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Spindle-shaped waves of oscillations emerge in EEG scalp recordings during human and rodent non-REM sleep. The association of these 10-16 Hz oscillations with events during prior wakefulness suggests a role in memory consolidation. Human and rodent depth electrodes in the brain record strong spindles throughout the cortex and hippocampus, with possible origins in the thalamus. However, the source and targets of the spindle oscillations from the hippocampus are unclear. Here, we employed an in vitro reconstruction of four subregions of the hippocampal formation with separate microfluidic tunnels for single axon communication between subregions assembled on top of a microelectrode array. We recorded spontaneous 400-1000 ms long spindle waves at 10-16 Hz in single axons passing between subregions as well as from individual neurons in those subregions. Spindles were nested within slow waves. The highest amplitudes and most frequent occurrence suggest origins in CA3 neurons that send feed-forward axons into CA1 and feedback axons into DG. Spindles had 50-70% slower conduction velocities than spikes and were not phase-locked to spikes suggesting that spindle mechanisms are independent of action potentials. Therefore, consolidation of declarative-cognitive memories in the hippocampus may be separate from the more easily accessible consolidation of memories related to thalamic motor function.

Stroke, trauma, and neurodegenerative disorders cause loss of neurites (axons and dendrites) in addition to neuronal death. Neurite loss may result directly from a primary insult, secondary to parental neuron death, or secondary to a post-injury inflammatory response. Here, we use lipopolysaccharide and the alarmin S100β to selectively evaluate neurite loss caused by the inflammatory response. Activation of microglia and infiltrating macrophages by these stimuli causes neurite loss that far exceeds neuronal death, both in vitro and in vivo. Neurite loss is accompanied by the formation of cofilactin rods and aggregates (CARs), which are polymers of cofilin-1 and actin induced by oxidative stress and other factors. Mice deficient in either cofilin-1 or the superoxide-generating enzyme NADPH oxidase-2 show reduced CAR formation, neurite loss, and motor impairment. The findings identify a mechanism by which inflammation leads to neurite loss via CAR formation and highlight the relevance of neurite loss to functional impairment.

Neuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by spheroid (swollen axon) formation in the nervous system. In the present study, we focused on a newly established autosomal recessive mutant strain of F344-kk/kk rats with hind limb gait abnormalities and ataxia from a young age. Histopathologically, a number of axonal spheroids were observed throughout the central nervous system, including the spinal cord (mainly in the dorsal cord), brain stem, and cerebellum in F344-kk/kk rats. Transmission electron microscopic observation of the spinal cord revealed accumulation of electron-dense bodies, degenerated abnormal mitochondria, as well as membranous or tubular structures in the axonal spheroids. Based on these neuropathological findings, F344-kk/kk rats were diagnosed with NAD. By a positional cloning approach, we identified a missense mutation (V95E) in the Hspa8 (heat shock protein family A (Hsp70) member 8) gene located on chromosome 8 of the F344-kk/kk rat genome. Furthermore, we developed the Hspa8 knock-in (KI) rats with the V95E mutation using the CRISPR-Cas system. Homozygous Hspa8-KI rats exhibited ataxia and axonal spheroids similar to those of F344-kk/kk rats. The V95E mutant HSC70 protein exhibited the significant but modest decrease in the maximum hydrolysis rate of ATPase when stimulated by co-chaperons DnaJB4 and BAG1 in vitro, which suggests the functional deficit in the V95E HSC70. Together, our findings provide the first evidence that the genetic alteration of the Hspa8 gene caused NAD in mammals.

A review of different models of spike neural networks has been conducted. A spike type neural network is developed in the article. The mathematical model of exchange of neurotransmitters between neurons is proposed. An algorithm for network operation and neuron interaction is proposed, as well as an approach to training the network based on the formation of new connections from dendrites and increasing the signal transmission coefficient. The model of neural network was created in Python using the developed algorithm and mathematical model. To speed up the calculations, they were paralleled using the Numba library. The library Matplotlib was used for visual modelling and plotting the number of neurotransmitters on neurons. Experimental studies of the developed model of biological type network were carried out. It was shown that the developed network after training responds faster to the signals that were applied to it in the process of training. [ABSTRACT FROM AUTHOR]

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is an uncommon entity and a rare cause of third cranial nerve palsy. We review the case of a 17-year-old male with a 9-month history of progressive left third cranial nerve palsy. Cerebral magnetic resonance image showed a left clinoidal lesion with low signal intensity in T2 and T1 sequences with signs of calcification in the computed tomography and without vascular lesion in AngioMRI. A left pterional approach was performed with posterior clinoidectomy and total resection of the lesion. Calcifying pseudoneoplasm of the neuraxis is an infrequent pathology that presents in the skull base and spine that requires surgical treatment in the presence of compressive phenomena and differential diagnosis as meningioma, chordoma, and metastasis should be considered. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aβ axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia. [ABSTRACT FROM AUTHOR]

The neuronal endoplasmic reticulum (ER) consists of a dynamic, tubular network that extends all the way from the soma into dendrites, axons, and synapses. This morphology gives rise to an enormous membrane surface area that, through the presence of tethering proteins, lipid transfer proteins, and ion channels, plays critical roles in local calcium regulation, membrane dynamics, and the supply of ions and lipids to other organelles. Here, we summarize recent advances that highlight the various roles of the neuronal ER in axonal growth, repair, and presynaptic function. We review the variety of contact sites between the ER and other axonal organelles and describe their influence on neurodevelopment and neurotransmission. [ABSTRACT FROM AUTHOR]

Rotenone is a mitochondrial complex I inhibitor that causes retinal degeneration. A study of a rat model of rotenone-induced retinal degeneration suggested that this model is caused by indirect postsynaptic N-methyl-D-aspartate (NMDA) stimulation triggered by oxidative stress-mediated presynaptic intracellular calcium signaling. To elucidate the mechanisms by which rotenone causes axonal degeneration, we investigated morphological changes in optic nerves and the change in retinal ganglion cell (RGC) number in rats. Optic nerves and retinas were collected 3 and 7 days after the intravitreal injection of rotenone. The cross-sections of the optic nerves were subjected to a morphological analysis with axon quantification. The axons and somas of RGCs were analyzed immunohistochemically in retinal flatmounts. In the optic nerve, rotenone induced axonal swelling and degeneration with the incidence of reactive gliosis. Rotenone also significantly reduced axon numbers in the optic nerve. Furthermore, rotenone caused axonal thinning, fragmentation, and beading in RGCs on flatmounts and decreased the number of RGC soma. In conclusion, the intravitreal injection of rotenone in rats induced morphological abnormities with a reduced number of optic nerve axons and RGC axons when the RGC somas were degenerated. These findings help elucidate the pathogenesis of optic neuropathy induced by mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Abstract Accessory nerve (CNXI) has been known to be the primary conduit for motor control of the trapezius, while the supplementary cervical nerves (C3 and C4) are responsible for processing sensory information from muscle. However, the lack of substantial direct evidence has led to these conclusions being regarded as mere speculation. This study used immunostaining (using antibodies against neurofilament 200 for all axons, choline acetyltransferase for cholinergic axons, tyrosine hydroxylase for sympathetic axons, and alpha 3 sodium potassium ATPase for proprioceptive afferent axons) of human samples to verify the functional contributions of nerves. Study highlights the pivotal role of C3 and C4 in regulating precise movements of trapezius, contributing to motor control, proprioceptive feedback, and sympathetic modulation. CNXI is composed primarily of somatic efferent fibers, with significant numbers of sympathetic or sensory fibers. Furthermore, C3-4 have both cholinergic and non-cholinergic axons, suggesting their involvement in proprioceptive feedback and somatic efferent functions. Although less common, mechanosensors such as nociceptive sensor and sympathetic fibers are also supplied by these cervical nerves. The study demonstrated that these nerves contain motor fibers and significant proprioceptive and sympathetic axons, challenging the long-held notion that CNXI are motor and upper spinal nerves are sensory.

Peripheral nerve injuries are potentially devastating injuries leading to pain and impairment in motor and sensory functions. Since the first published use of microsurgical epineural repair of peripheral nerves in 1964, a wide variety of adjuncts have been studied. Polyethylene glycol is a fusogen that has been shown to restore axolemmal membranes. The use of polyethylene glycol in nerve injuries was first described in 1986, and animal studies have shown fusion of transected sensory and motor nerves following early application at the time of surgical repair with improved motor and sensory outcomes. Early human clinical trials have shown promising results, although more data are needed to provide specific indications and protocols. This article summarizes the background, current evidence, and future directions as well as potential applications of polyethylene glycol–mediated nerve fusion.

Abstract Neurons, exhibiting unique polarized structures, rely primarily on the mitochondrial production of ATP to maintain their hypermetabolic energy requirements. To maintain a normal energy supply, mitochondria are transported to the distal end of the axon. When mitochondria within the axon are critically damaged beyond their compensatory capacity, they are cleared via autophagosomal phagocytosis, and the degradation products are recycled to replenish energy. When the mitochondria are dysfunctional or their transport processes are blocked, axons become susceptible to degeneration triggered by energy depletion, resulting in neurodegenerative diseases. As the final checkpoint for mitochondrial quality control, axonal mitophagy is vital for neuronal growth, development, injury, and regeneration. Furthermore, abnormal axonal mitophagy is crucial in the pathogenesis of optic nerve-related diseases such as glaucoma. We review recent studies on axonal mitophagy and summarize the progress of research on axonal mitophagy in optic nerve-related diseases to provide insights into diseases associated with axonal damage in optic ganglion cells.

This editorial published in the journal Frontiers in Cellular Neuroscience discusses the significance of myelination and remyelination in the nervous system. Myelin, which surrounds nerve axons, is essential for proper nervous system development and function. Disruptions in myelination can lead to neurological deficits, but the nervous system has the ability to repair itself through remyelination. The editorial highlights recent advancements in neuroimaging and cellular biology that enhance our understanding of myelin dynamics and the potential for targeted interventions in neurological disorders. The article also explores the transcriptional control of myelination and remyelination in the central nervous system, emphasizing the importance of understanding these mechanisms for potential therapeutic interventions in demyelinating diseases. Additionally, another article mentioned in the editorial provides insights into the molecular and cellular processes involved in initial myelination in the central nervous system. These articles contribute to our understanding of the complex processes underlying myelination and offer potential avenues for further research and treatment development. [Extracted from the article]

Myelin is a vital structure that is key to rapid saltatory conduction in the central and peripheral nervous systems. Much work has been done over the decades examining the biochemical composition and morphology of myelin at the light and electron microscopic levels. Here we report a method to study myelin based on the fluorescent probe Nile Red. This lipophilic dye readily partitions into live and chemicallyfixed myelin producing bright, well‐resolved images of the sheath. Using spectral confocal microscopy, a complete emission spectrum of Nile Red fluorescence can be acquired for each pixel in an image. The solvatochromic properties of Nile Red cause its emission spectrum to change depending on the polarity of its local environment. Therefore, measuring spectral shifts can report subtle changes in the physicochemical properties of myelin. We show differences in myelin polarity in central versus peripheral nervous system and in different regions of central nervous system white matter of the mouse brain, together with developmental and sex variations. This technique is also well suited for measuring subtle changes in myelin properties in live ex vivo white matter specimens. We also demonstrate how light deprivation induces a myelin polarity change in adult mouse optic nerve underscoring a continuing myelin plasticity in response to axonal activity well into adulthood. The Nile Red spectroscopic method allows measurement of subtle physicochemical changes in myelin that can importantly influence its electrical properties and by extension, conduction velocities in axons. [ABSTRACT FROM AUTHOR]

