Regions Of Spinal Cord Research Articles

Spinal cord cross sign: a potential marker for hereditary spastic paraplegia type 5.

Spastic paraplegia type 5 (SPG5) is a rare neurodegenerative disease diagnosed primarily through genetic testing.We identified a specific spinal cord sign on conventional MR imaging to help narrow the scope of genetic screening. In 25 patients with SPG5 and 21 healthy controls (HCs), the spinal cord cross sign was evaluated on T2*-weighted imaging. The morphological and signal characteristics of the dorsal column (DC), ventral funiculi (VF), dorsal horn (DH), ventral horn (VH), and intermediate zone (IMZ) were assessed. Differences in fractional anisotropy (FA) values within specific regions between HC and SPG5 were tested using Student's t-test. Spearman correlation was used to evaluate associations between cross-sign scores, FA values, and clinical indicators. The cross sign was detected in the cervical spinal cord of all SPG5 patients. The occurrence of T2 hyperintensity in the DC, VF and IMZ was 100%,100% and 88%,respectively. Bilateral VH morphology was normal in 14.4% of cases, blurred in 49.6%, and absent in 36%.Bilateral DH morphology was normal in 13.6%, blurred in 56%, and absent in 30.4%. FA values were reduced in these spinal cord regions. Cross-sign scores were negatively correlated with FA values in both grey (r = -0.70~-0.37) and white matter (r = -0.78~-0.70). Cross-sign scores were positively correlated with Spastic Paraplegia Rating Scale (r = 0.57) and disease duration (r = 0.42). The spinal cord cross sign was a potential imaging marker for SPG5. Cross-sign scores were associated with disease duration and severity in SPG5 patients. A Registered Cohort Study on Spastic Paraplegia,NCT04006418Registered 1 July 2019, https://clinicaltrials.gov/study/NCT04006418 .

Comparative Sensitivity of MRI Indices for Myelin Assessment in Spinal Cord Regions.

Background/Objectives: Although multiple magnetic resonance imaging (MRI) indices are known to be sensitive to the noninvasive assessment of myelin integrity, their relative sensitivities have not been directly compared. This study aimed to identify the most sensitive MRI index for characterizing myelin composition in the spinal cord's gray matter (GM) and white matter (WM). Methods: MRI was performed on a deer's ex vivo cervical spinal cord. Quantitative indices known to be sensitive to myelin, including the myelin water fraction (MWF), magnetization transfer ratio (MTR), the signal ratio between T1- and T2-weighted images (T1W/T2W), fractional anisotropy (FA), mean diffusivity (MD), electrical conductivity (σ), and T1, T2, and T1ρ relaxation times were calculated. Their mean values were compared using repeated measures analysis of variance (ANOVA) and post hoc Bonferroni tests or Friedman and post hoc Wilcoxon tests to identify differences across GM and WM columns possessing distinct myelin distributions, as revealed by histological analysis. Relationships among the indices were examined using Spearman's rank-order correlation analysis. Corrected p < 0.05 was considered statistically significant. Results: All indices except σ differed significantly between GM and all WM columns. Two of the three WM columns had significantly different MWF, FA, MD, and T2, whereas one WM column had significantly different MTR, σ, T1, and T1ρ from the others. A significant moderate to very strong correlation was observed among most indices. Conclusions: The sensitivity of MRI indices in distinguishing spinal cord regions varied. A strategic combination of two or more indices may allow the accurate differentiation of spinal cord regions.

Characterisation of the effects of the chemotherapeutic agent paclitaxel on neuropathic pain-related behaviour, anxiodepressive behaviour, cognition, and the endocannabinoid system in male and female rats.

