Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid.

Recent work has shown that meningeal lymphatic vessels (mLVs), mainly in the dorsal part of the skull, are involved in the clearance of cerebrospinal fluid (CSF), but the precise route of CSF drainage is still unknown. Here we reveal the importance of mLVs in the basal part of the skull for this process by visualizing their distinct anatomical location and characterizing their specialized morphological features, which facilitate the uptake and drainage of CSF. Unlike dorsal mLVs, basal mLVs have lymphatic valves and capillaries located adjacent to the subarachnoid space in mice. We also show that basal mLVs are hotspots for the clearance of CSF macromolecules and that both mLV integrity and CSF drainage are impaired with ageing. Our findings should increase the understanding of how mLVs contribute to the neuropathophysiological processes that are associated with ageing.

Measurement of changes in cerebrospinal fluid pulsation after traumatic brain injury using echo-planar imaging-based functional MRI.

Traumatic brain injury (TBI) is a major public health concern worldwide, with a high incidence and a significant impact on morbidity and mortality. The alteration of cerebrospinal fluid (CSF) dynamics after TBI is a well-known phenomenon; however, the underlying mechanisms and their implications for cognitive function are not fully understood. In this study, we propose a new approach to studying the alteration of CSF dynamics in TBI patients. Our approach involves using conventional echo-planar imaging-based functional MRI with no additional scan, allowing for simultaneous assessment of functional CSF dynamics and blood oxygen level-dependent-based functional brain activities. We utilized two previously suggested indices of (i) CSFpulse, and (ii) correlation between global brain activity and CSF inflow. Using CSFpulse, we demonstrated a significant decrease in CSF pulsation following TBI (p < 0.05), which was consistent with previous studies. Furthermore, we confirmed that the decrease in CSF pulsation was most prominent in the early months after TBI, which could be explained by ependymal ciliary loss, intracranial pressure increment, or aquaporin-4 dysregulation. We also observed a decreasing trend in the correlation between global brain activity and CSF inflow in TBI patients (p < 0.05). Our findings suggest that the decreased CSF pulsation after TBI could lead to the accumulation of toxic substances in the brain and an adverse effect on brain function. Further longitudinal studies with larger sample sizes, TBI biomarker data, and various demographic information are needed to investigate the association between cognitive decline and CSF dynamics after TBI. Overall, this study sheds light on the potential role of altered CSF dynamics in TBI-induced neurologic symptoms and may contribute to the development of novel therapeutic interventions.

Unsupervised machine learning for clustering forward head posture, protraction and retraction movement patterns based on craniocervical angle data in individuals with nonspecific neck pain.

OBJECTIVES: The traditional understanding of craniocervical alignment emphasizes specific anatomical landmarks. However, recent research has challenged the reliance on forward head posture as the primary diagnostic criterion for neck pain. An advanced relationship exists between neck pain and craniocervical alignment, which requires a deeper exploration of diverse postures and movement patterns using advanced techniques, such as clustering analysis. We aimed to explore the complex relationship between craniocervical alignment, and neck pain and to categorize alignment patterns in individuals with nonspecific neck pain using the K-means algorithm. METHODS: This study included 229 office workers with nonspecific neck pain who applied unsupervised machine learning techniques. The craniocervical angles (CCA) during rest, protraction, and retraction were measured using two-dimensional video analysis, and neck pain severity was assessed using the Northwick Park Neck Pain Questionnaire (NPQ). CCA during sitting upright in a comfortable position was assessed to evaluate the resting CCA. The average of midpoints between repeated protraction and retraction measures was considered as the midpoint CCA. The K-means algorithm helped categorize participants into alignment clusters based on age, sex and CCA data. RESULTS: We found no significant correlation between NPQ scores and CCA data, challenging the traditional understanding of neck pain and alignment. We observed a significant difference in age (F = 140.14, p < 0.001), NPQ total score (F = 115.83, p < 0.001), resting CCA (F = 79.22, p < 0.001), CCA during protraction (F = 33.98, p < 0.001), CCA during retraction (F = 40.40, p < 0.001), and midpoint CCA (F = 66.92, p < 0.001) among the three clusters and healthy controls. Cluster 1 was characterized by the lowest resting and midpoint CCA, and CCA during pro- and -retraction, indicating a significant forward head posture and a pattern of retraction restriction. Cluster 2, the oldest group, showed CCA measurements similar to healthy controls, yet reported the highest NPQ scores. Cluster 3 exhibited the highest CCA during protraction and retraction, suggesting a limitation in protraction movement. DISCUSSION: Analyzing 229 office workers, three distinct alignment patterns were identified, each with unique postural characteristics; therefore, treatments addressing posture should be individualized and not generalized across the population.

