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The spinal cord receives, relays and processes sensory information from the periphery and integrates this information with descending inputs from supraspinal centres to elicit precise and appropriate behavioural responses and orchestrate body movements. Understanding how the spinal cord circuits that achieve this integration are wired during development is the focus of much research interest. Several families of proteins have well-established roles in guiding developing spinal cord axons, and recent findings have identified new axon guidance molecules. Nevertheless, an integrated view of spinal cord network development is lacking, and many current models have neglected the cellular and functional diversity of spinal cord circuits. Recent advances challenge the existing spinal cord axon guidance dogmas and have provided a more complex, but more faithful, picture of the ontogenesis of vertebrate spinal cord circuits.Spinal neural circuits are established through the navigation of multiple types of neuronal axon to their appropriate synaptic targets. Chédotal reviews the cellular and molecular mechanisms that control this complex wiring, incorporating recent discoveries of new guidance factors.

Glial spatial organization is critical for neural repair after spinal cord injury (SCI). In response to injury, reactive astrocytes extend hypertrophic processes to corral the lesion core and sequester debris and inflammatory cells. How these long, arborized processes remain intact, and how astrocytes avoid collisions to assemble a glial bridge to guide axon pathfinding across lesion site remains unclear. Here we identify the guidance receptor Plexin‑B1 as a regulator of membrane integrity, process plasticity, and astrocyte alignment. Live‑cell imaging reveal that Plexin‑B1 deletion triggers membrane shedding and slows extension and retraction of astrocytic processes. The loss of astrocyte agility disrupts contact‑dependent avoidance, leading to disorganized astrocytes and misguided axons in vitro and in vivo. Mice with astrocyte‑specific Plexin‑B1 deletion show defective glial border, enlarged lesions, inflammatory spill‑over, and dysregulated astrocyte–microglia signaling. These defects result in impaired axon regeneration and poorer functional recovery after spinal‑cord injury. Thus, Plexin‑B1-mediated agility of astrocyte processes safeguards membrane integrity and spatial alignment, enabling effective wound corralling and axon pathfinding during neural repair following SCI. Effective neural repair after spinal cord injury requires alignment of astrocytes to contain the lesion, but the molecular mechanisms that orchestrate glial cell arrangement in injury response are poorly defined. Here, the authors identify guidance receptor Plexin-B1 as a regulator of astrocyte membrane integrity and process plasticity, promoting glial border formation, wound corralling, and functional recovery.

In the developing brain, groups of neurons organize into functional circuits that direct diverse behaviors. One such behavior is the evolutionarily conserved acoustic startle response, which in zebrafish is mediated by a well-defined hindbrain circuit. While numerous molecular pathways that guide neurons to their synaptic partners have been identified, it is unclear if and to what extent distinct neuron populations in the startle circuit utilize shared molecular pathways to ensure coordinated development. Here, we show that the planar cell polarity (PCP)-associated atypical cadherins Celsr3 and Celsr2, as well as the Celsr binding partner Frizzled 3a/Fzd3a, are critical for axon guidance of two neuron types that form synapses with each other: the command-like neuron Mauthner cells that drive the acoustic startle escape response, and spiral fiber neurons which provide excitatory input to Mauthner cells. We find that Mauthner axon growth towards synaptic targets is vital for Mauthner survival. We also demonstrate that symmetric spiral fiber input to Mauthner cells is critical for escape direction, which is necessary to respond to directional threats. Moreover, we identify distinct roles for Celsr3 and Celsr2, as Celsr3 is required for startle circuit development while Celsr2 is dispensable, though Celsr2 can partially compensate for loss of Celsr3 in Mauthner cells. This contrasts with facial branchiomotor neuron migration in the hindbrain, which requires Celsr2 while we find that Celsr3 is dispensable. Combined, our data uncover critical and distinct roles for individual PCP components during assembly of the acoustic startle hindbrain circuit.