Paclitaxel (PTX) is a commonly used chemotherapeutic drug, however, one of its major adverse effects is chronic neuropathic pain, with the incidence being higher in women than in men. The neurobiological mechanisms behind this sex difference are still largely unclear, and the endocannabinoid system, which exhibits sexual dimorphism and plays a key role in pain regulation, is a promising area for further studies. The present study aimed to characterise pain-, cognition-, anxiety-, and depression-related behaviours in male and female rats following PTX administration, and associated alterations in the endocannabinoid system. After the induction of the model, pain-related behaviours were assessed using von Frey, Acetone Drop and Hargreaves' tests, Novel Object Recognition and T-Maze Spontaneous Alternation tests were used for cognition-related behaviours, Elevated Plus Maze, Open Field, and Light Dark Box tests were used to assess anxiety-related behaviours, and Sucrose Preference, Sucrose Splash, and Forced Swim tests for depression-related behaviours. At each time point analysed, animals treated with PTX exhibited mechanical and cold hypersensitivity, with females displaying lower hind paw withdrawal thresholds to mechanical stimulation than males. No PTX-induced alterations in the other behavioural tests were detected. Post-mortem measurement of endocannabinoid and related N-acylethanolamine levels in spinal cord and discrete brain regions revealed a PTX-induced increase of 2-Arachidonoyl Glycerol (2-AG), N-Palmitoylethanolamine (PEA) and N-Oleoylethanolamine (OEA) levels in the amygdala of male and female animals, but not in the other areas. Collectively, these results suggest that PTX causes similar long-lasting hypersensitivity to mechanical and cold stimuli, but not heat, in rats of both sexes, effects accompanied by increases in amygdalar levels of endocannabinoids and N-acylethanolamines.

Intracisternal AAV9-MAG-hABCD1 Vector Reverses Motor Deficits in Adult Adrenomyeloneuropathy Mice.

Worldwide, thousands of male patients who carry ATP Binding Cassette Subfamily D Member 1 (ABCD1) mutations develop adrenomyeloneuropathy (AMN) in mid-adulthood, a debilitating axonopathy of the spinal cord. Today AAV gene therapy brings the most hope for this orphan disease. We previously reported that an AAV9-MAG-hABCD1 vector injected intravenously in the neonatal period prevented the disease in 2-year-old Abcd1-/- mice, the AMN mouse model. In the current study, the same vector was injected intracisternally at 18 months of age, when about half of Abcd1-/- mice start losing balance and motricity. As soon as 1-3 months after vector injection, motor tests have evolved differently in treated and untreated (UT) mice. Six months after vector, treated mice (n = 24) had near-normal motor performances, whereas neurological state had deteriorated in UT mice (n = 34). In five white matter regions of the cervical spinal cord, hABCD1 expression at 24 months of age was present in 22% (18-27) of oligodendrocytes (OLs) and 22% (17-26) of astrocytes and not detected in neurons or microglia. Abundant hABCD1 expression was also observed in OLs and astrocytes in the cerebellum and brainstem and, to a lesser level, in the lower spinal cord, not in the dorsal root ganglia or brain cortex. In conclusion, the effect of the AAV9-MAG-hABCD1 vector at an early symptomatic stage of the Abcd1-/- mouse model paves a new oligotropic way for the gene therapy of AMN.

Diffusion tensor imaging of spinal cord in healthy children

Introduction. Diffusion tensor imaging (DTI) is a technique that allows evaluating diffusion of water molecules along the myelin sheath of nerve fibers and obtaining information about the integrity of brain and spinal cord pathways. Obtaining reproducible values of diffusion parameters is an urgent and feasible task. The aim of this study was to establish the values of DTI parameters along the entire length of the spinal cord in healthy children for further use in the assessment of acute injury, its consequences and other spinal cord diseases. Materials and methods. The study included fifteen healthy patients of 13 to 18 years, including 6 girls and 8 boys, average age was 15.2 ± 1.2 years. The study was performed on a Philips Achieva dStream 3T MRI scanner (Netherlands). As part of this study, a spine MRI protocol was developed to cover the entire volume of spinal cord with separate visualization of cervical and thoracic spine (duration: 9 min 48 sec). The IRIS ZOOM sequence (Philips) was used to obtain DTI images. Spinal Cord Toolbox software package was used to process the data. Statistical analysis was performed using GraphPad Prism software, and significance was determined at p &lt; 0.05. Results. Mapping and calculation of the following diffusion parameters: fractional anisotropy (FA), medial (MD), longitudinal or axial (AD) and transverse (RD) diffusion showed the average values of the parameters FA, AD, MD, RD of the spinal cord of children to be: FA, AD, MD, RD of spinal cord were: FA = 0.63 ± 0.06, AD = 2.1 ± 0.3 × 10−3 mm2/s, MD = 1.15 ± 0.16 × 10−3 mm2/s, RD = 0.68 ± 0.12 × 10−3 mm2/s. An increase in FA was detected at the Th2–Th9 level compared to the values at the C6–Th1 and Th10–Th12 levels. The AD coefficient at the Th2–Th9 level is increased relative to the C2–C5 and C6–Th1 levels. MD values in spinal cord areas at the Th2–Th9 and Th10–Th12 levels are statistically higher relative to higher levels of the spinal cord. RD values in the zone at the Th10–Th12 level are increased relative to all other areas. Conclusion. The study established the diffusion indices of FA, MD, AD, RD of spinal cord in children aged 12 to 18 years and showed small differences between the spinal cord regions. The data obtained can be used as reference values for assessing spinal cord condition in various pathological processes (trauma, demyelinating and tumor diseases) in children for the corresponding age group.