Prediction model of subacromial pain syndrome in assembly workers using shoulder range of motion and muscle strength based on support vector machine.

Subacromial pain syndrome (SAPS) is the most common upper-extremity musculoskeletal problem among workers. In this study, a machine learning model was built to predict and classify the presence or absence of SAPS in assembly workers with shoulder joint range of motion (ROM) and muscle strength data using support vector machine (SVM). Permutation importance was used to determine important variables for predicting workers with or without SAPS. The accuracy of the support vector classifier (SVC) polynomial model for classifying workers with SAPS was 82.4%. The important variables in model construction were internal rotation and abduction of shoulder ROM and internal rotation of shoulder muscle strength. It is possible to accurately perform SAPS classification of workers with relatively easy-to-obtain shoulder ROM and muscle strength data using this model. In addition, preventing SAPS in workers is possible by adjusting the factors affecting model building using exercise or rehabilitation programs.Practitioner summary: This study aimed to create a machine learning model that can predict and classify SAPS using shoulder ROM and muscle strength and identify the variables that are of high importance in model construction. This model could be used to predict or classify workers' SAPS and manage or prevent SAPS.

Measurement of CSF pulsation from EPI-based human fMRI.

It is recently discovered that the glymphatic system and meningeal lymphatic system are the primary routes for the clearance of brain waste products. The CSF flow is part of these systems, facilitating the clearance procedure. Nonetheless, the relationship between CSF flow and brain functional activity has been underexplored. To investigate CSF dynamics and functional brain activity simultaneously, recent studies have proposed a CSF inflow index measured on edge slices (CSFedge) of echo-planar imaging (EPI) based functional magnetic resonance imaging (fMRI), however, it lacks the quantitative aspect of the CSF pulsation. We proposed a new method for quantifying CSF pulsation (CSFpulse) based on an interslice CSF pulsation model in the 4th ventricle of EPI-based fMRI. The proposed CSFpulse successfully detected the higher CSF flow during the resting state than the typical task states (visual and motor) (p<.05), which is consistent with previous studies based on phase contrast (PC) MRI and CSF volume MRI, while it was not detected in CSFedge based indices or baseline CSF signals in various regions of interest (ROIs). Moreover, CSFpulse demonstrated dynamic functional changes in CSF pulsation: it decreased during the activation-on blocks while it increased during the activation-off blocks. CSFpulse significantly correlated with stroke volume measured using PC MRI, a standard method for CSF pulsation quantification, under the same functional state, while CSFedge based indices or CSF ROIs showed no correlation with the PC MRI stroke volume. Lastly, the correlation of CSFpulse with global BOLD was weaker than that of CSFedge, suggesting that CSFpulse may reflect distinct CSF physiological information that is less affected by global BOLD effects. Based on these results, the proposed CSFpulse provides CSF pulsatility information more accurately in a quantitative manner than CSFedge based indices from the recent CSF studies or the conventional ROI-based analysis. In addition to the high correlation with PC MRI, CSFpulse is much faster than PC MRI and provides information of functional brain activations simultaneously, advantageous over PC MRI or CSF volume MRI. Accordingly, the suggested CSFpulse can be used for investigating intra-subject functional changes in BOLD and CSF pulsation simultaneously and inter-subject CSF pulsation variations based on conventional EPI-based fMRI, which warrants further investigation.

Development of Ultrasound-Assisted Extraction to Produce Skin-Whitening and Anti-Wrinkle Substances from Safflower Seed.