This study focuses on the design, production and testing of a micropatterned PDMS surface, featuring micropillars and microchannels to study the regeneration of individual axons of PC12 nerve cells after injury. Micropillar organization on the surface was designed to restrict the PC12 cell bodies while axons were guided into microchannels, allowing observation of individual axons. Surfaces were coated with poly(L-lysine) to improve cell attachment and proliferation. Netrin-1, a chemoattractant molecule and axonal elongation enhancer, was introduced in a gelatin methacrylate (GelMA) hydrogel carrier at the opposite end of the channels. Schwann cells (SC) were co-cultured with PC12 cells to enhance axon extension. MTT and Live-Dead assays showed 90% viability of the PC12 and Schwann cells on surfaces. The average PC12 axon length in the channels was 51 ± 19 μm; which increased to 75 ± 16 μm and 177 ± 31 μm upon co-culture with Schwann cells and Netrin-1 incorporation along with co-culturing, respectively, showing their synergistic effect on axon elongation. To study axon damage and regeneration processes, PC12 axons extended into the microchannels were cut using a microtome blade. An increase in the expression of injury markers ATF3, GFAP and S100β was observed after the injury with confocal microscopy, and their decrease from days 14 to 21 indicated the initiation of axon regeneration. The platform consisting of patterned PDMS surface, Schwann cells and Netrin-1 holds potential as a valuable tool for nerve damage and repair studies, and for in vitro testing of novel nerve tissue engineering strategies. Highlights A novel micropatterned platform was designed for neural axon guidance and regeneration studies. Axons of PC12 neural cells were directed into microchannels. Presence of Schwann cells and chemoattractant Netrin-1 enhanced axon extension. Regeneration of severed axons were detected by the expression intensity of the injury markers ATF3, GFAP and S100β.

The mammalian brain exhibits notable interspecies variation. Microanatomical and molecular differences in homologous neurons, those with similar locations and developmental origins across species, are best characterized in the neocortical mantle, the center of complex brain functions; however, the purpose of these differences remains unclear. We performed whole-cell microelectrode recordings along with microanatomical and molecular analyses of human fast-spiking parvalbumin (pvalb)-expressing interneurons in neocortical tissue resected during brain surgery, comparing them with similar data obtained from the mouse neocortex. The action potential (AP) firing threshold was lower in human neurons than in mouse neurons. This was due to a deficiency in low-voltage–activated inhibitory Kv1.1 and Kv1.2 potassium channels in the axon initial segment (AIS), a specialized axonal region that determines AP threshold and initiation, in human cells. In contrast, Kv1 ion channels were prominent in mouse neurons. The AIS was also moderately elongated in humans. Computational simulations of fast-spiking interneurons revealed that the human-type AIS lowers the AP threshold and shortens the time lag for AP initiation. We found that the low membrane AP firing threshold in pvalb neurons is closely linked to slow membrane potential kinetics in the soma. Thus, the human AIS supports fast in–fast out circuit function in human pvalb neurons, compensating for electrically slow somatic membrane responses. When formulating therapeutic strategies that involve fast-spiking neurons, it is crucial to take into account the molecular and functional species differences.

Axon guidance requires interactions between extracellular signaling molecules and transmembrane receptors, but how appropriate context-dependent decisions are coordinated outside the cell remains unclear. Here we show that the transmembrane glycoprotein Dystroglycan interacts with a changing set of environmental cues that regulate the trajectories of extending axons throughout the mammalian brain and spinal cord. Dystroglycan operates primarily as an extracellular scaffold during axon guidance, as it functions non-cell autonomously and does not require signaling through its intracellular domain. We identify the transmembrane receptor Celsr3/Adgrc3 as a binding partner for Dystroglycan, and show that this interaction is critical for specific axon guidance events in vivo. These findings establish Dystroglycan as a multifunctional scaffold that coordinates extracellular matrix proteins, secreted cues, and transmembrane receptors to regulate axon guidance.

