like processes, using N1E-115 cells, a well-utilized neuronal differentiation model. Similar results were obtained in primary cortical neurons. In contrast, the knockdown of Rab11b, a Rab11a homolog, did not significantly affect their cell morphological changes. It is of note that treatment with hesperetin, a citrus flavonoid (also known as Vitamin P), recovered the neuronal morphological phenotypes induced by Rab11a knockdown. Also, the knockdown of Rab11a or Rab11b led to a decrease in glial marker expression levels and in morphological changes in FBD-102b cells, which serve as the oligodendroglial differentiation model. Rab11a is specifically involved in the regulation of neuronal morphological differentiation. The knockdown effect mimicking the loss of function of C9orf72 is reversed by treatment with hesperetin. These findings may reveal a clue for identifying one of the potential molecular and cellular phenotypes underlying FTDALS1.

Generating multi-scroll chaotic attractor in a three-dimensional memristive neuron model

The tabu learning single neuron model with external stimulus is a significant model for describing the firing activities of neurons. The current generated by a magnetic-controlled memristor has the properties of electromagnetic induction current, which can be taken as special external interference in a complex physical environment. Can this neuron model still exhibit complex and diverse firing activities when memristive current is used instead of external stimulus? To solve this puzzle, this article proposes a novel three-dimensional (3-D) memristive tabu learning neuron (MTLN) model by substituting external stimulus with memristive current, which can generate a multi-scroll chaotic attractor (MSCA) whose scrolls grow with time. The MTLN model has a line equilibrium set with different stability types relied on the initial position of the memristor internal state. Using some numerical methods, complex dynamical behaviors and scroll-growing MSCAs are uncovered. Further, a simple scroll-control scheme is designed and its effectiveness is demonstrated numerically and theoretically. The results manifest that the scrolls of the generated MSCAs can grow with time and can be also controlled by bounding the memristor internal state. In addition, an FPGA hardware platform is exploited for the 3-D MTLN model and the scroll-growing and scroll-controlled MSCAs are yielded experimentally to confirm the numerical results.

ATH-1105, a small-molecule positive modulator of the neurotrophic HGF system, is neuroprotective, preserves neuromotor function, and extends survival in preclinical models of ALS.

Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder, primarily affects the motor neurons of the brain and spinal cord. Like other neurodegenerative conditions, ongoing pathological processes such as increased inflammation, excitotoxicity, and protein accumulation contribute to neuronal death. Hepatocyte growth factor (HGF) signaling through the MET receptor promotes pro-survival, anti-apoptotic, and anti-inflammatory effects in multiple cell types, including the neurons and support cells of the nervous system. This pleiotropic system is therefore a potential therapeutic target for treatment of neurodegenerative disorders such as ALS. Here, we test the effects of ATH-1105, a small-molecule positive modulator of the HGF signaling system, in preclinical models of ALS. In vitro, the impact of ATH-1105 on HGF-mediated signaling was assessed via phosphorylation assays for MET, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Neuroprotective effects of ATH-1105 were evaluated in rat primary neuron models including spinal motor neurons, motor neuron-astrocyte cocultures, and motor neuron-human muscle cocultures. The anti-inflammatory effects of ATH-1105 were evaluated in microglia- and macrophage-like cell systems exposed to lipopolysaccharide (LPS). In vivo, the impact of daily oral treatment with ATH-1105 was evaluated in Prp-TDP43A315T hemizygous transgenic ALS mice. In vitro, ATH-1105 augmented phosphorylation of MET, ERK, and AKT. ATH-1105 attenuated glutamate-mediated excitotoxicity in primary motor neurons and motor neuron- astrocyte cocultures, and had protective effects on motor neurons and neuromuscular junctions in motor neuron-muscle cocultures. ATH-1105 mitigated LPS-induced inflammation in microglia- and macrophage-like cell systems. In vivo, ATH-1105 treatment resulted in improved motor and nerve function, sciatic nerve axon and myelin integrity, and survival in ALS mice. Treatment with ATH-1105 also led to reductions in levels of plasma biomarkers of inflammation and neurodegeneration, along with decreased pathological protein accumulation (phospho-TDP-43) in the sciatic nerve. Additionally, both early intervention (treatment initiation at 1 month of age) and delayed intervention (treatment initiation at 2 months of age) with ATH-1105 produced benefits in this preclinical model of ALS. The consistent neuroprotective and anti-inflammatory effects demonstrated by ATH-1105 preclinically provide a compelling rationale for therapeutic interventions that leverage the positive modulation of the HGF pathway as a treatment for ALS.

