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Cell Reports May 2024Chronic pain is associated with alterations in fundamental cellular processes. Here, we investigate whether Beclin 1, a protein essential for initiating the cellular...
Chronic pain is associated with alterations in fundamental cellular processes. Here, we investigate whether Beclin 1, a protein essential for initiating the cellular process of autophagy, is involved in pain processing and is targetable for pain relief. We find that monoallelic deletion of Becn1 increases inflammation-induced mechanical hypersensitivity in male mice. However, in females, loss of Becn1 does not affect inflammation-induced mechanical hypersensitivity. In males, intrathecal delivery of a Beclin 1 activator, tat-beclin 1, reverses inflammation- and nerve injury-induced mechanical hypersensitivity and prevents mechanical hypersensitivity induced by brain-derived neurotrophic factor (BDNF), a mediator of inflammatory and neuropathic pain. Pain signaling pathways converge on the enhancement of N-methyl-D-aspartate receptors (NMDARs) in spinal dorsal horn neurons. The loss of Becn1 upregulates synaptic NMDAR-mediated currents in dorsal horn neurons from males but not females. We conclude that inhibition of Beclin 1 in the dorsal horn is critical in mediating inflammatory and neuropathic pain signaling pathways in males.
PubMed: 38814784
DOI: 10.1016/j.celrep.2024.114293 -
Heliyon May 2024Neuropathic pain (NP) is a common debilitating chronic pain condition with limited effective therapeutics. Further investigating mechanisms underlying NP is therefore of...
Neuropathic pain (NP) is a common debilitating chronic pain condition with limited effective therapeutics. Further investigating mechanisms underlying NP is therefore of great importance for discovering more promising therapeutic targets. In the current study, we employed high-throughput RNA sequencing to explore transcriptome profiles of mRNAs and microRNAs in the dorsal root ganglia (DRG) following chronic constriction injury (CCI) and also integrated published datasets for comprehensive analysis. First, we established CCI rat model confirmed by behavioral testings, and excavated 467 differentially expressed mRNAs (DEGs) and 16 differentially expressed microRNAs (DEmiRNAs) in the ipsilateral lumbar 4-6 DRG of CCI rats 11 days after surgery. Functional enrichment analysis of 337 upregulated DEGs showed that most of the DEGs were enriched in inflammation- and immune-associated biological processes and signaling pathways. The protein-protein interaction networks were constructed and hub DEGs were screened. Besides hub DEGs, we also identified 113 overlapped DEGs by intersecting our dataset with dataset GSE100122. Subsequently, we predicted potential miRNA-mRNA regulatory pairs using DEmiRNAs and a given set of key DEGs (including hub and overlapped DEGs). By integrative analysis, we found commonly differentially expressed mRNAs and miRNAs following CCI of different time points and different nerve injury types. Highlighted mRNAs include Atf3, Vip, Gal, Npy, Adcyap1, Reg3b, Jun, Cd74, Gadd45a, Tgm1, Csrp3, Sprr1a, Serpina3n, Gap43, Serpinb2 and Vtcn1, while miRNAs include miR-21-5p, miR-34a-5p, miR-200a-3p, miR-130a-5p, miR-216b-5p, miR-217-5p, and miR-541-5p. Additionally, 15 DEGs, including macrophages-specific (Cx3cr1, Arg1, Cd68, Csf1r) and the ones related to macrophages' involvement in NP (Ccl2, Fcgr3a, Bdnf, Ctss, Tyrobp) were verified by qRT-PCR. By functional experiments in future studies, promising therapeutic targets for NP treatment may be identified among these mRNAs and miRNAs.
PubMed: 38813203
DOI: 10.1016/j.heliyon.2024.e31481 -
Turkish Journal of Medical Sciences 2023The firing rate of the mirror neuron system in monkeys decreases systematically with more repetitions. The aim of this study is to investigate whether the activity of...
BACKGROUND/AIM
The firing rate of the mirror neuron system in monkeys decreases systematically with more repetitions. The aim of this study is to investigate whether the activity of the mirror neuron system varies based on the observed movement and the contents of the action, as well as whether there is inhibition in the mirror neuron system when humans observe repeated actions. If inhibition is present, the second question of the study is whether it is related to the organization of the observed action.
MATERIALS AND METHODS
Fourteen healthy volunteers participated in the study. Transcranial magnetic stimulation was applied to the left primary motor cortex and motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous and abductor pollicis brevis muscles while the participants were watching videos specially prepared for the study.