4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model.

Sandhoff disease (SD), a fatal and rare lysosomal storage disorder (LSD), is caused by a deficiency of the enzyme β-hexosaminidase B and leads to severe accumulation of GM2 gangliosides in lysosomes, primarily within the central nervous system (CNS). This accumulation results in severe neurological impairment, lower motor neuron disease, and death. Currently, there are no effective therapies available for SD. Here, we explored the role of endoplasmic reticulum (ER) stress in the spinal cord during disease progression in an established mouse model of SD and revealed the beneficial outcome of off-label treatment with the FDA-approved drug, 4-phenylbutyric acid (4-PBA). We analyzed the expression and localization of ER stress and cellular apoptosis markers, which revealed significant upregulation of these factors within motor neurons. Additionally, we observed a > 50% reduction in neuronal numbers throughout all spinal cord regions. Our studies also tested the impact of the chemical chaperone 4-PBA on ER stress in mice, and following administration, we observed significant improvements in motor neuromuscular function and life span throughout disease progression. 4-PBA treatment significantly reduced apoptosis in spinal cord neurons and increased the number of choline acetyltransferase (ChAT)-positive neurons, with little effect on astrogliosis or sensory interneurons. Overall, this study provides strong evidence for the role of chronic ER stress in the pathophysiology of SD and highlights 4-PBA as a promising therapeutic treatment for SD and potentially other related LSDs.

TMIC-34. INFILTRATIVE BEHAVIOR OF PATIENT-DERIVED GLIOBLASTOMA CELL LINES IN REGION-SPECIFIC HUMAN BRAIN ORGANOIDS

Abstract Glioblastoma (GBM) is the most common malignant brain tumor in adults. GBMs are known for their highly invasive and proliferative properties and are associated with a dismal prognosis (~12-18 months post-diagnosis). Neuroanatomical disparities in the occurrence of GBMs suggest that in addition to microenvironmental impacts, tumor cells are impacted by the cellular and molecular diversity across varying regions of this nervous system. This idea has been difficult to study due to the lack of human-specific models that effectively recapitulate the biological behaviors of GBMs in region-specific microenvironments. To address these challenges, we engrafted GFP-tagged patient-derived glioma cell lines into human induced pluripotent stem cell (hiPSC)-derived organoids patterned to mimic the most forebrain (dorsal cortex) and hindbrain (spinal cord) regions of the nervous system. Immunostaining assays at 2, 7, 14, and 21 days post-engraftment compared the extent of infiltration, as measured by the distance traveled by glioma cells, in both regions. We found that glioma cells infiltrated a significantly greater distance in the dorsal cortical organoids compared to the spinal cord organoids. This suggests a more conducive environment for glioma infiltration in the forebrain vs. hindbrain at baseline. We are currently determining if these regional biases in infiltration capacity are modified with either optogenetic stimulation of the host brain organoids or in the presence of interregional interactions in an assembloid system. Thus, using this fully human-specific platform, we aim to gain insights into the infiltrative behaviors of GBM cells, which will advance our understanding of this devastating disease.

Direct anterior decompression in patients with ossification of the posterior longitudinal ligament significantly relieves short-segment spinal cord high signal