MLKL overexpression leads to Ca2+ and metabolic dyshomeostasis in a neuronal cell model

The necroptotic effector molecule MLKL accumulates in neurons over the lifespan of mice, and its downregulation has the potential to improve cognition through neuroinflammation, and changes in the abundance of synaptic proteins and enzymes in the central nervous system. Notwithstanding, direct evidence of cell-autonomous effects of MLKL expression on neuronal physiology and metabolism are lacking. Here, we tested whether the overexpression of MLKL in the absence of cell death in the neuronal cell line Neuro-2a recapitulates some of the hallmarks of aging at the cellular level. Using genetically-encoded fluorescent biosensors, we monitored the cytosolic and mitochondrial Ca2+ levels, along with the cytosolic concentrations of several metabolites involved in energy metabolism (lactate, glucose, ATP) and oxidative stress (oxidized/reduced glutathione). We found that MLKL overexpression marginally decreased cell viability, however, it led to reduced cytosolic and mitochondrial Ca2+ elevations in response to Ca2+ influx from the extracellular space. On the contrary, Ca2+ signals were elevated after mobilizing Ca2+ from the endoplasmic reticulum. Transient elevations in cytosolic Ca2+, mimicking neuronal stimulation, lead to higher lactate levels and lower glucose concentrations in Neuro-2a cells when overexpressing MLKL, which suggest enhanced neuronal glycolysis. Despite these alterations, energy levels and glutathione redox state in the cell bodies remained largely preserved after inducing MLKL overexpression for 24–48 h. Taken together, our proof-of-concept experiments are consistent with the hypothesis that MLKL overexpression in the absence of cell death contributes to both Ca2+ and metabolic dyshomeostasis, which are cellular hallmarks of brain aging.

Prospects for the pharmacological validation of the use of platelets as a “peripheral model” of neurons

Depressive disorders often occur in patients with cardiovascular pathologies and are a predictor of the development of thrombotic events, such as myocardial infarction, acute ischemic cerebrovascular accident, and pulmonary embolism. These are believed to be caused by the structural and biochemical relationship between platelets and brain neurons, which allows us to consider platelets as a marker of central nervous system (CNS) pathologies. This review aimed to assess the relationship between the hemostasis system and the development of depressive disorders using platelets as a “peripheral model” of neurons and evaluate the effectiveness of drugs for the treatment of depression. The study was conducted in accordance with the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A systematic literature search was conducted using PubMed, Cochrane, and CINAHL databases from 2018 to 2023, according to the following keywords: “hemostasis,” “acute cerebrovascular accident,” “depression,” “depressive disorders,” “platelets,” “cardiovascular diseases.” The data obtained indicate both a clinical link between depressive disorders and vascular events and the commonality of platelets and CNS cells because of the commonality of the following proteins: transporters and receptors of serotonin or 5-hydroxytryptamine, amyloid precursor protein, and brain neurotrophic factor, which were previously considered specific neural proteins. In addition, a relationship exists between hemostasis dynamics and drug therapy for depression. In this review, changes in hemostasis in terms of platelet activation in patients with depression and vascular disease were critically analyzed. The literature presents diverse mechanisms of platelet induction, which require further study. A rational study of the pathways of platelet activation in patients with depressive disorders will provide a comprehensive understanding of the molecular mechanisms underlying the relationship between hemostasis and depression in various vascular pathologies. Platelet activation in patients with depression and the dynamics of changes in hemostasis parameters during the treatment of depressive disorders allow us to consider hemostasis as a peripheral marker of the CNS and pharmacotherapy.

A biophysically comprehensive model of urothelial afferent neurons: implications for sensory signalling in urinary bladder.

The urothelium is the innermost layer of the bladder wall; it plays a pivotal role in bladder sensory transduction by responding to chemical and mechanical stimuli. The urothelium also acts as a physical barrier between urine and the outer layers of the bladder wall. There is intricate sensory communication between the layers of the bladder wall and the neurons that supply the bladder, which eventually translates into the regulation of mechanical activity. In response to natural stimuli, urothelial cells release substances such as ATP, nitric oxide (NO), substance P, acetylcholine (ACh), and adenosine. These act on adjacent urothelial cells, myofibroblasts, and urothelial afferent neurons (UAN), controlling the contractile activity of the bladder. There is rising evidence on the importance of urothelial sensory signalling, yet a comprehensive understanding of the functioning of the urothelium-afferent neurons and the factors that govern it remains elusive to date. Until now, the biophysical studies done on UAN have been unable to provide adequate information on the ion channel composition of the neuron, which is paramount to understanding the electrical functioning of the UAN and, by extension, afferent signalling. To this end, we have attempted to model UAN to decipher the ionic mechanisms underlying the excitability of the UAN. In contrast to previous models, our model was built and validated using morphological and biophysical properties consistent with experimental findings for the UAN. The model included all the channels thus far known to be expressed in UAN, including; voltage-gated sodium and potassium channels, N, L, T, P/Q, R-type calcium channels, large-conductance calcium-dependent potassium (BK) channels, small conductance calcium-dependent (SK) channels, Hyperpolarisation activated cation (HCN) channels, transient receptor potential melastatin (TRPM8), transient receptor potential vanilloid (TRPV1) channel, calcium-activated chloride(CaCC) channels, and internal calcium dynamics. Our UAN model a) was constrained as far as possible by experimental data from the literature for the channels and the spiking activity, b) was validated by reproducing the experimental responses to current-clamp and voltage-clamp protocols c) was used as a base for modelling the non-urothelial afferent neurons (NUAN). Using our models, we also gained insights into the variations in ion channels between UAN and NUAN neurons.

Dexmedetomidine Alleviates Brain Ischemia/Reperfusion Injury by Regulating Metastasis-associated Lung Adenocarcinoma Transcript 1/MicroRNA-140-5p/ Nuclear Factor Erythroid-derived 2-like 2 Axis

Background: Dexmedetomidine (Dex) is widely used in perioperative anesthesia, and recent studies have reported that it protects organs from ischemia/reperfusion (I/R) injury. Objective: This study was performed to investigate the role of Dex in alleviating cerebral I/R injury and its regulatory effects on metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-140-5p (miR-140-5p)/nuclear factor erythroid-derived 2-like 2 (Nrf2) axis. Methods: In vivo rat middle cerebral artery occlusion (MCAO) model and in vitro oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced neuronal injury model were constructed. Dex was injected into the animals or used to culture HT22 cells to observe the pharmacological effects. The neurological defect, brain water content, infarct volume of the rats, and neuron viability were evaluated. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were detected. Besides, the regulatory effects of Dex on MALAT1, miR-140-5p, and Nrf2 expression levels and regulatory relationships among them were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and dual-luciferase reporter assay. Results: Dex significantly alleviated the neurological injury of rats with MCAO and promoted the viability of neurons. Dex treatment suppressed miR-140-5p expression, but elevated MALAT1 and Nrf2 expressions. MALAT1 knockdown down-regulated Nrf2 expression and promoted oxidative stress in neurons. Additionally, miR-140-5p directly targeted Nrf2, and it also functioned as a downstream target miRNA of MALAT1. Conclusion: Dex, via regulating MALAT1/miR-140-5p/Nrf2 axis, plays a neuroprotective role against I/R-induced brain injury.

Abstract WP28: A Multiscale, Anatomically, and Neurochemically Realistic In Silico Toolbox for the Simulation of Cerebrovascular Ischemia

Introduction: Despite therapeutic advances, roughly half of acute ischemic stroke (AIS) patients fail to achieve independence. Multiscale tools permitting nano- to macroscalar representations of the hemodynamic, electrical, and neurochemical disturbance in AIS are thus demanded. The vastness of potential scenarios evolving in individual patients renders full investigation into all possible courses of disease unattainable in human or animal subjects. Digital phantoms have proliferated in the precision medicine era, yet such frameworks remain immature in neuroscience. Here, we introduce a realistic simulation toolbox governed by a vast parameter space to model AIS. Methods: A numerical implementation of a 4-compartment (neuronal, astrocytic, extracellular, and capillary) model (www.cellml.org) was modified to simulate evolution of AIS, including the dynamic interplay of >80 neurochemical processes related to cellular energetics and tuned with hemodynamic (e.g. CBF) aberrations relevant to the neurovascular unit. Two different ischemic conditions are simulated to illustrate use of the framework: i. ~50% CBF reduction; ii. ~80% CBF reduction. Results: As seen in Fig. 1, while a 50% reduction in CBF reduces glucose concentration ([GLC]) in extracellular, glial, and neuronal spaces, ATP concentrations are maintained (with glial levels dropping slightly in order that glial cells can offer support to neuronal function), and sodium concentrations ([Na+]) in both cell spaces remain constant. By comparison, an 80% CBF reduction yields falling [ATP], such that Na homeostasis is disturbed and dynamic alterations in [Na+] in the cellular compartments can be observed, leading to time-dependent cytotoxicity. Conclusion: We present a digital model and generalized framework for modeling the evolution of hemodynamic, thermal, ionic, and other disturbances in AIS, conceived as a multifaceted tool for hypothesis building and testing pathologic scenarios