RESULTS
There were no significant changes in MEP amplitudes compared to baseline MEPs while observing aimless action. However, while participants watched the repeated action video, the mean MEP amplitude increased at the beginning of the movement, but neither facilitation nor inhibition was detected when the participants watched the phase of grasping the object of the action compared to the baseline MEP amplitude. On the other hand, while participants were watching different activities, an increased MEP amplitude was observed at the beginning of the movement and in the grasping of the object of the action. Additionally, there was no significant reduction in MEP amplitude during any movement stages while observing the repeated action video.
CONCLUSION
The findings of this study suggest that the activation of the mirror neuron system in humans depends on the content and stages of the observed movement. Additionally, there was no inhibition or systematic reduction in MEP amplitudes while watching a repeated action.
Topics: Humans; Mirror Neurons; Transcranial Magnetic Stimulation; Male; Evoked Potentials, Motor; Female; Adult; Motor Cortex; Young Adult; Muscle, Skeletal; Movement; Electromyography
PubMed: 38813024
DOI: 10.55730/1300-0144.5710 -
Turkish Journal of Medical Sciences 2023Dorsal root ganglia (DRG) are structures containing primary sensory neurons. Intraganglionic (IG) and intrathecal (IT) applications are the most common methods used for... (Comparative Study)
Comparative Study
BACKGROUND/AIM
Dorsal root ganglia (DRG) are structures containing primary sensory neurons. Intraganglionic (IG) and intrathecal (IT) applications are the most common methods used for viral vector transfer to DRG. We aim to compare the efficiencies and pathological effects of IT and IG viral vector delivery methods to DRG, through in vivo imaging.
MATERIALS AND METHODS
Mice were divided into four groups of six each: IT, IG, IT-vehicle, and IG-vehicle. Adeno-associated virus (AAV) injection was performed for EGFP expression in IT/IG groups. DRGs were made visible through vertebral window surgery and visualized with multiphoton microscopy. After imaging, spinal cords and DRGs were removed and cleared, then imaged with light sheet microscopy.
RESULTS
No neuronal death was observed after IT injection, while the death rate was 17% 24 h after IG injection. EGFP expression efficiencies were 90%-95% of neurons in both groups. EGFP expression was only observed in targeted L2 DRG after IG injection, while it was observed in DRGs located between L1-L5 levels after IT injection.
CONCLUSION
IT injection is a more suitable method for labeling DRG neurons in neurodegenerative injury models. However, when the innervation of DRG needs to be specifically studied, IT injection reduces this specificity due to its spread. In these studies, IG injection is the most suitable method for labeling single DRG neurons.
Topics: Animals; Ganglia, Spinal; Injections, Spinal; Mice; Dependovirus; Green Fluorescent Proteins; Genetic Vectors; Male
PubMed: 38813001
DOI: 10.55730/1300-0144.5702 -
Frontiers in Psychiatry 2024Transcranial direct current stimulation (tDCS) has emerged as a therapeutic option to mitigate symptoms in individuals with autism spectrum disorder (ASD). Our study...
INTRODUCTION
Transcranial direct current stimulation (tDCS) has emerged as a therapeutic option to mitigate symptoms in individuals with autism spectrum disorder (ASD). Our study investigated the effects of a two-week regimen of tDCS targeting the left dorsolateral prefrontal cortex (DLPFC) in children with ASD, examining changes in rhythmic brain activity and alterations in functional connectivity within key neural networks: the default mode network (DMN), sensorimotor network (SMN), and dorsal attention network (DAN).
METHODS
We enrolled twenty-six children with ASD and assigned them randomly to either an active stimulation group (n=13) or a sham stimulation group (n=13). The active group received tDCS at an intensity of 1mA to the left DLPFC for a combined duration of 10 days. Differences in electrical brain activity were pinpointed using standardized low-resolution brain electromagnetic tomography (sLORETA), while functional connectivity was assessed via lagged phase synchronization.
RESULTS
Compared to the typically developing children, children with ASD exhibited lower current source density across all frequency bands. Post-treatment, the active stimulation group demonstrated a significant increase in both current source density and resting state network connectivity. Such changes were not observed in the sham stimulation group.
CONCLUSION
tDCS targeting the DLPFC may bolster brain functional connectivity in patients with ASD, offering a substantive groundwork for potential clinical applications.
PubMed: 38812483
DOI: 10.3389/fpsyt.2024.1407267 -
PloS One 2024Predating Darwin's theory of evolution, the holotype of Saurodesmus robertsoni is a long-standing enigma. Found at the beginning of 1840s, the specimen is a damaged...
Predating Darwin's theory of evolution, the holotype of Saurodesmus robertsoni is a long-standing enigma. Found at the beginning of 1840s, the specimen is a damaged stylopodial bone over decades variably assigned to turtles, archosaurs, parareptiles, or synapsids, and currently nearly forgotten. We redescribe and re-assess that curious specimen as a femur and consider Saurodesmus robertsoni as a valid taxon of a derived cynodont (?Tritylodontidae). It shares with probainognathians more derived than Prozostrodon a mainly medially oriented lesser trochanter and with the clade reuniting tritylodontids, brasilodontids, and mammaliaforms (but excluding tritheledontids) the presence of a projected femoral head, offset from the long axis of the femoral shaft; a thin, plate-like greater trochanter; a distinct dorsal eminence proximal to the medial (tibial) condyle located close to the level of the long axis of the femoral shaft and almost in the middle of the width of the distal expansion; and a pocket-like fossa proximally to the medial (tibial) condyle. Saurodesmus robertsoni is most similar to tritylodontids, sharing at least with some forms: the relative mediolateral expansion of the proximal and distal regions of the femur, the general shape and development of the greater trochanter, the presence of a faint intertrochanteric crest separating the shallow intertrochanteric and adductor fossae, and the general outline of the distal region as observed dorsally and distally. This makes Saurodesmus robertsoni the first Triassic cynodont from Scotland and, possibly, one of the earliest representatives of tritylodontids and one of the latest non-mammaliaform cynodonts worldwide. Moreover, it highlights the need for revisiting historical problematic specimens, the identification of which could have been previously hampered by the lack of adequate comparative materials in the past.
Topics: Animals; Fossils; Femur; Scotland; Biological Evolution; Phylogeny
PubMed: 38809839
DOI: 10.1371/journal.pone.0303973 -
ELife May 2024The flow of neural activity across the neocortex during active sensory discrimination is constrained by task-specific cognitive demands, movements, and internal states....
The flow of neural activity across the neocortex during active sensory discrimination is constrained by task-specific cognitive demands, movements, and internal states. During behavior, the brain appears to sample from a broad repertoire of activation motifs. Understanding how these patterns of local and global activity are selected in relation to both spontaneous and task-dependent behavior requires in-depth study of densely sampled activity at single neuron resolution across large regions of cortex. In a significant advance toward this goal, we developed procedures to record mesoscale 2-photon Ca imaging data from two novel preparations that, between them, allow for simultaneous access to nearly all 0f the mouse dorsal and lateral neocortex. As a proof of principle, we aligned neural activity with both behavioral primitives and high-level motifs to reveal the existence of large populations of neurons that coordinated their activity across cortical areas with spontaneous changes in movement and/or arousal. The methods we detail here facilitate the identification and exploration of widespread, spatially heterogeneous neural ensembles whose activity is related to diverse aspects of behavior.
Topics: Animals; Mice; Wakefulness; Neurons; Behavior, Animal; Neocortex; Male; Calcium; Microscopy, Fluorescence, Multiphoton
PubMed: 38808733
DOI: 10.7554/eLife.94167 -
Frontiers in Veterinary Science 2024Diet is one of the main factors influencing the intestinal microbiota in horses, yet a systematic characterization of the microbiota along the length of the digestive...
INTRODUCTION
Diet is one of the main factors influencing the intestinal microbiota in horses, yet a systematic characterization of the microbiota along the length of the digestive tract in clinically healthy horses, homogenous for age and breed and receiving a specific diet is lacking.
METHODS
The study used 16S rRNA amplicon sequencing to characterize the microbiota of the intestinal tracts of 19 healthy Bardigiano horses of 14.3 ± 0.7 months of age fed one of two diets. Nine horses received a high-starch diet (HS), and ten horses received a high-fiber diet (HF). After 129 days, the horses were slaughtered, and samples were collected from the different intestinal tract compartments.
RESULTS AND DISCUSSION
The microbiota alpha diversity indices were lower in the caecum, pelvic flexure and right dorsal colon of the horses fed the HS diet (False Discovery Rate, FDR < 0.05). The values of beta diversity indicated significant compositional differences between the studied intestinal tract compartments according to the diet received (FDR < 0.05). At the lower taxonomic level (genus or family), the HS diet was associated with a higher relative frequency of within the small intestine (jejunum and duodenum) (FDR < 0.05). Within the hindgut (caecum and sternal flexure), the HS diet was associated with lower relative frequencies (i.e., a smaller core community) of bacteria belonging to and (FDR < 0.05). Moreover, horses fed the HS diet displayed a higher relative abundance of in the caecum (FDR < 0.05) and in the sternal flexure (FDR < 0.05), both of which are pathogenic bacteria responsible for inflammation diseases. Samples collected from the pelvic flexure and rectum of horses fed the HS diet showed significantly higher relative frequencies of (FDR < 0.05) - amylolytic bacteria associated with acidosis. The relative frequencies of the and were lower in the feces collected from the rectum of horses receiving the HS diet vs. HF diet, indicating smaller core communities of these bacteria (FDR < 0.05). Fibrous diets should be promoted to prevent dysbiosis of the microbiota associated with high-starch diet.
PubMed: 38807937
DOI: 10.3389/fvets.2024.1386135 -
Frontiers in Behavioral Neuroscience 2024Drug seeking behavior occurs in response to environmental contexts and drug-associated cues. The presence of these pervasive stimuli impedes abstinence success....
BACKGROUND
Drug seeking behavior occurs in response to environmental contexts and drug-associated cues. The presence of these pervasive stimuli impedes abstinence success. β-adrenergic receptors (β-ARs) have a long-standing historical implication in driving processes associated with contextual memories, including drug-associated memories in substance use disorders. However, sex differences in the role of β-adrenergic receptors in drug memories remain unknown.
HYPOTHESIS
Prior reports indicate a selective role for β2-ARs in retrieval and retention of contextual drug memories in males, and substantial sex differences exist in the expression of β-ARs of male and female rats. Therefore, we hypothesized that there are sex differences in selective recruitment of β-ARs during different stages of memory encoding and retrieval.
METHODS
The role of β-ARs in driving retrieval and learning of contextual cocaine memories was investigated using cocaine conditioned place preference (CPP) in adult male and female Sprague-Dawley rats. Rats were infused directly to the dorsal hippocampus with Propranolol (β1 and β2) or ICI-118,551 (β1) and/or Betaxolol (β2), immediately prior to testing (retrieval), or paired to each cocaine (10 mg/kp, IP) conditioning session (learning).
RESULTS
In males, administration of either β1, β2, or combined β1 and β2-ARs before the initial CPP testing reduced the expression of a CPP compared to vehicle administration. In females, β2-ARs transiently decreased CPP memories, whereas β1 had long lasting but not immediate effects to decrease CPP memories. Additionally, β1 and combined β1 and β2-ARs had immediate and persistent effects to decrease CPP memory expression. DG Fos + neurons predicted cocaine CPP expression in males, whereas CA1 and CA3 Fos + neurons predicted cocaine CPP expression in females.
CONCLUSION
There are significant sex differences in the role of dorsal hippocampus β-ARs in the encoding and expression of cocaine conditioned place preference. Furthermore, sub regions of the dorsal hippocampus appear to activate differently between male and female rats during CPP. Therefore DG, CA3, and CA1 may have separate region- and sex-specific impacts on driving drug- associated, or context-associated cues.
PubMed: 38807929
DOI: 10.3389/fnbeh.2024.1379866 -
Surgical Case Reports May 2024Biliary obstruction due to compression by a B-cell solid tumor occurs rarely. A few reports have described biliary reconstruction surgery for obstructive jaundice caused...
BACKGROUND
Biliary obstruction due to compression by a B-cell solid tumor occurs rarely. A few reports have described biliary reconstruction surgery for obstructive jaundice caused by Burkitt's lymphoma. However, there are no detailed reports on pediatric cases. We report a pediatric case of obstructive jaundice due to malignant lymphoma treated with biliary reconstruction surgery.
CASE PRESENTATION
A 5-year-old girl presented to our hospital with a massive abdominal tumor that caused biliary stricture. Chemotherapy was initiated after an open tumor biopsy. However, endoscopic biliary stent placement was performed owing to elevated bilirubin levels. We treated the patient with chemotherapy for 9 months while endoscopically replacing the biliary stent every few months. She achieved complete tumor remission. However, sclerotic lymph nodes were persistent on the dorsal side of the cholecystic duct junction, and biliary stricture at the same site had changed to stent-dependent biliary obstruction. Therefore, we performed choledochojejunostomy and retrocolic Roux-en-Y reconstruction 15 months after initial admission. There were no postoperative complications or tumor recurrences, and the bilirubin level remained low. Histopathologically, the resected bile duct wall was fibrotic and thick, and the bile duct lumen narrowed.
CONCLUSIONS
Biliary reconstruction is effective to achieve long-term biliary patency in pediatric patients with stent-dependent biliary obstruction due to malignant lymphoma. However, the decision on when to stop biliary stent replacement and proceed to biliary reconstruction surgery is a matter of debate. Further case studies are required to address this issue.
PubMed: 38806890
DOI: 10.1186/s40792-024-01935-5