BackgroundIn patients with ossification of the posterior longitudinal ligament of the cervical spine (OPLL), high spinal cord signal (HCS) is frequently observed in the spinal cord of the corresponding segment. However, studies on the differences in the improvement of high spinal cord signal due to different surgical approaches are limited. The aim of this study was to investigate the improvement of high spinal cord signal in long and short segments with different choices of surgical approaches.MethodsIn this study, we conducted a meticulous review of medical records for patients diagnosed with ossification of the posterior longitudinal ligament (OPLL). Demographic variables, including gender, age, and body mass index (BMI), were systematically recorded. We evaluated the severity of neurological impairment using the Japanese Orthopaedic Association (JOA) scores both preoperatively and at multiple postoperative follow-up points. Neurological assessments were complemented by serial magnetic resonance imaging (MRI) T2-weighted imaging (T2WI) to measure the extent of high-signal changes (HCS) in the spinal cord, and the alteration of the HCS was quantified by the SCR (the ratio between the signal intensity value of the HCS region and the signal intensity value of the normal spinal cord region at C7-T1).ResultsIn the short-segment high signal change (HCS) group, comparisons of JOA score improvement (Recovery1) and HCS improvement (CR1) at 6 months postoperatively did not demonstrate significant differences between the surgical approaches (P > 0.05; Table 1). However, at the 2-year follow-up, patients who underwent anterior surgery exhibited significantly greater improvements in both JOA scores (Recovery2) and HCS (CR2), with statistical significance achieved (P < 0.05; Table 1). In contrast, in the long-segment HCS group, there was no significant difference between the anterior and posterior surgical approaches in terms of JOA improvement and HCS improvement at 6 months and 2 years postoperatively (P > 0.05; Table 2).ConclusionsIn patients with OPLL who present with spinal cord high signal, anterior surgery by resection of the ossified posterior longitudinal ligament and direct decompression is more conducive to regression of small spinal cord high signal and improvement of clinical neurological function if the extent of spinal cord high signal is small.

Neurotropic Murine β-Coronavirus Infection Causes Differential Expression of Connexin 47 in Oligodendrocyte Subpopulations Associated with Demyelination.

Gap junctions (GJs) play a crucial role in the survival of oligodendrocytes and myelination of the central nervous system (CNS). In this study, we investigated the spatiotemporal changes in the expression of oligodendroglial GJ protein connexin 47 (Cx47), its primary astroglial coupling partner, Cx43, and their association with demyelination following intracerebral infection with mouse hepatitis virus (MHV). Neurotropic strains of MHV, a β-coronavirus, induce an acute encephalomyelitis followed by a chronic demyelinating disease that shares similarities with the human disease multiple sclerosis (MS). Our results reveal that Cx47 GJs are persistently lost in mature oligodendrocytes, not only in demyelinating lesions but also in surrounding normal appearing white and gray matter areas, following an initial loss of astroglial Cx43 GJs during acute infection. At later stages after viral clearance, astroglial Cx43 GJs re-emerge but mature oligodendrocytes fail to fully re-establish GJs with astrocytes due to lack of Cx47 GJ expression. In contrast, at this later demyelinating stage, the increased oligodendrocyte precursor cells appear to exhibit Cx47 GJs. Our findings further highlight varying degrees of demyelination in distinct spinal cord regions, with the thoracic cord showing the most pronounced demyelination. The regional difference in demyelination correlates well with dynamic changes in the proportion of different oligodendrocyte lineage cells exhibiting differential Cx47 GJ expression, suggesting an important mechanism of progressive demyelination even after viral clearance.

Detecting Manifestations of Neurofibromatosis: Cutaneous Diagnostic Criteria for NF1 and NF2

Neurofibromatosis is a hereditary condition that causes tumors to form in the brain, spinal cord, and nerve regions. Neurofibromatosis Type 1 (NF1) and Neurofibromatosis Type 2 (NF2) are the two of the most common subtypes. We performed a literature review on Pubmed under the following search and included the 24 most cited papers between 2012 and 2024: “Neurofibromatosis AND (Cutaneous OR Skin) AND (Diagnostic Criteria OR Diagnosis) AND (NF1 OR NF2)”. In our review, both types can manifest cutaneous symptoms, which aid in early detection. Between the two types, NF1 is more common with an estimated prevalence of 1 in 3000, compared to NF2’s 1 in 60,000. NF1 is distinguished by café-au-lait spots, freckling, and neurofibromas; NF2 presents similar to NF1 but may also have characteristic bilateral vestibular schwannomas. While both conditions may exhibit cutaneous manifestations, NF1 primarily presents with such features, whereas NF2 is distinguished by intracranial manifestations. Early detection of cutaneous symptoms is critical for prompt intervention and management of neurofibromatosis. More research is needed to elucidate the detection of neurofibromatosis in clinical practice as differentiation may be challenging.

Multidimensional Analgesia of Acupuncture by Increasing Expression of MD2 in Central Nervous System.