Rapid changes in synchronizability in conductance-based neuronal networks with conductance-based coupling.

Real neurons connect to each other non-randomly. These connectivity graphs can potentially impact the ability of networks to synchronize, along with the dynamics of neurons and the dynamics of their connections. How the connectivity of networks of conductance-based neuron models like the classical Hodgkin-Huxley model or the Morris-Lecar model impacts synchronizability remains unknown. One powerful tool to resolve the synchronizability of these networks is the master stability function (MSF). Here, we apply and extend the MSF approach to networks of Morris-Lecar neurons with conductance-based coupling to determine under which parameters and for which graphs the synchronous solutions are stable. We consider connectivity graphs with a constant non-zero row sum, where the MSF approach can be readily extended to conductance-based synapses rather than the more well-studied diffusive connectivity case, which primarily applies to gap junction connectivity. In this formulation, the synchronous solution is a single, self-coupled, or "autaptic" neuron. We find that the primary determining parameter for the stability of the synchronous solution is, unsurprisingly, the reversal potential, as it largely dictates the excitatory/inhibitory potential of a synaptic connection. However, the change between "excitatory" and "inhibitory" synapses is rapid, with only a few millivolts separating stability and instability of the synchronous state for most graphs. We also find that for specific coupling strengths (as measured by the global synaptic conductance), islands of synchronizability in the MSF can emerge for inhibitory connectivity. We verified the stability of these islands by direct simulation of pairs of neurons coupled with eigenvalues in the matching spectrum.

Context association in pyramidal neurons through local synaptic plasticity in apical dendrites.

The unique characteristics of neocortical pyramidal neurons are thought to be crucial for many aspects of information processing and learning in the brain. Experimental data suggests that their segregation into two distinct compartments, the basal dendrites close to the soma and the apical dendrites branching out from the thick apical dendritic tuft, plays an essential role in cortical organization. A recent hypothesis states that layer 5 pyramidal cells associate top-down contextual information arriving at their apical tuft with features of the sensory input that predominantly arrives at their basal dendrites. It has however remained unclear whether such context association could be established by synaptic plasticity processes. In this work, we formalize the objective of such context association learning through a mathematical loss function and derive a plasticity rule for apical synapses that optimizes this loss. The resulting plasticity rule utilizes information that is available either locally at the synapse, through branch-local NMDA spikes, or through global Ca2+events, both of which have been observed experimentally in layer 5 pyramidal cells. We show in computer simulations that the plasticity rule enables pyramidal cells to associate top-down contextual input patterns with high somatic activity. Furthermore, it enables networks of pyramidal neuron models to perform context-dependent tasks and enables continual learning by allocating new dendritic branches to novel contexts.

A novel image encryption scheme based on ccnn

With the advancement of computational capacity, the key space will become one of the crucial factors influencing the security of digital cryptographic systems. Despite chaotic-based digital cryptographic systems possessing large key spaces, the post-Moore’s era rapid growth in computational capacity continues to pose challenges to the security of chaotic-based cryptographic systems. To address this issue, a novel image encryption scheme based on non-autonomous chaotic system is presented in this paper. In particular, a brain inspired neuron called continuous-coupled neural network (CCNN) is utilized to design image encryption scheme. To achieve the efficient image encryption scheme, firstly, the CCNN model is simplified to uncoupled-linking neuron model. The dynamic behavior under various driving signals is studied. The analysis showed that uncoupled-linking CCNN neuron exhibit various dynamic behavior under sine waves, triangular waves, sawtooth, superimposed sine waves, etc. Secondly, the decorrelation operation method is utilized to enhance the pseudo-randomness of the sequence. On this basis, thirdly, the image encryption scheme is proposed. It uses bit-level pixel scrambling, row scrambling, column scrambling and diffusion to modify the pixel value and the pixel position of the image. Security analysis shows that the proposed scheme is able to resist differential attack, statistics attack, known-plaintext attack and brute force attack. Moreover, the key space of the proposed scheme can be extended by the combination of drive signals. This unique feature makes the key space of the proposed scheme to be infinite, leading this kind of chaos-based cryptographic system to be a competitive candidate in post-Moore’s era.

NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport

BackgroundBioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) in CNS neurons. NMNAT2 mRNA levels are reduced in the brains of Alzheimer’s, Parkinson’s, and Huntington’s disease. Here we addressed whether NMNAT2 is required for axonal health of cortical glutamatergic neurons, whose long-projecting axons are often vulnerable in neurodegenerative conditions. We also tested if NMNAT2 maintains axonal health by ensuring axonal ATP levels for axonal transport, critical for axonal function.MethodsWe generated mouse and cultured neuron models to determine the impact of NMNAT2 loss from cortical glutamatergic neurons on axonal transport, energetic metabolism, and morphological integrity. In addition, we determined if exogenous NAD supplementation or inhibiting a NAD hydrolase, sterile alpha and TIR motif-containing protein 1 (SARM1), prevented axonal deficits caused by NMNAT2 loss. This study used a combination of techniques, including genetics, molecular biology, immunohistochemistry, biochemistry, fluorescent time-lapse imaging, live imaging with optical sensors, and anti-sense oligos.ResultsWe provide in vivo evidence that NMNAT2 in glutamatergic neurons is required for axonal survival. Using in vivo and in vitro studies, we demonstrate that NMNAT2 maintains the NAD-redox potential to provide “on-board” ATP via glycolysis to vesicular cargos in distal axons. Exogenous NAD+ supplementation to NMNAT2 KO neurons restores glycolysis and resumes fast axonal transport. Finally, we demonstrate both in vitro and in vivo that reducing the activity of SARM1, an NAD degradation enzyme, can reduce axonal transport deficits and suppress axon degeneration in NMNAT2 KO neurons.ConclusionNMNAT2 ensures axonal health by maintaining NAD redox potential in distal axons to ensure efficient vesicular glycolysis required for fast axonal transport.

Dynamic Gain Decomposition Reveals Functional Effects of Dendrites, Ion Channels, and Input Statistics in Population Coding.

Modern, high-density neuronal recordings reveal at ever higher precision how information is represented by neural populations. Still, we lack the tools to understand these processes bottom-up, emerging from the biophysical properties of neurons, synapses, and network structure. The concept of the dynamic gain function, a spectrally resolved approximation of a population's coding capability, has the potential to link cell-level properties to network-level performance. However, the concept is not only useful but also very complex because the dynamic gain's shape is co-determined by axonal and somato-dendritic parameters and the population's operating regime. Previously, this complexity precluded an understanding of any individual parameter's impact. Here, we decomposed the dynamic gain function into three components corresponding to separate signal transformations. This allowed attribution of network-level encoding features to specific cell-level parameters. Applying the method to data from real neurons and biophysically plausible models, we found: (1) The encoding bandwidth of real neurons, approximately 400 Hz, is constrained by the voltage dependence of axonal currents during early action potential initiation. (2) State-of-the-art models only achieve encoding bandwidths around 100 Hz and are limited mainly by subthreshold processes instead. (3) Large dendrites and low-threshold potassium currents modulate the bandwidth by shaping the subthreshold stimulus-to-voltage transformation. Our decomposition provides physiological interpretations when the dynamic gain curve changes, for instance during spectrinopathies and neurodegeneration. By pinpointing shortcomings of current models, it also guides inference of neuron models best suited for large-scale network simulations.

