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Late-onset hypersensitivity after a lesion in the ventral posterolateral nucleus of the thalamus: A macaque model of central post-stroke pain.

ABSTRACT: Central post-stroke pain (CPSP) can occur as a result of a cerebrovascular accident in the ventral posterolateral nucleus (VPL) of the thalamus. Developing therapeutic interventions for CPSP is difficult because its pathophysiology is unclear. Here we developed and characterized a macaque model of CPSP. The location of the VPL was determined by magnetic resonance imaging (MRI) and extracellular recording of neuronal activity during tactile stimulation, after which a hemorrhagic lesion was induced by injecting collagenase type IV. Histological analysis revealed that most of the lesion was localized within the VPL. Several weeks after the injection, the macaques displayed behavioral changes that were interpreted as reflecting the development of both mechanical allodynia and thermal hyperalgesia. Immunohistochemistry revealed that microglial and astrocytic activation in the perilesional areas lasted at least 3 months after injection. The present model reproduced the symptoms of patients suffering from CPSP, in which both mechanical allodynia and thermal hyperalgesia often develop several weeks after cerebrovascular accident. Further, the long-lasting glial activation revealed here may be characteristic of primate brains following injury. The present model will be useful not only for examining the neurological changes underlying CPSP, but also for testing therapeutic interventions for CPSP.

SUBMITTER: Nagasaka K

PROVIDER: S-EPMC5583363 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Late-onset hypersensitivity after a lesion in the ventral posterolateral nucleus of the thalamus: A macaque model of central post-stroke pain.

Nagasaka Kazuaki K Takashima Ichiro I Matsuda Keiji K Higo Noriyuki N

Scientific reports 20170904 1

Central post-stroke pain (CPSP) can occur as a result of a cerebrovascular accident in the ventral posterolateral nucleus (VPL) of the thalamus. Developing therapeutic interventions for CPSP is difficult because its pathophysiology is unclear. Here we developed and characterized a macaque model of CPSP. The location of the VPL was determined by magnetic resonance imaging (MRI) and extracellular recording of neuronal activity during tactile stimulation, after which a hemorrhagic lesion was induce ...[more]

PMID: 28871156

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Project description:BackgroundAs the relay centre for processing sensory information, the thalamus may involve in the abnormal sensory procedure caused by cortical spreading depression (CSD). However, few studies have focused on the transient response of thalamus during CSD. Our study aimed to investigate the neuronal activity of mouse thalamus ventral posteromedial nucleus (VPM) during CSD by in vivo micro-endoscopic fluorescence imaging of the genetic calcium probe GCaMP6s expressed in excitatory glutamatergic neurons.MethodsThirty-four transgenic VGluT2-GCaMP6s mice were used in the experiments. An endoscope was inserted into the VPM for image acquisition. CSD was induced by KCl topically applied unilaterally on the cranial dura. Data were acquired in awake (ipsilateral or contralateral VPM, saline instead of KCl, MK-801 treatment) and anaesthetized (isoflurane, pentobarbital) states. Statistical analysis was performed using analysis of variance (ANOVA) by SPSS.ResultsWe found that after CSD induced in ipsilateral motor cortex, the neuronal activity increased and propagated from the posterior-lateral to the anterior-medial part of the VPM with an average speed of 3.47 mm/min. When CSD was induced in visual cortex, the response propagated in opposite direction, from the anterior-medial to the posterior-lateral part of the VPM. Aanaesthetics resulted in the suppression of VPM activation induced by CSD. No significant VPM activation was detected when CSD was induced in contralateral cortex or KCl was replaced by saline. When 5 mM MK-801 was applied to the dura, the electrode failed to record the DC shift of CSD, and there was no significant VPM activation after KCl application.ConclusionCSD induced propagating activation of the ipsilateral VPM in awake mice. The response might correlate to the cortical location where CSD was induced and might be affected by anaesthetics. No significant VPM activation was detected in saline and mk801 experiment results indicated that this VPM activation is due to CSD rather than mouse motion or direct effect of the KCl applying to the intact dura. This finding suggests the potential involvement of thalamus in the migraine auras.

Project description:PurposeThe purpose of this study was to describe the surgical findings and clinical outcomes in a series of patients with occult posterolateral meniscocapsular separations diagnosed arthroscopically after a negative magnetic resonance imaging (MRI) scan.MethodsA retrospective analysis of prospectively collected data of consecutive patients who underwent surgical arthroscopy with repair of an occult posterolateral meniscocapsular separation by 2 fellowship-trained orthopaedic sports medicine surgeons at a single institution was performed. All lesions were identified arthroscopically in the posterolateral aspect of the lateral compartment as a distinct pathologic separation between the posterolateral capsule and adjacent meniscal tissue with increased excursion on probing. Clinical examination notes, MRI scans, and operative reports were reviewed. Patient-reported outcome measures were assessed via patient questionnaire.ResultsA total of 6 patients were included for analysis. MRI evaluation of the lateral meniscus was unrevealing in 4 patients, suggesting a possible tear of the body of the lateral meniscus in one patient and demonstrating a parameniscal cyst abutting the anterior root of the lateral meniscus in another patient. Arthroscopic examination revealed meniscocapsular separations of the posterolateral meniscus in all 6 knees, with 2 knees demonstrating concomitant bucket-handle meniscus tears. Patient-reported outcomes were determined for 67% of study patients. The average reported International Knee Documentation Committee score was 63.8, the average Knee Outcome Survey Activities of Daily Living Scale score was reported as 63, the 12-Item Short Form Survey (SF-12) Physical score averaged 46.8 with an average SF-12 Mental score of 59.9.ConclusionsThe diagnosis of occult posterolateral meniscocapsular separations (MCS) could be missed on advanced imaging, such as MRI, so arthroscopic diagnosis may be required. This study indicates that arthroscopic diagnosis and repair of occult posterolateral MCS results in good functional and clinical outcomes.Level of evidenceIV, therapeutic case series.

Project description:Women approximate one-third of the annual 2.8 million people in the United States who sustain traumatic brain injury (TBI). Several clinical reports support or refute that menstrual cycle-dependent fluctuations in sex hormones are associated with severity of persisting post-TBI symptoms. Previously, we reported late-onset sensory hypersensitivity to whisker stimulation that corresponded with changes in glutamate neurotransmission at 1-month following diffuse TBI in male rats. Here, we incorporated intact age-matched naturally cycling females into the experimental design while monitoring daily estrous cycle. We hypothesized that sex would not influence late-onset sensory hypersensitivity and associated in vivo amperometric extracellular recordings of glutamate neurotransmission within the behaviorally relevant thalamocortical circuit. At 28 days following midline fluid percussion injury (FPI) or sham surgery, young adult Sprague-Dawley rats were tested for hypersensitivity to whisker stimulation using the whisker nuisance task (WNT). As predicted, both male and female rats showed significantly increased sensory hypersensitivity to whisker stimulation after FPI, with females having an overall decrease in whisker nuisance scores (sex effect), but no injury and sex interaction. In males, FPI increased potassium chloride (KCl)-evoked glutamate overflow in primary somatosensory barrel cortex (S1BF) and ventral posteromedial nucleus of the thalamus (VPM), while in females the FPI effect was discernible only within the VPM. Similar to our previous report, we found the glutamate clearance parameters were not influenced by FPI, while a sex-specific effect was evident with female rats showing a lower uptake rate constant both in S1BF and VPM and longer clearance time (in S1BF) in comparison to male rats. Fluctuations in estrous cycle were evident among brain-injured females with longer diestrus (low circulating hormone) phase of the cycle over 28 days post-TBI. Together, these findings add to growing evidence indicating both similarities and differences between sexes in a chronic response to TBI. A better understanding of the influence of gonadal hormones on behavior, neurotransmission, secondary injury and repair processes after TBI is needed both clinically and translationally, with potential impact on acute treatment, rehabilitation, and symptom management.

Project description:BackgroundMicroglia participate in the immune response upon central nervous system (CNS) infections. However, the role of these cells during herpes simplex encephalitis (HSE) has not been fully characterized. We sought to identify different microglia/microglia-like cells and describe the potential mechanisms and signaling pathways involved during HSE.MethodsThe transcriptional response of CD11b+ immune cells, including microglia/microglia-like cells, was investigated using single-cell RNA sequencing (scRNA-seq) on cells isolated from the ventral posterolateral nucleus (VPL)-enriched thalamic regions of C57BL/6 N mice intranasally infected with herpes simplex virus-1 (HSV-1) (6 × 105 PFUs/20 µl). We further performed scanning electronic microscopy (SEM) analysis in VPL regions on day 6 post-infection (p.i.) to provide insight into microglial functions.ResultsWe describe a novel microglia-like transcriptional response associated with a rare cell population (7% of all analyzed cells), named "in transition" microglia/microglia-like cells in HSE. This new microglia-like transcriptional signature, found in the highly infected thalamic regions, was enriched in specific genes (Retnlg, Cxcr2, Il1f9) usually associated with neutrophils. Pathway analysis of this cell-type transcriptome showed increased NLRP3-inflammasome-mediated interleukin IL-1β production, promoting a pro-inflammatory response. These cells' increased expression of viral transcripts suggests that the distinct "in transition" transcriptome corresponds to the intrinsic antiviral immune signaling of HSV-1-infected microglia/microglia-like cells in the thalamus. In accordance with this phenotype, we observed several TMEM119+/IBA-I+ microglia/microglia-like cells immunostained for HSV-1 in highly infected regions.ConclusionsA new microglia/microglia-like state may potentially shed light on how microglia could react to HSV-1 infection. Our observations suggest that infected microglia/microglia-like cells contribute to an exacerbated CNS inflammation. Further characterization of this transitory state of the microglia/microglia-like cell transcriptome may allow the development of novel immunomodulatory approaches to improve HSE outcomes by regulating the microglial immune response.

Dataset Information

Late-onset hypersensitivity after a lesion in the ventral posterolateral nucleus of the thalamus: A macaque model of central post-stroke pain.

Publications

Late-onset hypersensitivity after a lesion in the ventral posterolateral nucleus of the thalamus: A macaque model of central post-stroke pain.

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