To investigate changes of myeloid differentiation factor 2 (MD2) in inflammation-induced pain and acupuncture-mediated analgesia. Mice were randomly divided into three groups by a random number table method: saline group (n=16), complete Freund's adjuvant (CFA) group (n=24) and CFA+electroacupuncture (EA) group (n=26). Inflammation-induced pain was modelled by injecting CFA to the plantar surface of the hind paw of mice and EA was applied to bilateral Zusanli (ST 36) to alleviate pain. Only mice in the CFA+EA group received EA treatment (30 min/d for 2 weeks) 24 h after modelling. Mice in the saline and CFA groups received sham EA. von-Frey test and Hargreaves test were used to assess the pain threshold. Brain and spinal tissues were collected for immunofluorescence staining or Western blotting to quantify changes of MD2 expression. CFA successfully induced plantar pain and EA significantly alleviated pain 3 days after modelling (P<0.01). Compared with the CFA group, the number of MD2+/c-fos+ neurons was significantly increased in the dorsal horn of the spinal cord 7 and 14 days after EA, especially in laminae I - IIo (P<0.01). The proportion of double positive cells to the number of c-fos positive cells and the mean fluorescence intensity of MD2 neurons were also significantly increased in laminae I - IIo (P<0.01). Western blotting showed that the level of MD2 was significantly decreased by EA only in the hippocampus on day 7 and 14 (both P<0.01) and no significant changes were observed in the cortex, thalamus, cerebellum, or the brainstem (P<0.05). Fluorescence staining showed significant decrease in the level of MD2 in periagueductal gray (PAG) and locus coeruleus (LC) after CFA injection on day 7 (P<0.01 for PAG, P<0.05 for LC) and EA significantly reversed this decrease (P<0.01 for PAG, P<0.05 for LC). The unique changes of MD2 suggest that EA may exert the analgesic effect through modulating neuronal activities of the superficial laminae of the spinal cord and certain regions of the brain.

Approach for Electrophysiological Studies of Spinal Lamina X Neurons.

Despite playing diverse physiological roles, the area surrounding the central canal, lamina X, remains one of the least studied spinal cord regions. Technical challenges and limitations of the commonly used experimental approaches are the main difficulties that hamper lamina X research. In the current protocol, we describe a reliable method for functional investigation of lamina X neurons that requires neither time-consuming slicing nor sophisticated in vivo experiments. Our approach relies on ex vivo hemisected spinal cord preparation that preserves the rostrocaudal and mediolateral spinal architecture as well as the dorsal roots, and infrared LED oblique illumination for visually guided patch clamp in thick blocks of tissue. When coupled with electric stimulation of the spared dorsal roots, electrophysiological recordings provide information on primary afferent inputs to lamina X neurons from myelinated and non-myelinated fibers and allow estimating primary afferent-driven presynaptic inhibition. Overall, we describe a simple, time-efficient, inexpensive, and versatile approach for lamina X research. Key features • Quick and easy preparation procedure that grants access to lamina X neurons without spinal cord slicing • Preserved rostrocaudal and mediolateral connectivity and preserved primary afferent supply • Ability to perform electrophysiological recordings in combination with dorsal root stimulations allowing to study afferent inputs and presynaptic inhibition of lamina X neurons.

Clinical characteristics analysis of 4 cases with acute flaccid myelitis in children

Objective: To summarize the clinical manifestations, diagnosis, treatment and prognosis of acute flaccid myelitis (AFM) in children. Methods: Clinical characteristics of 4 AFM cases from Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics, from September 2018 to November 2022, were analyzed retrospectively. Results: The age of 4 children with AFM was 7 years, 4 years and 3 months, 7 years and 1 month, 6 years and 5 months, respectively. There were 2 boys and 2 girls. Prodromal infection status showed 3 children of respiratory tract infection and 1 child of digestive tract infection. The main manifestation was asymmetrical limb weakness after infection, and the affected limb range was from monoplegia to quadriplegia. Cranial nerve injury was involved in 1 child, no encephalopathy. Magnetic resonance imaging in the spinal cord of all 4 children showed long T1 and T2 signals, mainly involving gray matter. Cerebrospinal fluid cell-protein separation was observed in 2 children. Pathogen detected in 1 child pharyngeal swab was enterovirus D68. Antibody IgM to adenovirus was positive in the blood of 1 child. Antibody IgG against Echo and Coxsackie B virus were positive in the blood of another child. After glucocorticoid, human immunoglobulin or simple symptomatic treatment and at the same time under later rehabilitation training, muscle strength recovered to different degrees, but there were disabilities left in 3 children. Conclusions: AFM should be considered in children with acute and asymmetrical flaccid paralysis accompanied by abnormal magnetic resonance imaging signal in the central region of spinal cord, especially post-infection. The effective treatment is limited and the prognosis is poor.

Old age alters inflammation and autophagy signaling in the brain, leading to exacerbated neurological outcomes after spinal cord injury in male mice

Older patients with spinal cord injury (SCI) have different features with regard to neurological characteristics after injury. Recent large-scale longitudinal population-based studies showed that individuals with SCI are at a higher risk of developing dementia than non-SCI patients, indicating that SCI is a potential risk factor for dementia. Aging is known to potentiate inflammation and neurodegeneration at the injured site leading to impaired recovery from SCI. However, no research has been aimed at studying the mechanisms of SCI-mediated cognitive impairment in the elderly. The present study examined neurobehavioral and molecular changes in the brain and the underlying mechanisms associated with brain dysfunction in aged C57BL/6 male mice using a contusion SCI model. At 2 months post-injury, aged mice displayed worse performance in locomotor, cognitive and depressive-like behavioral tests compared to young adult animals. Histopathology in injured spinal cord tissue was exacerbated in aged SCI mice. In the brain, transcriptomic analysis with NanoString neuropathology panel identified activated microglia and dysregulated autophagy as the most significantly altered pathways by both age and injury. These findings were further validated by flow cytometry, which demonstrated increased myeloid and lymphocytes infiltration at both the injured site and brain of aged mice. Moreover, SCI in aged mice altered microglial function and dysregulated autophagy in microglia, resulting in worsened neurodegeneration. Taken together, our data indicate that old age exacerbates neuropathological changes in both the injured spinal cord and remote brain regions leading to poorer functional outcomes, at least in part, through altered inflammation and autophagy function.

Identification of Matrine as a Kirsten rats Arcomaviral oncogene homolog inhibitor alleviating chemotherapy-induced neuropathic pain

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) represents a prevailing and severe clinical concern, characterized by limited availability of clinically effective treatment strategies. Current evidence endorses matrine's potential as a neuroprotective and analgesic agent for CIPN. Nevertheless, the precise targets and mechanisms of action of matrine remain insufficiently explored, impeding comprehensive pharmacological investigation and clinical application. ObjectiveThis study endeavors to elucidate the analgesic and neuroprotective effects of matrine in mice with vincristine-induced neuropathic pain. A focal point is the identification of matrine's specific target and the underlying molecular mechanisms governing its analgesic and neuroprotective actions. MethodsTo discern matrine's analgesic effects in CIPN mice, we conducted behavioral experiments encompassing the Von Frey filament test and Hargreaves Test. Furthermore, we conducted electrophysiological and histopathological assessments involving HE staining, Nissl staining, and Fluoro-Jade B staining to evaluate matrine's effects on neuroprotection within dorsal root ganglia and the spinal cord of CIPN mice. Sequentially, thermal shift assay, GTP hydrolysis assay, and nucleotide exchange assay were executed to validate matrine's inhibitory effects on KRAS. Molecular docking and site-directed mutagenesis experiments were implemented to identify the precise binding pocket of matrine on KRAS. Lastly, matrine's inhibitory effects on downstream signaling pathways of KRAS were confirmed through experiments conducted at animal model. ResultsMatrine exhibited a notable increase in mechanical withdrawal threshold and thermal withdrawal latency in vincristine-treated mice. This compound substantially ameliorated the neurofunctional blockade associated with sensory and motor functions induced by vincristine. Moreover, matrine mitigated pathological damage within DRG and the L4-L5 spinal cord regions. The study's MST experiments indicated matrine's substantial elevation of KRAS's melting temperature. The GTP hydrolysis and nucleotide exchange assays revealed concentration-dependent inhibition of KRAS activity by matrine. Molecular docking provided insight into the binding mode of matrine with KRAS, while site-directed mutagenesis verified the specific binding site of matrine on KRAS. Lastly, matrine's inhibition of downstream Raf/Erk1/2 and PI3K/Akt/mTOR signaling pathways of KRAS was confirmed in VCR mice. ConclusionCompared to previous studies, our research has identified matrine as a natural inhibitor of the elusive protein KRAS, often considered "undruggable." Furthermore, this study has revealed that matrine exerts its therapeutic effects on chemotherapy-induced peripheral neuropathy (CIPN) by inhibiting KRAS activation, subsequently suppressing downstream signaling pathways such as Raf/Erk1/2 and PI3K/Akt/mTOR. This investigation signifies the discovery of a novel target for matrine, thus expanding the potential scope of its involvement in KRAS-related biological functions and diseases. These findings hold the promise of providing a crucial experimental foundation for forthcoming drug development initiatives centered around matrine, thereby advancing the field of pharmaceutical research.