A novel memristive neuron model and its energy characteristics

A novel memristive neuron model and its energy characteristics

Switching dynamics of a Filippov memristive Hindmash–Rose neuron model with time delay

Considering the existence of magnetic induction effect with different intensities in the process of subthreshold and suprathreshold oscillations of bioelectrical activities, a non-smooth feedback strategy for memristive current with time delay is proposed, and then a four-dimensional Filippov Hindmarsh–Rose (HR) neuron model is established. The local stability and bifurcation patterns of delayed subsystems are qualitatively analyzed. Accordingly, the discriminant formula for the direction and stability of periodic solutions generated by Hopf bifurcation is obtained on the center manifold. Importantly, the stability of subsystems has switching behavior, which is accompanied by abundant hidden electrical activities under the effect of time delay. The theoretical analysis clarifies that the proposed feedback strategy leads to complex sliding mode dynamics, including sliding segments, various equilibrium points and sliding bifurcations. Meanwhile, the analytical conditions for motions of grazing, sliding, and crossing are developed and verified based on the flow switching theory. Moreover, the mechanism and evolutive rule of the self-excited and hidden sliding electrical activities are revealed by the fast-slow variable dissection method. Finally, it is verified that the time delay can not only induce bistable structures composed of the quiescent state and periodic bursting, but also eliminate the hidden sliding dynamics.

Effect of Hydroxytyrosol Derivatives of Donepezil on the Activity of Enzymes Involved in Neurodegenerative Diseases and Oxidative Damage.

Monoamine oxidase and xanthine oxidase inhibitors represent useful multi-target drugs for the prevention, attenuation, and treatment of oxidative damage and neurodegenerative disorders. Chimeric molecules, constituted by naturally derived compounds linked to drugs, represent lead compounds to be explored for the discovery of new synthetic drugs acting as enzyme inhibitors. We have previously reported that seven hydroxytyrosol-donepezil hybrid compounds play a protective role in an in vitro neuronal cell model of Alzheimer's disease. In this work, we analyzed the effects exerted by the hybrid compounds on the activity of monoamine oxidase A (MAO-A) and B (MAO-B), as well as on xanthine oxidase (XO), enzymes involved in both neurodegenerative disorders and oxidative stress. The results pointed to the identification, among the compounds tested, of selective inhibitors between the two classes of enzymes. While the 4-hydroxy-3-methoxyphenethyl 1-benzylpiperidine-4-carboxylate- (HT3) and the 4-hydroxyphenethyl 1-benzylpiperidine-4-carboxylate- donepezil derivatives (HT4) represented the best inhibitors of MAO-A, with a scarce effect on MAO-B, they were almost ineffective on XO. On the other hand, the 4,5-dihydroxy-2-nitrophenethyl 1-benzylpiperidine-4-carboxylate donepezil derivative (HT2), the least efficient MAO inhibitor, acted like the best XO inhibitor. Therefore, the differential enzymatic targets identified among the hybrid compounds synthesized enhance the possible applications of these polyphenol-donepezil hybrids in neurodegenerative disorders and oxidative stress.

Celastrol inhibits oligodendrocyte and neuron ferroptosis to promote spinal cord injury recovery

BackgroundSpinal cord injury (SCI) is a traumatic injury to the central nervous system and can cause lipid peroxidation in the spinal cord. Ferroptosis, an iron-dependent programmed cell death, plays a key role in the pathophysiology progression of SCI. Celastrol, a widely used antioxidant drug, has potential therapeutic value for nervous system. PurposeTo investigate whether celastrol can be a reliable candidate for ferroptosis inhibitor and the molecular mechanism of celastrol in repairing SCI by inhibiting ferroptosis. MethodsFirst, a rat SCI model was constructed, and the recovery of motor function was observed after treatment with celastrol. The regulatory effect of celastrol on ferroptosis pathway Nrf2-xCT-GPX4 was detected by Western blot and immunofluorescence. Finally, the ferroptosis model of neurons and oligodendrocytes was constructed in vitro to further verify the mechanism of inhibiting ferroptosis by celastrol. ResultsOur results demonstrated that celastrol promoted the recovery of spinal cord tissue and motor function in SCI rats. Further in vitro and in vivo studies showed that celastrol significantly inhibited ferroptosis in neurons and oligodendrocytes and reduced the accumulation of ROS. Finally, we found that celastrol could inhibit ferroptosis by up-regulating the Nrf2-xCT-GPX4 axis to repair SCI. ConclusionCelastrol effectively inhibits ferroptosis after SCI by upregulating the Nrf2-xCT-GPX4 axis, reducing the production of lipid ROS, protecting the survival of neurons and oligodendrocytes, and improving the functional recovery.