In humans and other adult mammals, axon regeneration is difficult in axotomized neurons. Therefore, spinal cord injury (SCI) is a devastating event that can lead to permanent loss of locomotor and sensory functions. Moreover, the molecular mechanisms of axon regeneration in vertebrates are not very well understood, and currently, no effective treatment is available for SCI. In striking contrast to adult mammals, many nonmammalian vertebrates such as reptiles, amphibians, bony fishes and lampreys can spontaneously resume locomotion even after complete SCI. In recent years, rapid progress in the development of next‐generation sequencing technologies has offered valuable information on SCI. In this review, we aimed to provide a comparison of axon regeneration process across classical model organisms, focusing on crucial genes and signalling pathways that play significant roles in the regeneration of individually identifiable descending neurons after SCI. Considering the special evolutionary location and powerful regenerative ability of lamprey and zebrafish, they will be the key model organisms for ongoing studies on spinal cord regeneration. Detailed study of SCI in these model organisms will help in the elucidation of molecular mechanisms of neuron regeneration across species. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders, including traumatic injuries to the central nervous system (CNS) and neurodegenerative diseases, are characterized by early axonal damage, which does not regenerate in the adult mammalian CNS, leading to permanent neurological deficits. One of the primary causes of the loss of regenerative ability is thought to be a developmental decline in neurons' intrinsic capability for axon growth. Different molecules are involved in the developmental loss of the ability for axon regeneration, including many transcription factors. However, the function of microRNAs (miRNAs), which are also modulators of gene expression, in axon re-growth is still unclear. Among the various miRNAs recently identified with roles in the CNS, miR-17, which is highly expressed during early development, emerges as a promising target to promote axon regeneration. Here, we used adeno-associated viral (AAV) vectors to overexpress miR-17 (AAV.miR-17) in primary cortical neurons and evaluate its effects on neurite and axon regeneration in vitro. Although AAV.miR-17 had no significant effect on neurite outgrowth and arborization, it significantly enhances neurite regeneration after scratch lesion and axon regeneration after axotomy of neurons cultured in microfluidic chambers. Target prediction and functional annotation analyses suggest that miR-17 regulates gene expression associated with autophagy and cell metabolism. Our findings suggest that miR-17 promotes regenerative response and thus could mitigate neurodegenerative effects. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) remodeling is vital for cellular organization. ER-phagy, a selective autophagy targeting ER, plays an important role in maintaining ER morphology and function. The FAM134 protein family, including FAM134A, FAM134B, and FAM134C, mediates ER-phagy. While FAM134B mutations are linked to hereditary sensory and autonomic neuropathy in humans, the physiological role of the other FAM134 proteins remains unknown. To address this, we investigate the roles of FAM134 proteins using single and combined knockouts (KOs) in mice. Single KOs in young mice show no major phenotypes; however, combined Fam134b and Fam134c deletion (Fam134b/c dKO ), but not the combination including Fam134a deletion, leads to rapid neuromuscular and somatosensory degeneration, resulting in premature death. Fam134b/c dKO mice show rapid loss of motor and sensory axons in the peripheral nervous system. Long axons from Fam134b/c dKO mice exhibit expanded tubular ER with a transverse ladder-like appearance, whereas no obvious abnormalities are present in cortical ER. Our study unveils the critical roles of FAM134C and FAM134B in the formation of tubular ER network in axons of both motor and sensory neurons. Synopsis: Combined deletion of Fam134b and Fam134c in mice results in rapid axonal degeneration, highlighting the critical role of FAM134 proteins in preserving axonal architecture and function by controlling tubular ER organization in vivo. Combined deletion of Fam134b and Fam134c (Fam134b/c dKO ) in mice leads to growth retardation, neurological defects, and premature death. Fam134b/c dKO mice exhibit sensory and motor axonal degeneration without showing defects in the neuronal cell bodies. Fam134b and Fam134c play critical roles in shaping the tubular ER network along axons. Combined deletion of Fam134b and Fam134c in mice results in rapid axonal degeneration, highlighting the critical role of FAM134 proteins in preserving axonal architecture and function by controlling tubular ER organization in vivo. [ABSTRACT FROM AUTHOR]

Background: During neurogenesis, growing axons must navigate through the complex extracellular environment and make correct synaptic connections for the proper functioning of neural circuits. The mechanisms underlying the formation of functional neural networks are still only partially understood. Results: Here we analyzed the role of a novel gene si:ch73‐364h19.1/drish in the neural and vascular development of zebrafish embryos. We show that drish mRNA is expressed broadly and dynamically in multiple cell types including neural, glial, retinal progenitor and vascular endothelial cells throughout the early stages of embryonic development. To study Drish function during embryogenesis, we generated drish genetic mutant using CRISPR/Cas9 genome editing. drish loss‐of‐function mutant larvae displayed defects in early retinal ganglion cell, optic nerve and the retinal inner nuclear layer formation, as well as ectopic motor axon branching. In addition, drish mutant adults exhibited deficient retinal outer nuclear layer and showed defective light response and locomotory behavior. However, vascular patterning and blood circulation were not significantly affected. Conclusions: Together, these data demonstrate important roles of zebrafish drish in the retinal ganglion cell, optic nerve and interneuron development and in spinal motor axon branching. Key Findings: si:ch73‐364h19.1 / drish gene encodes a putative transmembrane protein, which is expressed in neural, glial and vascular endothelial cells in zebrafish embryos.Drish zebrafish mutants show defects in retinal ganglion cell differentiation.Drish mutants exhibit defective branching of motor axons.Drish mutant larvae and adults display reduced swimming activity, a defective light response and deficient prey capture. [ABSTRACT FROM AUTHOR]

Axons are long slender portions of neurons that transmit electrical impulses to maintain proper physiological functioning. Axons in the central nervous system (CNS) and peripheral nervous system (PNS) do not exist in isolation but are found to form a complex association with their surrounding glial cells, oligodendrocytes and Schwann cells. These cells not only myelinate them for faster nerve impulse conduction but are also known to provide metabolic support. Due to their incredible length, continuous growth, and distance from the cell body (where major energy synthesis takes place), axons are in high energetic demand. The stability and integrity of axons have long been associated with axonal energy levels. The current mini-review is thus focused on how axons accomplish their high energetic requirement in a cell-autonomous manner and how the surrounding glial cells help them in maintaining their integrity by fulfilling their energy demands (non-cell autonomous trophic support). The concept that adjacent glial cells (oligodendrocytes and Schwann cells) provide trophic support to axons and assist them in maintaining their integrity comes from the conditional knockout research and the studies in which the metabolic pathways controlling metabolism in these glial cells are modulated and its effect on axonal integrity is evaluated. In the later part of the mini-review, the current knowledge of axon-glial metabolic coupling during various neurodegenerative conditions was discussed, along with the potential lacunae in our current understanding of axon-glial metabolic coupling. [ABSTRACT FROM AUTHOR]

Neurons, exhibiting unique polarized structures, rely primarily on the mitochondrial production of ATP to maintain their hypermetabolic energy requirements. To maintain a normal energy supply, mitochondria are transported to the distal end of the axon. When mitochondria within the axon are critically damaged beyond their compensatory capacity, they are cleared via autophagosomal phagocytosis, and the degradation products are recycled to replenish energy. When the mitochondria are dysfunctional or their transport processes are blocked, axons become susceptible to degeneration triggered by energy depletion, resulting in neurodegenerative diseases. As the final checkpoint for mitochondrial quality control, axonal mitophagy is vital for neuronal growth, development, injury, and regeneration. Furthermore, abnormal axonal mitophagy is crucial in the pathogenesis of optic nerve-related diseases such as glaucoma. We review recent studies on axonal mitophagy and summarize the progress of research on axonal mitophagy in optic nerve-related diseases to provide insights into diseases associated with axonal damage in optic ganglion cells. [ABSTRACT FROM AUTHOR]

A potassium channel blocker 4-AP has been shown to exert pronounced convulsive action to generate burst firings when applied to hippocampal slices. However, it remains unclear how the blockade of potassium channels leads to the generation of burst firings. One possibility is ectopic spiking from the sites different from those for physiological spike initiation at the axon initial segment, as suggested for several experimental models of epileptogenesis in vitro. To test for possible ectopic spiking at the distal axon by 4-AP application, direct recordings from large mossy fiber terminals were made with the loosepatch clamp technique in mouse hippocampal slices. To localize the action of 4-AP on the distal axon, focal perfusion, as well as micro-cut to disconnect soma and distal axons, were adopted. Focal application of 4-AP on the distal portion of mossy fibers reliably induced burst discharges of the mossy fiber terminals. Photochemical blockade of potassium channels at distal axons, by the application of RuBi-4-AP, a visible wavelength blue light-sensitive caged compound, and the illumination of blue light caused robust bursting activity originating from distal axons. Computer simulation suggested that local blockade of axonal potassium channels prolongs the duration of action potentials and thereby causes reverberating spiking activities at distal axons and subsequent antidromic propagation toward the soma. Taken together, it was suggested that local blockade of voltage-dependent potassium channels in distal axons by application of 4-AP is sufficient to cause a hyperexcitable state of hippocampal mossy fiber axons. [ABSTRACT FROM AUTHOR]

Myelinated axons conduct action potentials, or spikes, in a saltatory manner. Inward current caused by a spike occurring at one node of Ranvier spreads axially to the next node, which regenerates the spike when depolarized enough for voltage-gated sodium channels to activate, and so on. The rate at which this process progresses dictates the velocity at which the spike is conducted and depends on several factors including axial resistivity and axon diameter that directly affect axial current. Here we show through computational simulations in modified double-cable axon models that conduction velocity also depends on extracellular factors whose effects can be explained by their indirect influence on axial current. Specifically, we show that a conventional double-cable model, with its outside layer connected to ground, transmits less axial current than a model whose outside layer is less absorptive. A more resistive barrier exists when an axon is packed tightly between other myelinated fibers, for example. We show that realistically resistive boundary conditions can significantly increase the velocity and energy efficiency of spike propagation, while also protecting against propagation failure. Certain factors like myelin thickness may be less important than typically thought if extracellular conditions are more resistive than normally considered. We also show how realistically resistive boundary conditions affect ephaptic interactions. Overall, these results highlight the unappreciated importance of extracellular conditions for axon function. [ABSTRACT FROM AUTHOR]

Biological structures have evolved to very efficiently generate, transmit, and withstand mechanical forces. These biological examples have inspired mechanical engineers for centuries and led to the development of critical insights and concepts. However, progress in mechanical engineering also raises new questions about biological structures. The past decades have seen the increasing study of failure of engineered structures due to repetitive loading, and its origin in processes such as materials fatigue. Repetitive loading is also experienced by some neurons, for example in the peripheral nervous system. This perspective, after briefly introducing the engineering concept of mechanical fatigue, aims to discuss the potential effects based on our knowledge of cellular responses to mechanical stresses. A particular focus of our discussion are the effects of mechanical stress on axons and their cytoskeletal structures. Furthermore, we highlight the difficulty of imaging these structures and the promise of new microscopy techniques. The identification of repair mechanisms and paradigms underlying long-term stability is an exciting and emerging topic in biology as well as a potential source of inspiration for engineers. [ABSTRACT FROM AUTHOR]

Sterile alpha and TIR motif containing 1 (SARM1) is an inducible NADase that localizes to mitochondria throughout neurons and senses metabolic changes that occur after injury. Minimal proteomic changes are observed upon either SARM1 depletion or activation, suggesting that SARM1 does not exert broad effects on neuronal protein homeostasis. However, whether SARM1 activation occurs throughout the neuron in response to injury and cell stress remains largely unknown. Using a semiautomated imaging pipeline and a custom-built deep learning scoring algorithm, we studied degeneration in both mixed-sex mouse primary cortical neurons and male human-induced pluripotent stem cell-derived cortical neurons in response to a number of different stressors. We show that SARM1 activation is differentially restricted to specific neuronal compartments depending on the stressor. Cortical neurons undergo SARM1-dependent axon degeneration after mechanical transection, and SARM1 activation is limited to the axonal compartment distal to the injury site. However, global SARM1 activation following vacor treatment causes both cell body and axon degeneration. Context-specific stressors, such as microtubule dysfunction and mitochondrial stress, induce axonal SARM1 activation leading to SARM1-dependent axon degeneration and SARM1-independent cell body death. Our data reveal that compartment-specific SARM1–mediated death signaling is dependent on the type of injury and cellular stressor. [ABSTRACT FROM AUTHOR]

In humans, MAPK8IP3 (also known as JIP3) is a neurodevelopmental disorder-associated gene. In Caenorhabditis elegans , the UNC-16 ortholog of the MAPK8IP3 protein can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1 (LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3 , 2 genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3. [ABSTRACT FROM AUTHOR]

Myelin sheath, as the multilayer dense structure enclosing axons in humans and other higher organisms, may rupture due to various injury factors after spinal cord injury, thus producing myelin debris. The myelin debris contains a variety of myelin-associated inhibitors (MAIs) and lipid, all inhibiting the repair after spinal cord injury. Through summary and analysis, the present authors found that the inhibition of myelin debris can be mainly divided into two categories: firstly, the direct inhibition mediated by MAIs; secondly, the indirect inhibition mediated by lipid such as cholesterol. It is worth noting that phagocytes are required in the latter indirect inhibition, such as professional phagocytes (macrophages et al.) and non-professional phagocytes (astrocytes et al.). Moreover, complement and the immune system also participate in the phagocytosis of myelin debris, working together with phagocytes to aggravate spinal cord injury. In conclusion, this paper focuses on the direct and indirect effects of myelin debris on spinal cord injury, aiming to provide new inspiration and reflection for the basic research of spinal cord injury and the conception of related treatment.

Dual leucine zipper kinase (DLK) mediates multiple neuronal stress responses, and its expression levels are constantly suppressed to prevent excessive stress signaling. We found that Wallenda (Wnd), the Drosophila ortholog of DLK, is highly enriched in the axon terminals of Drosophila sensory neurons in vivo and that this subcellular localization is necessary for Highwire-mediated Wnd protein turnover under normal conditions. Our structure-function analysis found that Wnd palmitoylation is essential for its axon terminal localization. Palmitoylation-defective Wnd accumulated in neuronal cell bodies, exhibited dramatically increased protein expression levels, and triggered excessive neuronal stress responses. Defective intracellular transport is implicated in neurodegenerative conditions. Comprehensive dominant-negative Rab protein screening identified Rab11 as an essential factor for Wnd localization in axon terminals. Consequently, Rab11 loss-of-function increased the protein levels of Wnd and induced neuronal stress responses. Inhibiting Wnd activity significantly ameliorated neuronal loss and c-Jun N-terminal kinase signaling triggered by Rab11 loss-of-function. Taken together, these suggest that DLK proteins are constantly transported to axon terminals for protein turnover and a failure of such transport can lead to neuronal loss. Our study demonstrates how subcellular protein localization is coupled to protein turnover for neuronal stress signaling.

Abstract Spindle-shaped waves of oscillations emerge in EEG scalp recordings during human and rodent non-REM sleep. The association of these 10–16 Hz oscillations with events during prior wakefulness suggests a role in memory consolidation. Human and rodent depth electrodes in the brain record strong spindles throughout the cortex and hippocampus, with possible origins in the thalamus. However, the source and targets of the spindle oscillations from the hippocampus are unclear. Here, we employed an in vitro reconstruction of four subregions of the hippocampal formation with separate microfluidic tunnels for single axon communication between subregions assembled on top of a microelectrode array. We recorded spontaneous 400–1000 ms long spindle waves at 10–16 Hz in single axons passing between subregions as well as from individual neurons in those subregions. Spindles were nested within slow waves. The highest amplitudes and most frequent occurrence suggest origins in CA3 neurons that send feed-forward axons into CA1 and feedback axons into DG. Spindles had 50–70% slower conduction velocities than spikes and were not phase-locked to spikes suggesting that spindle mechanisms are independent of action potentials. Therefore, consolidation of declarative-cognitive memories in the hippocampus may be separate from the more easily accessible consolidation of memories related to thalamic motor function.

ABSTRACTGlycolysis is a metabolic pathway that directly generates adenosine triphosphate (ATP), provides metabolic intermediates for anabolism, and supports mitochondrial oxidative phosphorylation. This review addresses recent advances in our understanding of the functions of neuronal glycolysis during the development of neuronal morphogenesis, focusing on the emergent concept that neuronal glycolysis serves local subcellular bioenergetic roles in maintaining neuronal function. The current evidence indicates that glycolysis is subcellularly targeted to specific organelles and molecular machinery to locally supply bioenergetic support for defined subcellular mechanisms underlying neuronal morphogenesis (i.e. axon extension, axon retraction and axonal transport). Thus, the concept of glycolysis as a “housekeeping” mechanism in neurons would benefit revision and future work aim to further define its subcellular functions at varied developmental stages.