In this study, ultrasound-assisted extraction (UAE) was applied to extract bioactive substances with skin-whitening, anti-wrinkle, and antioxidant effects from safflower seeds, and the extraction conditions were optimized by a central composite design. The independent variables, including extraction time (5.0~55.0 min), extraction temperature (26.0~94.0 °C), and ethanol concentration (0.0~100%), were optimized to increase tyrosinase activity inhibitory (TAI), collagenase activity inhibitory (CAI), and radical scavenging activity (RSA), which are indicators of skin-whitening, anti-wrinkle, and antioxidant effects. An extraction time of 26.4 min, extraction temperature of 52.1 °C, and ethanol concentration of 50.7% were found to be optimum conditions of UAE, under which TAI, CAI, and RSA were 53.3%, 91.5%, and 27.7%, respectively. The extract produced by UAE was analyzed by LC-MS/MS, and maleic acid and levulinic acid were identified as the main substances. Therefore, UAE is evaluated as an effective process to extract skin-whitening, anti-wrinkle, and antioxidant substances from safflower seeds at lower temperatures and shorter extraction times compared to the conventional extraction methods. Overall, safflower seeds extract can be used as a material for value-added cosmetics, including maleic acid and levulinic acid, which have bioactive functions.

Enhancement of TRP Gene Expression and UV Absorption by Bioconverted Chestnut Inner Shell Extracts Using Lactiplantibacillus plantarum.

In this work, the suppression of tyrosinase-related genes, including an improvement in UV absorption effects of bioconverted CS extracts (BCS), was investigated to improve the skin-whitening effect. Total polyphenols and total flavonoids, which are bioactive components, increased 2.6- and 5.4-times in bioconversion using Lactiplantibacillus plantarum SM4, respectively, as compared to ultrasound-assisted extracts (UCS). The effect of BCS on radical scavenging activity, UV-A absorption, and tyrosinase activity inhibition, contributing to skin-whitening, were 1.3-, 1.2-, and 1.2-times higher than those of UCS, respectively. The main component identified in high-performance liquid chromatography (HPLC) was gallic acid in both UCS and BCS, which increased by 2.9-times following bioconversion. The gene expression of tyrosinase-related proteins, including TRP-1 and TRP-2 genes, was studied to confirm the suppression of melanin synthesis by BCS in order to identify the skin-whitening mechanism, and BCS decreased both genes' expression by 1.7- and 1.6-times, demonstrating that BCS effectively suppressed melanin synthesis. These findings imply that the chestnut inner shell can be employed as a cosmetic material by simultaneously inhibiting melanogenesis and enhancing UV-A absorption through bioconversion using L. plantarum SM4.

Nanoscale layer of a minimized defect area of graphene and hexagonal boron nitride on copper for excellent anti-corrosion activity.

In this work, we synthesized a monolayer of graphene and hexagonal boron nitride (hBN) using chemical vapor deposition. The physicochemical and electrochemical properties of the materials were evaluated to determine their morphology. High-purity materials and their atomic-scale coating on copper (Cu) foil were employed to prevent fast degradation rate. The hexagonal two-dimensional (2D) atomic structures of the as-prepared materials were assessed to derive their best anti-corrosion behavior. The material prepared under optimized conditions included edge-defect-free graphene nanosheets (∼0.0034µm2) and hBN (∼0.0038µm2) per unit area of 1µm2. The coating of each material on the Cu surface significantly reduced the corrosion rate, which was âˆ¼2.44 × 10-2/year and 6.57 × 10-3/year for graphene/Cu and hBN/Cu, respectively. Importantly, the corrosion rate of Cu was approximately 3-fold lower after coating with hBN relative to that of graphene/Cu. This approach suggests that the surface coating of Cu using cost-effective, eco-friendly, and the most abundant materials in nature is of interest for developing marine anti-corrosion micro-electronic devices and achieving surface modification of pure metals in industrial applications.

Comparison of the Shoulder External Rotator Strength and Asymmetry Ratio Between Workers With and Without Shoulder Impingement Syndrome.

ABSTRACT: Kim, J-H, Kwon, O-Y, Hwang, U-J, Jung, S-H, Ahn, S-H, and Kim, H-A. Comparison of shoulder external rotator strength and the asymmetry ratio between workers with and without shoulder impingement syndrome. J Strength Cond Res 35(12): 3364-3369, 2021-Shoulder impingement syndrome (SIS) is the most common shoulder problem causing shoulder pain. Several studies have indicated that shoulder external rotator muscles provide dynamic stability to the shoulder joint. However, the relationship of SIS to changes in shoulder external rotator muscle strength remains controversial. The purpose of the study was to compare the shoulder external rotator strength and asymmetry ratio between workers with SIS and the normal group in a side-lying position. Twelve male industrial workers with SIS and the normal group of 12 workers participated in this study. A pulling sensor measured shoulder external rotator muscle strength in a side-lying position with the shoulder at 0° and 90° of flexion. The asymmetry ratio was calculated by a specific formula using the shoulder external rotator muscle strength of the dominant side and the unaffected side. Two-way analysis of variance was used to determine between-group differences in shoulder external rotator muscle strength and the asymmetry ratio among the 2 positions. Subjects with SIS did not exhibit significant differences in shoulder external rotator muscle strength in the side-lying position with the shoulder at 0° and 90° of flexion relative to the normal group. However, subjects with SIS had a significantly increased asymmetry ratio of shoulder external rotation strength in the side-lying position with the shoulder at 90° of flexion compared with the normal group. In conclusion, workers with SIS had an asymmetry of shoulder external rotator strength in side-lying with the shoulder at 90° of flexion.

Skin-Whitening and Anti-Wrinkle Effects of Bioactive Compounds Isolated from Peanut Shell Using Ultrasound-Assisted Extraction.

Response surface methodology was employed to optimize the ultrasound-assisted extraction (UAE) conditions for simultaneous optimization of dependent variables, including DPPH radical scavenging activity (RSA), tyrosinase activity inhibition (TAI), and collagenase activity inhibition (CAI) of peanut shell extracts. The effects of the main variables including extraction time (5.0~55.0 min, X1), extraction temperature (26.0~94.0 °C, X2), and ethanol concentration (0.0%~99.5%, X3) were optimized. Based on experimental values from each condition, quadratic regression models were derived for the prediction of optimum conditions. The coefficient of determination (R2) of the independent variable was in the range of 0.89~0.96, which demonstrates that the regression model is suitable for the prediction. In predicting optimal UAE conditions based on the superimposing method, extraction time of 31.2 min, extraction temperature of 36.6 °C, and ethanol concentration of 93.2% were identified. Under these conditions, RSA of 74.9%, TAI of 50.6%, and CAI of 86.8% were predicted, showing good agreement with the experimental values. A reverse transcription polymerase chain reaction showed that peanut shell extract decreased mRNA levels of tyrosinase-related protein-1 and matrix metalloproteinase-3 genes in B16-F0 cell. Therefore, we identified the skin-whitening and anti-wrinkle effects of peanut shell extracts at protein as well as gene expression levels, and the results show that peanut shell is an effective cosmetic material for skin-whitening and anti-wrinkle effects. Based on this study, peanut shell, which was considered a byproduct, can be used for the development of healthy foods, medicines, and cosmetics.

Effects of Allium sativum Stem Extract on Growth and Migration in Melanoma Cells through Inhibition of VEGF, MMP-2, and MMP-9 Genes Expression.

The present study investigated the effects of Allium sativum stem extract (ASE) on B16-F0 cell growth and metastasis. Evaluation of the effects of ASE on B16-F0 cells' viability and migration showed that 0.5 mg/mL ASE inhibited B16-F0 cells' growth by 30.2% and migration by 38.5%, which indicates that the ASE has anticancer and antimetastatic effects on B16-F0 cells. To study the anticancer and antimetastatic mechanism, mRNA levels of vascular endothelial growth factor (VEGF), matrix metalloproteinases-2 (MMP-2), and matrix metalloproteinases-9 (MMP-9) expressions were evaluated with reverse transcription polymerase chain reaction, and 0.25 and 0.5 mg/mL ASE was found to exert significant inhibition on mRNA expressions of VEGF, MMP-2, and MMP-9 in B16-F0 cells. Thus, ASE reduce extracellular matrix degradation through inhibitions of expression of MMP-2 and MMP-9, and also showed an angiogenesis inhibitory effect through reduction of VEGF expression. High-performance liquid chromatography analysis showed that among various polyphenols, gallic acid (2.1 mg/g) was a major compound of ASE. Overall, our results demonstrated that ASE inhibited the growth and migration of B16-F0 cells through downregulation of the VEGF, MMP-2, and MMP-9 genes expression, which indicates ASE could be applied for the prevention and treatment of melanoma.

Effects of Sargassum thunbergii Extract on Skin Whitening and Anti-Wrinkling through Inhibition of TRP-1 and MMPs.

Sargassum thunbergii has been traditionally used as an edible and medicinal material in oriental countries. However, the skin-whitening and anti-wrinkling effects of S. thunbergii have not yet been investigated. This study was conducted to establish optimal extraction conditions for the production of bioactive compounds with antioxidant activity as well as skin-whitening and anti-wrinkle effects using ultrasound-assisted extraction (UAE) in S. thunbergii. The extraction time (5.30~18.7 min), extraction temperature (22.4~79.6 °C), and ethanol concentration (0.0~99.5%), which are the main variables of the UAE, were optimized using a central composite design. Quadratic regression equations were derived based on experimental data and showed a high coefficient of determination (R2 > 0.85), demonstrating suitability for prediction. The optimal UAE condition for maximizing all dependent variables, including radical scavenging activity (RSA), tyrosinase inhibitory activity (TIA), and collagenase inhibitory activity (CIA), was identified as an extraction time of 12.0 min, an extraction temperature of 65.2 °C, and ethanol of 53.5%. Under these conditions, the RSA, TIA, and CIA of S. thunbergii extract were 86.5%, 88.3%, and 91.4%, respectively. We also confirmed S. thunbergii extract had inhibitory effects on the mRNA expression of tyrosinase-related protein-1, matrix metalloproteinase-1, and matrix metalloproteinase-9, which are the main genes of melanin synthesis and collagen hydrolysis. Liquid chromatography-tandem mass spectrometry was used to identify the main phenolic compounds in S. thunbergii extract, and caffeic acid was identified as a major peak, demonstrating that high value-added ingredients with skin-whitening and anti-wrinkling effects can be produced from S. thunbergii and used for developing cosmetic materials.

Process Development for the Detoxification of Fermentation Inhibitors from Acid Pretreated Microalgae Hydrolysate.

The aim of this study was to remove 5-hydroxymethyl furfural (5-HMF) and furfural, known as fermentation inhibitors, in acid pretreated hydrolysates (APH) obtained from Scenedesmus obliquus using activated carbon. Microwave-assisted pretreatment was used to produce APH containing glucose, xylose, and fermentation inhibitors (5-HMF, furfural). The response surface methodology was applied to optimize key detoxification variables such as temperature (16.5-58.5 °C), time (0.5-5.5 h), and solid-liquid (S-L) ratio of activated carbon (0.6-7.4 w/v%). Three variables showed significant effects on the removal of fermentation inhibitors. The optimum detoxification conditions with the maximum removal of fermentation inhibitors and the minimum loss of sugars (glucose and xylose) were as follows: temperature of 36.6 °C, extraction time of 3.86 h, and S-L ratio of 3.3 w/v%. Under these conditions, removal of 5-HMF, furfural, and sugars were 71.6, 83.1, and 2.44%, respectively, which agreed closely with the predicted values. When the APH and detoxified APH were used for ethanol fermentation by S. cerevisiae, the ethanol produced was 38.5% and 84.5% of the theoretical yields, respectively, which confirmed that detoxification using activated carbon was effective in removing fermentation inhibitors and increasing fermentation yield without significant removal of fermentable sugars.

Effect of Abdominal Electrical Muscle Stimulation Training With and Without Superimposed Voluntary Muscular Contraction on Lumbopelvic Control.

CONTEXT: Electrical muscle stimulation (EMS) was designed for artificial muscle activation or superimposed training. OBJECTIVES: To compare the effects of 8 weeks of superimposed technique (ST; application of electrical stimulation during a voluntary muscle action) and EMS on the cross-sectional area of the rectus abdominis, lateral abdominal wall, and on lumbopelvic control. SETTING: University research laboratory. DESIGN: Randomized controlled trial. PARTICIPANTS: Fifty healthy subjects were recruited and randomly assigned to either the ST or EMS group. INTERVENTION: The participants engaged with the electrical stimulation techniques (ST or EMS) for 8 weeks. MAIN OUTCOME MEASURES: In all participants, the cross-sectional area of the rectus abdominis and lateral abdominal wall was measured by magnetic resonance imaging and lumbopelvic control, quantified using the single-leg and double-leg lowering tests. RESULTS: There were no significant differences in the cross-sectional area of the rectus abdominis (right: P = .70, left: P = .99) or lateral abdominal wall (right: P = .07, left: P = .69) between groups. There was a significant difference between groups in the double-leg lowering test (P = .03), but not in the single-leg lowering test (P = .88). There were significant differences between the preintervention and postintervention in the single-leg (P < .001) and double-leg lowering tests (P < .001). CONCLUSIONS: ST could improve lumbopelvic control in the context of athletic training and fitness.

Neuronal input triggers Ca2+ influx through AMPA receptors and voltage-gated Ca2+ channels in oligodendrocytes.

Communication between neurons and developing oligodendrocytes (OLs) leading to OL Ca2+ rise is critical for axon myelination and OL development. Here, we investigate signaling factors and sources of Ca2+ rise in OLs in the mouse brainstem. Glutamate puff or axon fiber stimulation induces a Ca2+ rise in pre-myelinating OLs, which is primarily mediated by Ca2+ -permeable AMPA receptors. During glutamate application, inward currents via AMPA receptors and elevated extracellular K+ caused by increased neuronal activity collectively lead to OL depolarization, triggering Ca2+ influx via P/Q- and L-type voltage-gated Ca2+ (Cav ) channels. Thus, glutamate is a key signaling factor in dynamic communication between neurons and OLs that triggers Ca2+ transients via AMPARs and Cav channels in developing OLs. The results provide a mechanism for OL Ca2+ dynamics in response to neuronal input, which has implications for OL development and myelination.

Comparison of MRI cross-sectional area and functions of core muscles among asymptomatic individuals with and without lumbar intervertebral disc degeneration.

BACKGROUND: Previous studies suggested that patients with symptomatic intervertebral disc degeneration (IDD) of lumbar spine have reduced cross-sectional area (CSA) and functions of core muscles. However, reduced CSA and functions of core muscles have been observed not only in patients with symptomatic IDD but also in patients with other subgroups of low back pain (LBP). Thus, it is uncertain whether reduced CSA and functions of core muscles lead to IDD and LBP, or pain leads to reduced CSA and functions of core muscles in patients with symptomatic IDD. Therefore, this study aimed to compare the CSA and functions of core muscles between asymptomatic participants with and without IDD in magnetic resonance imaging (MRI). METHODS: Twenty asymptomatic participants (12 men and 8 women) participated in this study. Ten participants had asymptomatic IDD at L4-5. The others were healthy controls (without IDD at all levels of lumbar spine). The CSA of core muscles was measured using MRI. Maximal isometric trunk flexor strength and side bridge strength were measured by a Smart KEMA strength sensor. Trunk flexor endurance test, side bridge endurance test and plank endurance test were used to measure core endurance. Double legs loading test was used to measure core stability. Mann-Whitney U test was used to compare the differences between two groups. RESULTS: There were no significant differences in core muscle functions between the two groups (p > 0.05). Moreover, there was no significant difference in CSA between the two groups (p > 0.05). CONCLUSIONS: There was no significant difference in CSA and core muscle functions between asymptomatic participants with and without IDD. These findings indicate that a degenerative or bulging disc in asymptomatic individuals has little effect on CSA and functions of core muscles, especially in young age. Therefore, the general core endurance test or strength test could not differentiate asymptomatic people with and without IDD of lumbar spine. TRIAL REGISTRATION NUMBER: Clinical Research information Service. KCT0004061. Registered 13 June 2019. retrospectively registered.

Activity-dependent formation and location of voltage-gated sodium channel clusters at a CNS nerve terminal during postnatal development.