Atg7 autophagy-independent role on governing neural stem cell fate could be potentially applied for regenerative medicine.

A literature review showed that Atg7 biological role was associated with the development and pathogenesis of nervous system, but very few reports focused on Atg7 role on neurogenesis at the region of spinal cord, so that we are committed to explore the subject. Atg7 expression in neural tube is incrementally increased during neurogenesis. Atg7 neural-specific knockout mice demonstrated the impaired motor function and imbalance of neuronal and glial cell differentiation during neurogenesis, which was similarly confirmed in primary neurosphere culture and reversely verified by Atg7 overexpression in unilateral neural tubes of gastrula chicken embryos. Furthermore, activating autophagy in neural stem cells (NSCs) of neurospheres did not rescue Atg7 deficiency-suppressed neuronal differentiation, but Atg7 overexpression on the basis of autophagy inhibition could reverse Atg7 deficiency-suppressed neuronal differentiation, which provides evidence for the existence of Atg7 role of autophagy-independent function. The underlying mechanism is that Atg7 deficiency directly caused the alteration of cell cycle length of NSCs, which is controlled by Atg7 through specifically binding Mdm2, thereby affecting neuronal differentiation during neurogenesis. Eventually, the effect of overexpressing Atg7-promoting neuronal differentiation was proved in spinal cord injury model as well. Taken together, this study revealed that Atg7 was involved in regulating neurogenesis by a non-autophagic signaling process, and this finding also shed light on the potential application in regenerative medicine.

Developmental Anatomy of Gray Matter of Spinal Cord in Animals with Special Reference to Prenatal Goat: A Review

Spinal cord is the major nerve tract of vertebrates, extending from the brain through the vertebral canal. Primordium, the neural tube was initially with thick lateral walls having three layers: inner germinal/ependymal layer, middle mantle layer forming the gray matter and outer marginal layer forming white matter. It presented a diamond-shaped lumen with a sulcus limitans, alar, basal, roof and floor plates and limiting membranes. Gray matter of the cord occupies the central region of spinal cord and in amniotes has in cross section, the well-known ‘H’ or butterfly-like shape. The white matter forms a thick peripheral zone of the cord and is divided by the gray columns into dorsal, lateral and ventral funiculi. There are three coumns for the gray matter, viz. the dorsal, ventral and lateral horns, with ventral ones being wider at the enlargements of the cord. Lateral horn appears only at thoracic, anterior lumbar and middle sacral levels. The layers of gray matter were laminae I to X. Lamina I or marginal zone capped the dorsal horn. Lamina II represented substantia gelatinosa and covered the dorsal horn, beneath marginal zone. Lamina III was an area with loosely arranged larger cells, entering the substantia gelatinosa. Lamina IV was a poorly defined cell column with nucleus proprius. Lamina V was a broad zone extending across the cervix of the dorsal horn; had spinal reticular nucleus and reticular processes. The region showed small to medium-sized cells which were most numerous in the zone between the ventral part of the dorsal horn and the lateral funiculus of white matter. Lamina VI was broad with unclear boundaries, related medially to central canal. It had compact medial and less compact lateral zones. Lamina VII shows the intermediate gray matter, with intermediolateral and intermediomedial nuclei, cervical nucleus of Stilling and Clark’s column. Lamina VIII had cells of small and medium size and was not sharply distinguished from lamina VII. Lamina IX had alpha and gamma type of neurons, which were larger at enlargements. Ventral horn had lateral and medial nuclear groups of multipolar neurons. Medial nuclear groups were seen in all regions and lateral groups only at enlargements. Medial nuclear group had dorsomedial and ventromedial nuclei; whereas the smaller lateral nuclear group had dorsolateral and ventrolateral nuclei. In addition, the enlargements also had central and retrodorsolateral nuclei. