Distinct forms of synaptic inhibition and neuromodulation regulate calretinin positive neuron excitability in the spinal cord dorsal horn

The dorsal horn (DH) of the spinal cord contains a heterogenous population of neurons that process incoming sensory signals before information ascends to the brain. We have recently characterized calretinin-expressing (CR+) neurons in the DH and shown that they can be divided into excitatory and inhibitory subpopulations. The excitatory population receives high-frequency excitatory synaptic input and expresses delayed firing action potential discharge, whereas the inhibitory population receives weak excitatory drive and exhibits tonic or initial bursting discharge. Here, we characterize inhibitory synaptic input and neuromodulation in the two CR+ populations, in order to determine how each is regulated. We show that excitatory CR+ neurons receive mixed inhibition from GABAergic and glycinergic sources, whereas inhibitory CR+ neurons receive inhibition, which is dominated by glycine. Noradrenaline and serotonin produced robust outward currents in excitatory CR+ neurons, predicting an inhibitory action on these neurons, but neither neuromodulator produced a response in CR+ inhibitory neurons. In contrast, enkephalin (along with selective mu and delta opioid receptor agonists) produced outward currents in inhibitory CR+ neurons, consistent with an inhibitory action but did not affect the excitatory CR+ population. Our findings show that the pharmacology of inhibitory inputs and neuromodulator actions on CR+ cells, along with their excitatory inputs can define these two subpopulations further, and this could be exploited to modulate discrete aspects of sensory processing selectively in the DH

The response of the magnetosphere to the passage of a coronal mass ejection on March 20-21 1990

International audienceThe geomagnetic response to the passage of a coronal mass ejection (CME) is studied. The passage of the CME resulted in a storm sudden commencement (SSC) at 2243 UT on March 20 1990 with disturbed magnetic activity during the following 24 h. The auroral, sub-auroral and equatorial magnetic response to the southward turning at 1314 (±5) UT on March 21 and the equatorial response to the southward turning associated with the SSC on 20 March are discussed in terms of existing models. It is found that the auroral and sub-auroral response to the southward turning associated with the SSC is a factor 2 or more quicker than normal due to the shock in the solar wind dynamic pressure. The low-latitude response time to the southward turning, characterised by Dst and the magnetopause current corrected Dst*, is unaffected by the shock. Dst and Dst*, characteristic of the equatorial magnetic field, responded to the 1314 (±5) UT southward turning prior to the first observed substorm expansion phase onset, suggesting that a dayside loading process was responsible for the initial enhancement in the ring current rather than nightside particle injection. The response time of the auroral and sub-auroral magnetic field to the southward turning at 1314 (±5) UT on March 21 is measured at a variety of longitudes and latitudes. The azimuthal propagation velocity of the response to the southward turning varied considerably with latitude, ranging from ~8 km s?1 at 67°N to ~4 km s?1 at 55°N. The southward velocity of the equatorward boundary of the northern polar convection pattern has been measured. This velocity was ~1.2 km s?1 at 1600 MLT, although there was evidence that this may vary at different local times

Phases of the Traditional 505 Test: Between Session and Direction Reliability

Change of direction (COD) testing has commonly reported a single total time to quantify performance despite that tests are made up of a number of different phases. No investigation into these phases has been completed, therefore the aim of this study was to examine the reliability between sessions and directions of the different phases of a 505 test. Twenty-one male youth athletes performed the 505 test in both directions on three occasions. Differences between directions and sessions were determined via a T-test and Two-way ANOVA respectively and a significance threshold was set at P ≤ 0.05. All strategy variables show acceptable relative and absolute reliability in both directions between sessions (ICC = 0.73-0.94; CV = 2.3-6.3%) apart from ground contact time (GCT) (ICC = 0.57-0.68, CV = 14.8–22.4%). Significant differences were identified between session one and three for entry time. Significant differences between directions for exit time on day two and for full approach, entry and GCT on day three. The non-dominant turning direction showed lower relative and absolute reliability between session for entry time (ICC = 0.73 vs 0.89; CV = 6.3% vs 3.7%) and GCT (ICC = 0.57 vs 0.68; CV = 14.8% vs 22.4%). Results indicate the phases of a 505 COD test have high relative and absolute reliability between sessions, although turning directions should be considered independently

Comparison of CT ventilation imaging and hyperpolarised gas MRI: effects of breathing manoeuvre.

Image registration of lung CT images acquired at different inflation levels has been proposed as a surrogate method to map lung 'ventilation'. Prior to clinical use, it is important to understand how this technique compares with direct ventilation imaging modalities such as hyperpolarised gas MRI. However, variations in lung inflation level have been shown to affect regional ventilation distributions. Therefore, the aim of this study was to evaluate the impact of lung inflation levels when comparing CT ventilation imaging to ventilation from 3He-MRI.
 
 7 asthma patients underwent breath-hold CT at total lung capacity (TLC) and functional residual capacity (FRC). 3He-MRI and a same-breath 1H-MRI were acquired at FRC+1L and TLC. Percentage ventilated volumes (%VVs) were calculated for FRC+1L and TLC 3He-MRI. TLC-CT and registered FRC-CT were used to compute a surrogate ventilation map from voxel-wise intensity differences in Hounsfield unit values, which was thresholded at the 10th and 20th percentiles. For direct comparison of CT and 3He-MRI ventilation, FRC+1L and TLC 3He-MRI were registered to TLC-CT indirectly via the corresponding same-breath 1H-MRI data. For 3He-MRI and CT ventilation comparison, Dice similarity coefficients (DSCs) between the binary segmentations were computed.
 
 The median (range) of %VVs for FRC+1L and TLC 3He-MRI were 90.5 (54.9-93.6) and 91.8 (67.8-96.2), respectively (p=0.018). For MRI versus CT ventilation comparison, statistically significant improvements in DSCs were observed for TLC 3He MRI when compared with FRC+1L, with median (range) values of 0.93 (0.86-0.93) and 0.86 (0.68-0.92), respectively (p=0.017), for the 10-100th percentile and 0.87 (0.83-0.88) and 0.81 (0.66-0.87), respectively (p=0.027), for the 20-100th percentile.
 
 Correlation of CT ventilation imaging and hyperpolarised gas MRI is sensitive to lung inflation level. For ventilation maps derived from CT acquired at FRC and TLC, a higher correlation with gas ventilation MRI can be achieved if the MRI is acquired at TLC. &#13

Functional and molecular analysis of proprioceptive sensory neuron excitability in mice

Neurons located in dorsal root ganglia (DRG) are crucial for transmitting peripheral sensations such as proprioception, touch, temperature, and nociception to the spinal cord before propagating these signals to higher brain structures. To date, difficulty in identifying modality-specific DRG neurons has limited our ability to study specific populations in detail. As the calcium-binding protein parvalbumin (PV) is a neurochemical marker for proprioceptive DRG cells we used a transgenic mouse line expressing green fluorescent protein (GFP) in PV positive DRGs, to study the functional and molecular properties of putative proprioceptive neurons. Immunolabeled DRGs showed a 100% overlap between GFP positive (GFP+) and PV positive cells, confirming the PVeGFP mouse accurately labeled PV neurons. Targeted patch-clamp recording from isolated GFP+ and GFP negative (GFP−) neurons showed the passive membrane properties of the two groups were similar, however, their active properties differed markedly. All GFP+ neurons fired a single spike in response to sustained current injection and their action potentials (APs) had faster rise times, lower thresholds and shorter half widths. A hyperpolarization-activated current (Ih) was observed in all GFP+ neurons but was infrequently noted in the GFP− population (100% vs. 11%). For GFP+ neurons, Ih activation rates varied markedly, suggesting differences in the underlying hyperpolarization-activated cyclic nucleotide-gated channel (HCN) subunit expression responsible for the current kinetics. Furthermore, quantitative polymerase chain reaction (qPCR) showed the HCN subunits 2, 1, and 4 mRNA (in that order) was more abundant in GFP+ neurons, while HCN 3 was more highly expressed in GFP− neurons. Likewise, immunolabeling confirmed HCN 1, 2, and 4 protein expression in GFP+ neurons. In summary, certain functional properties of GFP+ and GFP− cells differ markedly, providing evidence for modality-specific signaling between the two groups. However, the GFP+ DRG population demonstrates considerable internal heterogeneity when hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel) properties and subunit expression are considered. We propose this heterogeneity reflects the existence of different peripheral receptors such as tendon organs, muscle spindles or mechanoreceptors in the putative proprioceptive neuron population

The Deceleration Deficit: A Novel Field-Based Method to Quantify Deceleration During Change of Direction Performance

The study investigated the relationship between linear and change of direction (COD) speed performance components and the individual differences between deceleration deficit (DD) and COD deficit (CODD). Thirty-six subjects (mean ±SD: age = 20.3 ± 2.9 years; stature = 175.2 ± 7.7 cm; body mass = 78.0 ± 16.7 kg) completed three trials of a 505 test in both turning directions (dominant (D); non-dominant (ND)) and three 15m linear sprints. DD was calculated via the 15m approach in the 505 test, minus the athlete’s linear 15m sprint time. To compare individuals CODD and DD, z-scores were calculated, and moderate worthwhile changes (MWC) were identified between these deficit z-scores. Significant correlations were identified between linear sprints and 505 time (D: r = 0.71, 0.74; P < 0.01. ND: r = 0.76, 0.75; P < 0.01) for 10m and 15m sprint respectively, and between 505 performance and CODD (D: r = 0.74; P < 0.01. ND: r = 0.77; P < 0.01) and DD (D: r = 0.41, P < 0.05. ND: r = 0.44, P < 0.01). DD was significantly related to CODD (D: r = 0.59; P < 0.01. ND: r = 0.62; P < 0.01); however, 78% of subjects demonstrated differences between these deficit measures greater than an MWC. In conclusion, linear speed has the strongest significant relationship with 505 performance. DD could provide a more isolated construct than CODD which may be related to an athlete’s deceleration capabilities

A dual-channel deep learning approach for lung cavity estimation from hyperpolarized gas and proton MRI

Background Hyperpolarized gas MRI can quantify regional lung ventilation via biomarkers, including the ventilation defect percentage (VDP). VDP is computed from segmentations derived from spatially co-registered functional hyperpolarized gas and structural proton (1H)-MRI. Although acquired at similar lung inflation levels, they are frequently misaligned, requiring a lung cavity estimation (LCE). Recently, single-channel, mono-modal deep learning (DL)-based methods have shown promise for pulmonary image segmentation problems. Multichannel, multimodal approaches may outperform single-channel alternatives. Purpose We hypothesized that a DL-based dual-channel approach, leveraging both 1H-MRI and Xenon-129-MRI (129Xe-MRI), can generate LCEs more accurately than single-channel alternatives. Study Type Retrospective. Population A total of 480 corresponding 1H-MRI and 129Xe-MRI scans from 26 healthy participants (median age [range]: 11 [8–71]; 50% females) and 289 patients with pulmonary pathologies (median age [range]: 47 [6–83]; 51% females) were split into training (422 scans [88%]; 257 participants [82%]) and testing (58 scans [12%]; 58 participants [18%]) sets. Field Strength/Sequence 1.5-T, three-dimensional (3D) spoiled gradient-recalled 1H-MRI and 3D steady-state free-precession 129Xe-MRI. Assessment We developed a multimodal DL approach, integrating 129Xe-MRI and 1H-MRI, in a dual-channel convolutional neural network. We compared this approach to single-channel alternatives using manually edited LCEs as a benchmark. We further assessed a fully automatic DL-based framework to calculate VDPs and compared it to manually generated VDPs. Statistical Tests Friedman tests with post hoc Bonferroni correction for multiple comparisons compared single-channel and dual-channel DL approaches using Dice similarity coefficient (DSC), average boundary Hausdorff distance (average HD), and relative error (XOR) metrics. Bland–Altman analysis and paired t-tests compared manual and DL-generated VDPs. A P value < 0.05 was considered statistically significant. Results The dual-channel approach significantly outperformed single-channel approaches, achieving a median (range) DSC, average HD, and XOR of 0.967 (0.867–0.978), 1.68 mm (37.0–0.778), and 0.066 (0.246–0.045), respectively. DL-generated VDPs were statistically indistinguishable from manually generated VDPs (P = 0.710). Data Conclusion Our dual-channel approach generated LCEs, which could be integrated with ventilated lung segmentations to produce biomarkers such as the VDP without manual intervention. Evidence Level 4. Technical Efficacy Stage 1

Comparison of 3He and129Xe MRI for evaluation of lung microstructure and ventilation at 1.5T

BACKGROUND: To support translational lung MRI research with hyperpolarized129Xe gas, comprehensive evaluation of derived quantitative lung function measures against established measures from3He MRI is required. Few comparative studies have been performed to date, only at 3T, and multisession repeatability of129Xe functional metrics have not been reported. PURPOSE/HYPOTHESIS: To compare hyperpolarized129Xe and3He MRI-derived quantitative metrics of lung ventilation and microstructure, and their repeatability, at 1.5T. STUDY TYPE: Retrospective. POPULATION: Fourteen healthy nonsmokers (HN), five exsmokers (ES), five patients with chronic obstructive pulmonary disease (COPD), and 16 patients with nonsmall-cell lung cancer (NSCLC). FIELD STRENGTH/SEQUENCE: 1.5T. NSCLC, COPD patients and selected HN subjects underwent 3D balanced steady-state free-precession lung ventilation MRI using both3He and129Xe. Selected HN, all ES, and COPD patients underwent 2D multislice spoiled gradient-echo diffusion-weighted lung MRI using both hyperpolarized gas nuclei. ASSESSMENT: Ventilated volume percentages (VV%) and mean apparent diffusion coefficients (ADC) were derived from imaging. COPD patients performed the whole MR protocol in four separate scan sessions to assess repeatability. Same-day pulmonary function tests were performed. STATISTICAL TESTS: Intermetric correlations: Spearman's coefficient. Intergroup/internuclei differences: analysis of variance / Wilcoxon's signed rank. Repeatability: coefficient of variation (CV), intraclass correlation (ICC) coefficient. RESULTS: A significant positive correlation between3He and129Xe VV% was observed (r = 0.860, P < 0.001). VV% was larger for3He than129Xe (P = 0.001); average bias, 8.79%. A strong correlation between mean3He and129Xe ADC was obtained (r = 0.922, P < 0.001). MR parameters exhibited good correlations with pulmonary function tests. In COPD patients, mean CV of3He and129Xe VV% was 4.08% and 13.01%, respectively, with ICC coefficients of 0.541 (P = 0.061) and 0.458 (P = 0.095). Mean3He and129Xe ADC values were highly repeatable (mean CV: 2.98%, 2.77%, respectively; ICC: 0.995, P < 0.001; 0.936, P < 0.001). DATA CONCLUSION:129Xe lung MRI provides near-equivalent information to3He for quantitative lung ventilation and microstructural MRI at 1.5T. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage

Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo

Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids