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Journal of Neuroinflammation Feb 2024The spinal inflammatory signal often spreads to distant segments, accompanied by widespread pain symptom under neuropathological conditions. Multiple cytokines are...
BACKGROUND
The spinal inflammatory signal often spreads to distant segments, accompanied by widespread pain symptom under neuropathological conditions. Multiple cytokines are released into the cerebrospinal fluid (CSF), potentially inducing the activation of an inflammatory cascade at remote segments through CSF flow. However, the detailed alteration of CSF in neuropathic pain and its specific role in widespread pain remain obscure.
METHODS
A chronic constriction injury of the infraorbital nerve (CCI-ION) model was constructed, and pain-related behavior was observed on the 7th, 14th, 21st, and 28th days post surgery, in both vibrissa pads and hind paws. CSF from CCI-ION rats was transplanted to naïve rats through intracisternal injection, and thermal and mechanical allodynia were measured in hind paws. The alteration of inflammatory cytokines in CCI-ION's CSF was detected using an antibody array and bioinformatic analysis. Pharmacological intervention targeting the changed cytokine in the CSF and downstream signaling was performed to evaluate its role in widespread pain.
RESULTS
CCI-ION induced local pain in vibrissa pads together with widespread pain in hind paws. CCI-ION's CSF transplantation, compared with sham CSF, contributed to vibrissa pad pain and hind paw pain in recipient rats. Among the measured cytokines, interleukin-6 (IL-6) and leptin were increased in CCI-ION's CSF, while interleukin-13 (IL-13) was significantly reduced. Furthermore, the concentration of CSF IL-6 was correlated with nerve injury extent, which gated the occurrence of widespread pain. Both astrocytes and microglia were increased in remote segments of the CCI-ION model, while the inhibition of astrocytes in remote segments, but not microglia, significantly alleviated widespread pain. Mechanically, astroglial signal transducer and activator of transcription 3 (STAT3) in remote segments were activated by CSF IL-6, the inhibition of which significantly mitigated widespread pain in CCI-ION.
CONCLUSION
IL-6 was induced in the CSF of the CCI-ION model, triggering widespread pain via activating astrocyte STAT3 signal in remote segments. Therapies targeting IL-6/STAT3 signaling might serve as a promising strategy for the widespread pain symptom under neuropathological conditions.
Topics: Rats; Animals; Interleukin-6; Rats, Sprague-Dawley; STAT3 Transcription Factor; Gliosis; Constriction; Hyperalgesia; Neuralgia; Cytokines
PubMed: 38419042
DOI: 10.1186/s12974-024-03049-z -
Frontiers in Veterinary Science 2024Free-ranging white-tailed deer () in northeastern lower Michigan, (United States) are a self-sustaining reservoir for bovine tuberculosis (bTB). Farm mitigation...
INTRODUCTION
Free-ranging white-tailed deer () in northeastern lower Michigan, (United States) are a self-sustaining reservoir for bovine tuberculosis (bTB). Farm mitigation practices, baiting bans, and antlerless deer harvests have been ineffective in eliminating bTB in white-tailed deer and risks to cattle. The apparent prevalence has remained relatively constant in deer, prompting interest among wildlife researchers, managers, and veterinarians for an effective means of vaccinating deer against bTB. The commonly used human vaccine for bTB, Bacillus Calmette Guerin (BCG), is the primary candidate with oral delivery being the logical means for vaccinating deer.
MATERIALS AND METHODS
We developed vaccine delivery units and incorporated the biomarker Rhodamine B before delivering them to deer to assess the level of coverage achievable. Following deployment of Rhodamine B-laden vaccine delivery units on 17 agricultural study sites in Alpena County, MI in Mar/Apr 2016, we sampled deer to detect evidence of Rhodamine B consumption.
RESULTS AND DISCUSSION
We collected a total of 116 deer and sampled them for vibrissae/rumen marking and found 66.3% ( = 77) of the deer collected exhibited evidence of vaccine delivery unit consumption. Understanding the level of coverage we achieved with oral delivery of a biomarker in vaccine delivery units to deer enables natural resource professionals to forecast expectations of a next step toward further minimizing bTB in deer.
PubMed: 38414651
DOI: 10.3389/fvets.2024.1354772 -
Toxins Feb 2024Limited evidence suggests that stimulating adipose-derived stem cells (ASCs) indirectly promotes hair growth. We examined whether bee venom (BV) activated ASCs and...
Limited evidence suggests that stimulating adipose-derived stem cells (ASCs) indirectly promotes hair growth. We examined whether bee venom (BV) activated ASCs and whether BV-induced hair growth was facilitated by enhanced growth factor release by ASCs. The induction of the telogen-to-anagen phase was studied in mice. The underlying mechanism was investigated using organ cultures of mouse vibrissa hair follicles. When BV-treated ASCs were injected subcutaneously into mice, the telogen-to-anagen transition was accelerated and, by day 14, the hair weight increased. Quantitative polymerase chain reaction (qPCR) revealed that BV influenced the expression of several molecules, including growth factors, chemokines, channels, transcription factors, and enzymes. Western blot analysis was employed to verify the protein expression levels of extracellular-signal-regulated kinase (ERK) and phospho-ERK. Both the Boyden chamber experiment and scratch assay confirmed the upregulation of cell migration by BV. Additionally, ASCs secreted higher levels of growth factors after exposure to BV. Following BV therapy, the gene expression levels of alkaline phosphatase (ALP), fibroblast growth factor (FGF)-1 and 6, endothelial cell growth factor, and platelet-derived growth factor (PDGF)-C were upregulated. The findings of this study suggest that bee venom can potentially be utilized as an ASC-preconditioning agent for hair regeneration.
Topics: Animals; Mice; Bee Venoms; Cell Proliferation; Hair; Intercellular Signaling Peptides and Proteins; Stem Cells; Cells, Cultured
PubMed: 38393162
DOI: 10.3390/toxins16020084 -
Nature Communications Feb 2024Astrocytes express ionotropic receptors, including N-methyl-D-aspartate receptors (NMDARs). However, the contribution of NMDARs to astrocyte-neuron interactions,...
Astrocytes express ionotropic receptors, including N-methyl-D-aspartate receptors (NMDARs). However, the contribution of NMDARs to astrocyte-neuron interactions, particularly in vivo, has not been elucidated. Here we show that a knockdown approach to selectively reduce NMDARs in mouse cortical astrocytes decreases astrocyte Ca transients evoked by sensory stimulation. Astrocyte NMDAR knockdown also impairs nearby neuronal circuits by elevating spontaneous neuron activity and limiting neuronal recruitment, synchronization, and adaptation during sensory stimulation. Furthermore, this compromises the optimal processing of sensory information since the sensory acuity of the mice is reduced during a whisker-dependent tactile discrimination task. Lastly, we rescue the effects of astrocyte NMDAR knockdown on neurons and improve the tactile acuity of the animal by supplying exogenous ATP. Overall, our findings show that astrocytes can respond to nearby neuronal activity via their NMDAR, and that these receptors are an important component for purinergic signaling that regulate astrocyte-neuron interactions and cortical sensory discrimination in vivo.
Topics: Mice; Animals; Astrocytes; Receptors, N-Methyl-D-Aspartate; Vibrissae; Neurons; Signal Transduction
PubMed: 38383567
DOI: 10.1038/s41467-024-45989-3 -
Scientific Reports Feb 2024Gephyrin is the main scaffolding protein at inhibitory postsynaptic sites, and its clusters are the signaling hubs where several molecular pathways converge....
Gephyrin is the main scaffolding protein at inhibitory postsynaptic sites, and its clusters are the signaling hubs where several molecular pathways converge. Post-translational modifications (PTMs) of gephyrin alter GABA receptor clustering at the synapse, but it is unclear how this affects neuronal activity at the circuit level. We assessed the contribution of gephyrin PTMs to microcircuit activity in the mouse barrel cortex by slice electrophysiology and in vivo two-photon calcium imaging of layer 2/3 (L2/3) pyramidal cells during single-whisker stimulation. Our results suggest that, depending on the type of gephyrin PTM, the neuronal activities of L2/3 pyramidal neurons can be differentially modulated, leading to changes in the size of the neuronal population responding to the single-whisker stimulation. Furthermore, we show that gephyrin PTMs have their preference for selecting synaptic GABA receptor subunits. Our results identify an important role of gephyrin and GABAergic postsynaptic sites for cortical microcircuit function during sensory stimulation.
Topics: Animals; Receptors, GABA-A; Vibrissae; Carrier Proteins; Pyramidal Cells; Synapses; Membrane Proteins
PubMed: 38379020
DOI: 10.1038/s41598-024-54720-7 -
International Journal of Nanomedicine 2024Facial nerves have the potential for regeneration following injury, but this process is often challenging and slow. Schwann cells (SCs) are pivotal in this process. Bone...
Hypoxic Bone Mesenchymal Stem Cell-Derived Exosomes Direct Schwann Cells Proliferation, Migration, and Paracrine to Accelerate Facial Nerve Regeneration via circRNA_Nkd2/miR-214-3p/MED19 Axis.