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders (NDDs) in which children display differences in social interaction/communication and repetitive stereotyped behaviors along with variable associated features. Cul3, a gene linked to ASD, encodes CUL3 (CULLIN-3), a protein that serves as a key component of a ubiquitin ligase complex with unclear function in neurons. Cul3 homozygous deletion in mice is embryonic lethal; thus, we examine the role of Cul3 deletion in early synapse development and neuronal morphology in hippocampal primary neuronal cultures. Homozygous deletion of Cul3 significantly decreased dendritic complexity and dendritic length, as well as axon formation. Synaptic spine density significantly increased, mainly in thin and stubby spines along with decreased average spine volume in Cul3 knockouts. Both heterozygous and homozygous knockout of Cul3 caused significant reductions in the density and colocalization of gephyrin/vGAT puncta, providing evidence of decreased inhibitory synapse number, while excitatory synaptic puncta vGulT1/PSD95 density remained unchanged. Based on previous studies implicating elevated caspase-3 after Cul3 deletion, we demonstrated increased caspase-3 in our neuronal cultures and decreased neuronal cell viability. We then examined the efficacy of the caspase-3 inhibitor Z-DEVD-FMK to rescue the decrease in neuronal cell viability, demonstrating reversal of the cell viability phenotype with caspase-3 inhibition. Studies have also implicated caspase-3 in neuronal morphological changes. We found that caspase-3 inhibition largely reversed the dendrite, axon, and spine morphological changes along with the inhibitory synaptic puncta changes. Overall, these data provide additional evidence that Cul3 regulates the formation or maintenance of cell morphology, GABAergic synaptic puncta, and neuronal viability in developing hippocampal neurons in culture. [ABSTRACT FROM AUTHOR]

Myelination enables electrical impulses to propagate on axons at the highest speed, encoding essential life functions. The Rho family GTPases, RAC1 and CDC42, have been shown to critically regulate Schwann cell myelination. P21-activated kinase 2 (PAK2) is an effector of RAC1/CDC42, but its specific role in myelination remains undetermined. We produced a Schwann cell-specific knockout mouse of Pak2 (scPak2 −/−) to evaluate PAK2's role in myelination. Deletion of Pak2 , specifically in mouse Schwann cells, resulted in severe hypomyelination, slowed nerve conduction velocity and behaviour dysfunctions in the scPak2 −/− peripheral nerve. Many Schwann cells in scPak2 −/− sciatic nerves were arrested at the stage of axonal sorting. These abnormalities were rescued by reintroducing Pak2 , but not the kinase-dead mutation of Pak2 , via lentivirus delivery to scPak2 −/− Schwann cells in vivo. Moreover, ablation of Pak2 in Schwann cells blocked the promyelinating effect driven by neuregulin-1, prion protein and inactivated RAC1/CDC42. Conversely, the ablation of Pak2 in neurons exhibited no phenotype. Such PAK2 activity can also be either enhanced or inhibited by different myelin lipids. We have identified a novel promyelinating factor, PAK2, that acts as a critical convergence point for multiple promyelinating signalling pathways. The promyelination by PAK2 is Schwann cell-autonomous. Myelin lipids, identified as inhibitors or activators of PAK2, may be utilized to develop therapies for repairing abnormal myelin in peripheral neuropathies. [ABSTRACT FROM AUTHOR]

We used whole‐cell patch clamp to estimate the stationary voltage dependence of persistent sodium‐current density (iNaP) in rat hippocampal mossy fibre boutons. Cox's method for correcting space‐clamp errors was extended to the case of an isopotential compartment with attached neurites. The method was applied to voltage‐ramp experiments, in which iNaP is assumed to gate instantaneously. The raw estimates of iNaP led to predicted clamp currents that were at variance with observation, hence an algorithm was devised to improve these estimates. Optionally, the method also allows an estimate of the membrane specific capacitance, although values of the axial resistivity and seal resistance must be provided. Assuming that membrane specific capacitance and axial resistivity were constant, we conclude that seal resistance continued to fall after adding TTX to the bath. This might have been attributable to a further deterioration of the seal after baseline rather than an unlikely effect of TTX. There was an increase in the membrane specific resistance in TTX. The reason for this is unknown, but it meant that iNaP could not be determined by simple subtraction. Attempts to account for iNaP with a Hodgkin–Huxley model of the transient sodium conductance met with mixed results. One thing to emerge was the importance of voltage shifts. Also, a large variability in previously reported values of transient sodium conductance in mossy fibre boutons made comparisons with our results difficult. Various other possible sources of error are discussed. Simulations suggest a role for iNaP in modulating the axonal attenuation of EPSPs. Key points: We used whole‐cell patch clamp to estimate the stationary voltage dependence of persistent sodium‐current density (iNaP) in rat hippocampal mossy fibre boutons, using a KCl‐based internal (pipette) solution and correcting for the liquid junction potential (2 mV).Space‐clamp errors and deterioration of the patch‐clamp seal during the experiment were corrected for by compartmental modelling.Attempts to account for iNaP in terms of the transient sodium conductance met with mixed results. One possibility is that the transient sodium conductance is higher in mossy fibre boutons than in the axon shaft.The analysis illustrates the need to account for various voltage shifts (Donnan potentials, liquid junction potentials and, possibly, other voltage shifts).Simulations suggest a role for iNaP in modulating the axonal attenuation of excitatory postsynaptic potentials, hence analog signalling by dentate granule cells. [ABSTRACT FROM AUTHOR]

Elevated levels of iron occur in both cortical and subcortical regions of the CNS in patients with Alzheimer's disease. This accumulation is present early in the disease process as well as in more advanced stages. The factors potentially accounting for this increase are numerous, including: (1) Cells increase their uptake of iron and reduce their export of iron, as iron becomes sequestered (trapped within the lysosome, bound to amyloid β or tau, etc.); (2) metabolic disturbances, such as insulin resistance and mitochondrial dysfunction, disrupt cellular iron homeostasis; (3) inflammation, glutamate excitotoxicity, or other pathological disturbances (loss of neuronal interconnections, soluble amyloid β, etc.) trigger cells to acquire iron; and (4) following neurodegeneration, iron becomes trapped within microglia. Some of these mechanisms are also present in other neurological disorders and can also begin early in the disease course, indicating that iron accumulation is a relatively common event in neurological conditions. In response to pathogenic processes, the directed cellular efforts that contribute to iron buildup reflect the importance of correcting a functional iron deficiency to support essential biochemical processes. In other words, cells prioritize correcting an insufficiency of available iron while tolerating deposited iron. An analysis of the mechanisms accounting for iron accumulation in Alzheimer's disease, and in other relevant neurological conditions, is put forward. [ABSTRACT FROM AUTHOR]

Slow axonal transport (SAT) moves multiple proteins from the soma, where they are synthesized, to the axon terminal. Due to the great lengths of axons, SAT almost exclusively relies on active transport, which is driven by molecular motors. The puzzling feature of slow axonal transport is its bidirectionality. Although the net direction of SAT is anterograde, from the soma to the terminal, experiments show that it also contains a retrograde component. One of the proteins transported by SAT is the microtubule-associated protein tau. To better understand why the retrograde component in tau transport is needed, we used the perturbation technique to analyze how the full tau SAT model can be simplified for the specific case when retrograde motor-driven transport and diffusion-driven transport of tau are negligible and tau is driven only by anterograde (kinesin) motors. The solution of the simplified equations shows that without retrograde transport the tau concentration along the axon length stays almost uniform (decreases very slightly), which is inconsistent with the experimenal tau concentration at the outlet boundary (at the axon tip). Thus kinesin-driven transport alone is not enough to explain the empirically observed distribution of tau, and the retrograde motor-driven component in SAT is needed. [ABSTRACT FROM AUTHOR]

Examination of a fossil from a Miocene Konservat-Lagerstätte (c. 11–16 Mya) from Australia shows it to be an astioid jumping spider that is here described as Simaetha sp. indet. Fossilization in the iron oxide–hydroxide mineral goethite led to a high-fidelity preservation of not only the exterior, but of the pharyngeal plate and a neuropile in the cephalothorax. The discovery of the fossil supports the molecular-based hypothesis that the Late Oligocene/Early Miocene radiation of astioid genera occurred in Australasia. Modern Asian genera then would be the result of northward migrations from Australia rather than a movement in the other direction. Biogeographically, the Miocene Simaetha fits within the predicted bioclimatic distribution of the genus today, though the bioclimatic requirements of the fossil species are now found in eastern Queensland rather than in central New South Wales. Simaetha , it seems has retained its original bioclimatic profile for 15 Myr, even though climatic and ecological conditions in Australia have changed significantly. The fossil record now shows the independent evolution of modern genera during the Early Miocene in at least five different salticid lineages on two continents. These salticid radiations occurred at a time of planet-wide, rapid climatic and ecological change. [ABSTRACT FROM AUTHOR]

To investigate whether higher serum CCL11/Eotaxin-1, a biomarker for aging and neurodegenerative and neuroinflammatory disorders, is associated with diabetic sensorimotor polyneuropathy (DSPN), peripheral nerve dysfunction, and cardiac autonomic neuropathy in people with type 2 diabetes. This cross-sectional study included 106 patients with type 2 diabetes and 40 healthy controls, matched for the age and sex distribution of the diabetes group as a whole. The CC chemokines CCL11/Eotaxin-1 and CCL22/MDC were measured in fasting serum samples. DSPN and peripheral nerve function were assessed by neurological examination and nerve conduction studies, and cardiac autonomic function, by heart rate variability (HRV) and corrected QT (QTc) time. The cardio-ankle vascular index (CAVI) was measured as a marker for arterial stiffness. Serum CCL11/Eotaxin-1 levels were significantly higher in diabetic patients than in healthy controls (183 ± 63.5 vs. 113.1 ± 38.5 pg/ml, p < 0.001), but serum CCL22/MDC levels were not significantly different between the two groups. In the diabetes group, the serum CCL11/Eotaxin-1 level was positively correlated with ulnar and sural nerve conduction velocities (p = 0.0009, p = 0.0208, respectively) and sensory nerve action potential (p = 0.0083), and CAVI (p = 0.0005), but not with HRV indices or QTc time, and serum CCL22/MDC was not significantly correlated with any indices of nerve conduction. In a model adjusted for age and duration of diabetes, serum CCL11/Eotaxin-1 was still associated with ulnar nerve conduction velocity (p = 0.02124). Serum CCL11/Eotaxin-1, but not CCL22/MDC, was significantly higher in patients with than in those without DSPN (208.2 ± 71.6 vs. 159.1 ± 45.1 pg/ml, respectively; p < 0.0001). Serum CCL11/Eotaxin-1 is elevated in patients with DSPN and is associated with peripheral nerve dysfunction, in particular sensory nerve conduction velocity, suggesting that serum CCL11/Eotaxin-1 may be a potential biomarker for DSPN. University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000040631). [ABSTRACT FROM AUTHOR]

Introduction: In Alzheimer's disease (AD), neural circuit disconnection primarily causes memory dysfunction, which leads to the hypothesis that repairing neural networks may be an appropriate treatment strategy for AD. We previously found that diosgenin stimulated neurite regeneration and synapse formation in AD model mice, and diosgenin-rich Yam extract enhanced cognitive function in healthy people and normal mice. In this study, we investigated the efficacy and safety of Yam extract in patients with mild cognitive impairment (MCI) and mild AD. Methods: Patients were administered either diosgenin-rich Yam extract or placebo, respectively, for 24 weeks. The primary outcome was cognitive function, which was evaluated using the Mini Mental State Examination Japanese version (MMSE-J), Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog), and verbal fluency test; the secondary outcomes were plasma biomarker levels [neurofilament light chain (NfL); axonal marker, glial fibrillary acidic protein levels; reactive astrocyte marker, and the Aβ42/40 ratio; marker of brain Aβ]. Results: Diosgenin-rich Yam extract improved the ADAS-Cog Praxis domain score and plasma NfL (12 to 24 weeks) in all patients. The number of patients with improved/maintained ADAS-Cog total, Praxis or Memory scores was high in the Yam extract group, but not in placebo group. Divided by severity of pathology, diosgenin-rich Yam extract also improved the total and Memory domain in ADAS-Cog, and plasma NfL levels in patients with MCI. In the Yam extract group, improvement of MMSE-J was related to plasma Aβ42/40 increase, and improvement of plasma NfL was related to better MMSE-J. Conclusion: Treatment with diosgenin-rich Yam extract for 24 weeks resulted in modest cognitive improvement and a decrease in plasma NfL levels, which may suggest axonal protection in the brain.

Biological structures have evolved to very efficiently generate, transmit, and withstand mechanical forces. These biological examples have inspired mechanical engineers for centuries and led to the development of critical insights and concepts. However, progress in mechanical engineering also raises new questions about biological structures. The past decades have seen the increasing study of failure of engineered structures due to repetitive loading, and its origin in processes such as materials fatigue. Repetitive loading is also experienced by some neurons, for example in the peripheral nervous system. This perspective, after briefly introducing the engineering concept of mechanical fatigue, aims to discuss the potential effects based on our knowledge of cellular responses to mechanical stresses. A particular focus of our discussion are the effects of mechanical stress on axons and their cytoskeletal structures. Furthermore, we highlight the difficulty of imaging these structures and the promise of new microscopy techniques. The identification of repair mechanisms and paradigms underlying long-term stability is an exciting and emerging topic in biology as well as a potential source of inspiration for engineers.

Down syndrome (DS) is caused by the presence of an extra copy of the entire or a portion of human chromosome 21 (HSA21). This genomic alteration leads to elevated expression of numerous HSA21 genes, resulting in a variety of health issues in individuals with DS. Among the genes located in the DS “critical region” of HSA21, Down syndrome cell adhesion molecule (DSCAM) plays an important role in neuronal development. There is a growing body of evidence underscoring DSCAM’s involvement in various DS-related disorders. This review aims to provide a concise overview of the established functions of DSCAM, with a particular focus on its implications in DS. We delve into the roles that DSCAM plays in DS-associated diseases. In the concluding section of this review, we explore prospective avenues for future research to further unravel DSCAM’s role in DS and opportunities for therapeutic treatments.

Abstract Traumatic brain injury (TBI), particularly when moderate-to-severe and repetitive, is a strong environmental risk factor for several progressive neurodegenerative disorders. Mislocalization and deposition of transactive response DNA binding protein 43 (TDP-43) has been reported in both TBI and TBI-associated neurodegenerative diseases. It has been hypothesized that axonal pathology, an early event after TBI, may promote TDP-43 dysregulation and serve as a trigger for neurodegenerative processes. We sought to determine whether blocking the prodegenerative Sarm1 (sterile alpha and TIR motif containing 1) axon death pathway attenuates TDP-43 pathology after TBI. We subjected 111 male Sarm1 wild type, hemizygous, and knockout mice to moderate-to-severe repetitive TBI (rTBI) using a previously established injury paradigm. We conducted serial neurological assessments followed by histological analyses (NeuN, MBP, Iba-1, GFAP, pTDP-43, and AT8) at 1 month after rTBI. Genetic ablation of the Sarm1 gene attenuated the expression and mislocalization of phosphorylated TDP-43 (pTDP-43) and accumulation of pTau. In addition, Sarm1 knockout mice had significantly improved cortical neuronal and axonal integrity, functional deficits, and improved overall survival after rTBI. In contrast, removal of one Sarm1 allele delayed, but did not prevent, neurological deficits and neuroaxonal loss. Nevertheless, Sarm1 haploinsufficient mice showed significantly less microgliosis, pTDP-43 pathology, and pTau accumulation when compared to wild type mice. These data indicate that the Sarm1-mediated prodegenerative pathway contributes to pathogenesis in rTBI including the pathological accumulation of pTDP-43. This suggests that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after moderate-to-severe rTBI.

Mitogen-activated protein kinase kinase kinases (MAP3Ks) dual leucine kinase (DLK) and leucine zipper kinase (LZK) are essential mediators of axon damage responses, but their responses are varied, complex, and incompletely understood. To characterize their functions in axon injury, we generated zebrafish mutants of each gene, labeled motor neurons (MNs) and touch-sensing neurons in live zebrafish, precisely cut their axons with a laser, and assessed the ability of mutant axons to regenerate in larvae, before sex is apparent in zebrafish. DLK and LZK were required redundantly and cell autonomously for axon regeneration in MNs but not in larval Rohon-Beard (RB) or adult dorsal root ganglion (DRG) sensory neurons. Surprisingly, in dlk lzk double mutants, the spared branches of wounded RB axons grew excessively, suggesting that these kinases inhibit regenerative sprouting in damaged axons. Uninjured trigeminal sensory axons also grew excessively in mutants when neighboring neurons were ablated, indicating that these MAP3Ks are general inhibitors of sensory axon growth. These results demonstrate that zebrafish DLK and LZK promote diverse injury responses, depending on the neuronal cell identity and type of axonal injury.SIGNIFICANCE STATEMENT The MAP3Ks DLK and LZK are damage sensors that promote diverse outcomes to neuronal injury, including axon regeneration. Understanding their context-specific functions is a prerequisite to considering these kinases as therapeutic targets. To investigate DLK and LZK cell-type-specific functions, we created zebrafish mutants in each gene. Using mosaic cell labeling and precise laser injury we found that both proteins were required for axon regeneration in motor neurons but, unexpectedly, were not required for axon regeneration in Rohon-Beard or DRG sensory neurons and negatively regulated sprouting in the spared axons of touch-sensing neurons. These findings emphasize that animals have evolved distinct mechanisms to regulate injury site regeneration and collateral sprouting, and identify differential roles for DLK and LZK in these processes.