In auditory pathways, the precision of action potential (AP) propagation depends on axon myelination and high densities of voltage-gated Na (Nav) channels clustered at nodes of Ranvier. Changes in Nav channel expression at the heminode, the final node before the nerve terminal, can alter AP invasion into the presynaptic terminal. We studied the activity-dependent formation of Nav channel clusters before and after hearing onset at postnatal day 12 in the rat and mouse auditory brain stem. In rats, the Nav channel cluster at the heminode formed progressively during the second postnatal week, around hearing onset, whereas the Nav channel cluster at the nodes was present before hearing onset. Initiation of heminodal Nav channel clustering was correlated with the expression of scaffolding protein ankyrinG and paranodal protein Caspr. However, in whirler mice with congenital deafness, heminodal Nav channels did not form clusters and maintained broad expression, but Nav channel clustering was normal at the nodes. In addition, a clear difference in the distance from the heminodal Nav channel to the calyx across the mediolateral axis of the medial nucleus of the trapezoid body (MNTB) developed after hearing onset. In the medial MNTB, where neurons respond best to high-frequency sounds, the heminodal Nav channel cluster was located closer to the terminal than in the lateral MNTB, where neurons respond best to low-frequency sounds. Thus sound-mediated neuronal activities are potentially associated with the refinement of the heminode adjacent to the presynaptic terminal in the auditory brain stem. NEW & NOTEWORTHY: Clustering of voltage-gated sodium (Nav) channels and their distribution along the axon, specifically at the unmyelinated axon segment next to the nerve terminal, are essential for tuning propagated action potentials. Nav channel clusters near the nerve terminal and their location as a function of neuronal position along the mediolateral axis are controlled by auditory inputs after hearing onset. Thus sound-mediated neuronal activity influences the tonotopic organization of Nav channels at the nerve terminal in the auditory brain stem.

Functional and structural properties of ion channels at the nerve terminal depends on compact myelin.

KEY POINTS: In the present study, we document the role of compact myelin in regulating the structural and functional properties of ion channels at the nerve terminals, using electrophysiology, dynamic Na(+) imaging and immunohistochemistry. The subcellular segregation of Na(+) channel expression and intracellular Na(+) dynamics at the heminode and terminal was lost in the dysmyelinated axon from Long-Evans shaker rats, which lack compact myelin. In Long-Evans shaker rats, loss of the Nav ß4 subunit specifically at the heminode reduced resurgent and persistent Na(+) currents, whereas K(+) channel expression and currents were increased. The results of the present study suggest that there is a specific role for compact myelin in dictating protein expression and function at the axon heminode and in regulating excitability of the nerve terminal. ABSTRACT: Axon myelination increases the conduction velocity and precision of action potential propagation. Although the negative effects of demyelination are generally attributed to conduction failure, accumulating evidence suggests that myelination also regulates the structural properties and molecular composition of the axonal membrane. In the present study, we investigated how myelination affects ion channel expression and function, particularly at the last axon heminode before the nerve terminal, which regulates the presynaptic excitability of the nerve terminal. We compared the structure and physiology of normal axons and those of the Long-Evans shaker (LES) rat, which lacks compact myelin. The normal segregation of Na(+) channel expression and dynamics at the heminode and terminal was lost in the LES rat. Specifically, NaV -α subunits were dispersed and NaV ß4 subunit was absent, whereas the density of K(+) channels was increased at the heminode. Correspondingly, resurgent and persistent Na(+) currents were reduced and K(+) current was increased. Taken together, these data suggest a specific role for compact myelin in the orchestration of ion channel expression and function at the axon heminode and in regulating excitability of the nerve terminal.

Developmental profiles of the intrinsic properties and synaptic function of auditory neurons in preterm and term baboon neonates.

The human fetus starts to hear and undergoes major developmental changes in the auditory system during the third trimester of pregnancy. Although there are significant data regarding development of the auditory system in rodents, changes in intrinsic properties and synaptic function of auditory neurons in developing primate brain at hearing onset are poorly understood. We performed whole-cell patch-clamp recordings of principal neurons in the medial nucleus of trapezoid body (MNTB) in preterm and term baboon brainstem slices to study the structural and functional maturation of auditory synapses. Each MNTB principal neuron received an excitatory input from a single calyx of Held terminal, and this one-to-one pattern of innervation was already formed in preterm baboons delivered at 67% of normal gestation. There was no difference in frequency or amplitude of spontaneous excitatory postsynaptic synaptic currents between preterm and term MNTB neurons. In contrast, the frequency of spontaneous GABA(A)/glycine receptor-mediated inhibitory postsynaptic synaptic currents, which were prevalent in preterm MNTB neurons, was significantly reduced in term MNTB neurons. Preterm MNTB neurons had a higher input resistance than term neurons and fired in bursts, whereas term MNTB neurons fired a single action potential in response to suprathreshold current injection. The maturation of intrinsic properties and dominance of excitatory inputs in the primate MNTB allow it to take on its mature role as a fast and reliable relay synapse.