BACKGROUND
Facial nerves have the potential for regeneration following injury, but this process is often challenging and slow. Schwann cells (SCs) are pivotal in this process. Bone mesenchymal stem cells (BMSC)-derived exosomes promote tissue repair through paracrine action, with hypoxic preconditioning enhancing their effects. The main purpose of this study was to determine whether hypoxia-preconditioned BMSC-derived exosomes (Hypo-Exos) exhibit a greater therapeutic effect on facial nerve repair/regeneration and reveal the mechanism.
METHODS
CCK-8, EdU, Transwell, and ELISA assays were used to evaluate the functions of Hypo-Exos in SCs. Histological analysis and Vibrissae Movements (VMs) recovery were used to evaluate the therapeutic effects of Hypo-Exos in rat model. circRNA array was used to identify the significantly differentially expressed exosomal circRNAs between normoxia-preconditioned BMSC-derived exosomes (Nor-Exos) and Hypo-Exos. miRDB, TargetScan, double luciferase assay, qRT-PCR and WB were used to predict and identify potential exosomal cirRNA_Nkd2-complementary miRNAs and its target gene. The function of exosomal circRNA_Nkd2 in facial nerve repair/regeneration was evaluated by cell and animal experiments.
RESULTS
This study confirmed that Hypo-Exos more effectively promote SCs proliferation, migration, and paracrine function, accelerating facial nerve repair following facial nerve injury (FNI) compared with Nor-Exos. Furthermore, circRNA analysis identified significant enrichment of circRNA_Nkd2 in Hypo-Exos compared with Nor-Exos. Exosomal circRNA_Nkd2 positively regulates mediator complex subunit 19 (MED19) expression by sponging rno-miR-214-3p.
CONCLUSION
Our results demonstrated a mechanism by which Hypo-Exos enhanced SCs proliferation, migration, and paracrine function and facial nerve repair and regeneration following FNI through the circRNA_Nkd2/miR-214-3p/Med19 axis. Hypoxic preconditioning is an effective and promising method for optimizing the therapeutic action of BMSC-derived exosomes in FNI.
Topics: Animals; Rats; Cell Proliferation; Exosomes; Facial Nerve; Hypoxia; Mesenchymal Stem Cells; MicroRNAs; Nerve Regeneration; RNA, Circular; Schwann Cells; Mediator Complex; Carrier Proteins
PubMed: 38371458
DOI: 10.2147/IJN.S443036 -
BioRxiv : the Preprint Server For... Mar 2024Most mammals have specialized facial hairs known as vibrissae (whiskers), sensitive tactile structures that subserve both touch and flow sensing. Different animals have...
Most mammals have specialized facial hairs known as vibrissae (whiskers), sensitive tactile structures that subserve both touch and flow sensing. Different animals have different numbers and geometric arrangements of whiskers, and it seems nearly self-evident that these differences would correlate with functional and behavioral use. To date, however, cross-species comparisons of three-dimensional (3D) whisker array geometry have been limited because standard morphometric techniques cannot be applied. Our laboratory recently developed a novel approach to enable quantitative, cross-species vibrissal array comparisons. Here we quantify the 3D morphology of the vibrissal array of the harbor seal ( ), construct a CAD model of the array, and compare array morphologies of harbor seals, mice ( ) and rats ( ). In all three species whisker arclength decreases from caudal to rostral, whisker curvature increases from caudal to rostral, and whiskers emerge from the face in smooth orientation gradients. Two aspects of whisker orientation are strikingly consistent across species: the elevation angle is constant within a row, and the twist of the whisker about its own axis varies smoothly in a diagonal gradient across the array. We suggest that invariant whisker elevation within a row may aid localization behaviors, while variable twist-orientation may help the animal sense stimulus direction. We anticipate this work will serve as a starting point for quantitative comparisons of vibrissal arrays across species, help clarify the mechanical basis by which seal vibrissae enable efficient wake detection and following, and enable the creation of whole-body biomechanical models for neuroscience and robotics.
PubMed: 38293081
DOI: 10.1101/2024.01.15.575743 -
International Journal of Molecular... Jan 2024Peripheral nerve injuries (PNIs) occur frequently and can lead to devastating and permanent sensory and motor function disabilities. Systemic tacrolimus (FK506)...
Peripheral nerve injuries (PNIs) occur frequently and can lead to devastating and permanent sensory and motor function disabilities. Systemic tacrolimus (FK506) administration has been shown to hasten recovery and improve functional outcomes after PNI repair. Unfortunately, high systemic levels of FK506 can result in adverse side effects. The localized administration of FK506 could provide the neuroregenerative benefits of FK506 while avoiding systemic, off-target side effects. This study investigates the utility of a novel FK506-impregnated polyester urethane urea (PEUU) nerve wrap to treat PNI in a previously validated rat infraorbital nerve (ION) transection and repair model. ION function was assessed by microelectrode recordings of trigeminal ganglion cells responding to controlled vibrissae deflections in ION-transected and -repaired animals, with and without the nerve wrap. Peristimulus time histograms (PSTHs) having 1 ms bins were constructed from spike times of individual single units. Responses to stimulus onsets (ON responses) were calculated during a 20 ms period beginning 1 ms after deflection onset; this epoch captures the initial, transient phase of the whisker-evoked response. Compared to no-wrap controls, rats with PEUU-FK506 wraps functionally recovered earlier, displaying larger response magnitudes. With nerve wrap treatment, FK506 blood levels up to six weeks were measured nearly at the limit of quantification (LOQ ≥ 2.0 ng/mL); whereas the drug concentrations within the ION and muscle were much higher, demonstrating the local delivery of FK506 to treat PNI. An immunohistological assessment of ION showed increased myelin expression for animals assigned to neurorrhaphy with PEUU-FK506 treatment compared to untreated or systemic-FK506-treated animals, suggesting that improved PNI outcomes using PEUU-FK506 is mediated by the modulation of Schwann cell activity.
Topics: Animals; Rats; Tacrolimus; Myelin Sheath; Neurons; Urethane; Nerve Regeneration; Amides; Carbamates; Urea; Esters
PubMed: 38255920
DOI: 10.3390/ijms25020847 -
ENeuro Jan 2024The anterior dorsolateral striatum (DLS) is heavily innervated by convergent excitatory projections from the primary motor (M1) and sensory cortex (S1) and considered an...
The anterior dorsolateral striatum (DLS) is heavily innervated by convergent excitatory projections from the primary motor (M1) and sensory cortex (S1) and considered an important site of sensorimotor integration. M1 and S1 corticostriatal synapses have functional differences in their connection strength with striatal spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in the DLS and, as a result, exert distinct influences on sensory-guided behaviors. In the present study, we tested whether M1 and S1 inputs exhibit differences in the subcellular anatomical distribution of striatal neurons. We injected adeno-associated viral vectors encoding spaghetti monster fluorescent proteins (sm.FPs) into M1 and S1 in male and female mice and used confocal microscopy to generate 3D reconstructions of corticostriatal inputs to single identified SPNs and FSIs obtained through ex vivo patch clamp electrophysiology. We found that M1 and S1 dually innervate SPNs and FSIs; however, there is a consistent bias towards the M1 input in SPNs that is not found in FSIs. In addition, M1 and S1 inputs were distributed similarly across the proximal, medial, and distal regions of SPN and FSI dendrites. Notably, closely localized M1 and S1 clusters of inputs were more prevalent in SPNs than FSIs, suggesting that cortical inputs are integrated through cell-type specific mechanisms. Our results suggest that the stronger functional connectivity from M1 to SPNs compared to S1, as previously observed, is due to a higher quantity of synaptic inputs. Our results have implications for how sensorimotor integration is performed in the striatum through cell-specific differences in corticostriatal connections.
Topics: Mice; Male; Female; Animals; Vibrissae; Neurons; Interneurons; Corpus Striatum; Neostriatum
PubMed: 38164611
DOI: 10.1523/ENEURO.0503-23.2023 -
Cell Reports Jan 2024Goal-directed behaviors involve coordinated activity in many cortical areas, but whether the encoding of task variables is distributed across areas or is more...
Goal-directed behaviors involve coordinated activity in many cortical areas, but whether the encoding of task variables is distributed across areas or is more specifically represented in distinct areas remains unclear. Here, we compared representations of sensory, motor, and decision information in the whisker primary somatosensory cortex, medial prefrontal cortex, and tongue-jaw primary motor cortex in mice trained to lick in response to a whisker stimulus with mice that were not taught this association. Irrespective of learning, properties of the sensory stimulus were best encoded in the sensory cortex, whereas fine movement kinematics were best represented in the motor cortex. However, movement initiation and the decision to lick in response to the whisker stimulus were represented in all three areas, with decision neurons in the medial prefrontal cortex being more selective, showing minimal sensory responses in miss trials and motor responses during spontaneous licks. Our results reconcile previous studies indicating highly specific vs. highly distributed sensorimotor processing.
Topics: Mice; Animals; Somatosensory Cortex; Goals; Parietal Lobe; Neocortex; Neurons; Vibrissae
PubMed: 38150365
DOI: 10.1016/j.celrep.2023.113618