The peripheral nervous system may play an important role in normal bone maintenance and remodeling. Substance P (SP) is a neuropeptide associated with bone loss and formation that may mediate the effects of the nervous system. The purpose of this study is to determine if treadmill running combined with electro-acupuncture at Jiaji acupoints (Jiaji-EA) affects tibial bone mass and SP expression in rabbits with sciatic nerve injury. Twenty-four juvenile male New Zealand white rabbits were randomly assigned to one of 4 groups: sham injury control (sham), sciatic never crush control (SNCr), treadmill running (treadmill), and Jiaji-EA combined with treadmill running (ET group). The SNCr, treadmill, and ET groups all had an induced sciatic never crush injury of approximately 2mm. Control groups received no intervention; the treadmill and ET groups were trained by treadmill; the ET group also received Jiaji-EA. After the 4 weeks of treatment, toe-spreading index (TSI), BMD, bone strength, and SP expression in the tibia were significantly lower in the nerve injury groups (SNCr, treadmill, and ET) compared to the sham groups (p<0.05). Treatment (treadmill and ET groups) increased all measures compared to the SNCr group (p<0.05). Further, TSI, BMD, bone strength, and SP expression in the ET group were higher than the treadmill group (p<0.05). Our results indicate that treadmill therapy combined with electro-acupuncture at Jiaji acupoints prevents bone loss in rabbit tibias after sciatic nerve injury. This may occur in two ways: indirectly in association with axon regeneration and directly via loading on the bone mediated through increased SP expression. This study provides important evidence for the clinical treatment of bone loss after peripheral nerve injury.

In most vertebrate neurons, action potentials are triggered at the distal end of the axon initial segment (AIS). Both position and length of the AIS vary across and within neuron types, with activity, development and pathology. What is the impact of AIS geometry on excitability? Direct empirical assessment has proven difficult because of the many potential confounding factors. Here, we carried a principled theoretical analysis to answer this question. We provide a simple formula relating AIS geometry and sodium conductance density to the somatic voltage threshold. A distal shift of the AIS normally produces a (modest) increase in excitability, but we explain how this pattern can reverse if a hyperpolarizing current is present at the AIS, due to resistive coupling with the soma. This work provides a theoretical tool to assess the significance of structural AIS plasticity for electrical function.

The dorsal funiculus in the spinal cord relays somatosensory information to the brain. It is made of T-shaped bifurcation of dorsal root ganglion (DRG) sensory axons. Our previous study has shown that Slit signaling is required for proper guidance during bifurcation, but loss of Slit does not affect all DRG axons. Here, we examined the role of the extracellular molecule Netrin-1 (Ntn1). Using wholemount staining with tissue clearing, we showed that mice lacking Ntn1 had axons escaping from the dorsal funiculus at the time of bifurcation. Genetic labeling confirmed that these misprojecting axons come from DRG neurons. Single axon analysis showed that loss of Ntn1 did not affect bifurcation but rather altered turning angles. To distinguish their guidance functions, we examined mice with triple deletion of Ntn1, Slit1, and Slit2 and found a completely disorganized dorsal funiculus. Comparing mice with different genotypes using immunolabeling and single axon tracing revealed additive guidance errors, demonstrating the independent roles of Ntn1 and Slit. Moreover, the same defects were observed in embryos lacking their cognate receptors. These in vivo studies thus demonstrate the presence of multi-factorial guidance mechanisms that ensure proper formation of a common branched axonal structure during spinal cord development.

Nodes of Ranvier are regularly placed, nonmyelinated axon segments along myelinated nerves. Here we show that nodal membranes isolated from the central nervous system (CNS) of mammals restricted neurite outgrowth of cultured neurons. Proteomic analysis of these membranes revealed several inhibitors of neurite outgrowth, including the oligodendrocyte myelin glycoprotein (OMgp). In rat spinal cord, OMgp was not localized to compact myelin, as previously thought, but to oligodendroglia-like cells, whose processes converge to form a ring that completely encircles the nodes. In OMgp-null mice, CNS nodes were abnormally wide and collateral sprouting was observed. Nodal ensheathment in the CNS may stabilize the node and prevent axonal sprouting.