The peripheral nervous system has a limited innate capacity for self-repair following injury, and surgical intervention is often required. For injuries greater than a few millimeters autografting is standard practice although it is associated with donor site morbidity and is limited in its availability. Because of this, nerve guidance conduits (NGCs) can be viewed as an advantageous alternative, but currently have limited efficacy for short and large injury gaps in comparison to autograft. Current commercially available NGC designs rely on existing regulatory approved materials and traditional production methods, limiting improvement of their design. The aim of this study was to establish a novel method for NGC manufacture using a custom built laser-based microstereolithography (μSL) setup that incorporated a 405 nm laser source to produce 3D constructs with ∼ 50 μm resolution from a photocurable poly(ethylene glycol) resin. These were evaluated by SEM, in vitro neuronal, Schwann and dorsal root ganglion culture and in vivo using a thy-1-YFP-H mouse common fibular nerve injury model. NGCs with dimensions of 1 mm internal diameter × 5 mm length with a wall thickness of 250 μm were fabricated and capable of supporting re-innervation across a 3 mm injury gap after 21 days, with results close to that of an autograft control. The study provides a technology platform for the rapid microfabrication of biocompatible materials, a novel method for in vivo evaluation, and a benchmark for future development in more advanced NGC designs, biodegradable and larger device sizes, and longer-term implantation studies.
Inhibitory interneurons can evoke vasodilation and vasoconstriction, making them potential cellular drivers of neurovascular coupling. However, the specific regulatory roles played by particular interneuron subpopulations remain unclear. Our purpose was therefore to adopt a cell-specific optogenetic approach to investigate how somatostatin (SST) and neuronal nitric oxide synthase (nNOS)-expressing interneurons might influence the neurovascular relationship. In mice, specific activation of SST- or nNOS-interneurons was sufficient to evoke hemodynamic changes. In the case of nNOS-interneurons, robust hemodynamic changes occurred with minimal changes in neural activity, suggesting that the ability of blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) to reliably reflect changes in neuronal activity may be dependent on type of neuron recruited. Conversely, activation of SST-interneurons produced robust changes in evoked neural activity with shallow cortical excitation and pronounced deep layer cortical inhibition. Prolonged activation of SST-interneurons often resulted in an increase in blood volume in the centrally activated area with an accompanying decrease in blood volume in the surrounding brain regions, analogous to the negative BOLD signal. These results demonstrate the role of specific populations of cortical interneurons in the active control of neurovascular function.
BackgroundVoltage-gated sodium channels Nav1.8 and Nav1.9 are expressed preferentially in small diameter sensory neurons, and are thought to play a role in the generation of ectopic activity in neuronal cell bodies and/or their axons following peripheral nerve injury. The expression of Nav1.8 and Nav1.9 has been quantified in human lingual nerves that have been previously injured inadvertently during lower third molar removal, and any correlation between the expression of these ion channels and the presence or absence of dysaesthesia investigated.ResultsImmunohistochemical processing and quantitative image analysis revealed that Nav1.8 and Nav1.9 were expressed in human lingual nerve neuromas from patients with or without symptoms of dysaesthesia. The level of Nav1.8 expression was significantly higher in patients reporting pain compared with no pain, and a significant positive correlation was observed between levels of Nav1.8 expression and VAS scores for the symptom of tingling. No significant differences were recorded in the level of expression of Nav1.9 between patients with or without pain.ConclusionsThese results demonstrate that Nav1.8 and Nav1.9 are present in human lingual nerve neuromas, with significant correlations between the level of expression of Nav1.8 and symptoms of pain. These data provide further evidence that changes in expression of Nav1.8 are important in the development and/or maintenance of nerve injury-induced pain, and suggest that Nav1.8 may be a potential therapeutic target.
20Inhibitory interneurons can evoke vasodilation and vasoconstriction, making them 21 potential cellular drivers of neurovascular coupling. However, the specific regulatory 22 roles played by particular interneuron subpopulations remain unclear. Our purpose 23 was therefore to adopt a cell-specific optogenetic approach to investigate how 24 somatostatin (SST) and neuronal nitric oxide synthase (NOS1)-expressing 25 interneurons might influence neurovascular relationships. In mice, specific activation 26 of SST-or NOS1-interneurons was sufficient to evoke haemodynamic changes similar 27 to those evoked by physiological whisker stimulation. In the case of NOS1-28 interneurons, robust haemodynamic changes occurred with minimal changes in neural 29 activity. Conversely, activation of SST-interneurons produced robust changes in 30 evoked neural activity with shallow cortical excitation and pronounced deep layer 31 cortical inhibition. This often resulted in a central increase in blood volume with 32 corresponding surround decrease, analogous to the negative BOLD signal. These 33 results demonstrate the role of specific populations of cortical interneurons in the 34 active control of neurovascular function.35 36 80 of cortical GABAergic interneurons have specific roles in NVC. Also, that the ability of 81 BOLD signals to act as a surrogate measure of local neural activation may in part be 82 dependent upon which subpopulation of neurons are being activated.83 84 4 Results 85 Short duration optogenetic stimulation of specific interneurons evokes a 86 localised haemodynamic response 87 Genetically modified mice expressing channelrhodopsin-2 (ChR2) in either SST-or 88 NOS1-expressing interneurons (referred to as SST-ChR2 or NOS1-ChR2 mice, 89 respectively) were used to investigate how light induced activity of these inhibitory 90 interneurons may alter cortical haemodynamics. Using an anaesthetised mouse 91 (Figure 1), we assessed whether short duration optogenetic stimulation of specific 92 subtypes of interneuron evoked a localised haemodynamic response, comparable to 93 that evoked by a mild physiological stimulus (mechanical whisker stimulation). 2-94 dimensional optical imaging spectroscopy (2D-OIS) was used to record high-95 resolution 2D maps of the changes in blood volume (Hbt), oxygenated haemoglobin 96 (HbO2) and reduced haemoglobin (Hbr) evoked by stimulation. Each animal initially 97 received a mechanical whisker stimulation (2s, 5Hz), evoking changes in Hbt, HbO2 98 and Hbr which were localised to the whisker barrel cortex (Figure 2A). These 99 haemodynamic changes allowed us to map the whisker barrel cortex and, in turn, 100 guide the placement of the optical fibre used for photostimulation (Figure 1). The time 101 series of the haemodynamic response to whisker stimulation shows an increase in Hbt 102and HbO2 during the stimulation with a corresponding washout of Hbr (Figure 2A). 103 5 104 A fibre-coupled blue (470nm) LED, placed directly above the whisker barrel cortex, 105 was used to apply photostimulat...
HighlightsWe identified XCR1 in the peripheral and central nervous systems and demonstrated its upregulation following nerve injury.In injured nerve, XCR1 is present in nerve fibers, CD45-positive leucocytes and Schwann cells.In Vc, XCR1 labeling is consistent with expression in terminals of Aδ- and C-fiber afferents and excitatory interneurons.XCL1 increases neuronal excitability and activates intracellular signaling in Vc, a pain-processing region of the CNS.These data provide the first evidence that the XCL1-XCR1 axis may play a role in trigeminal pain pathways.
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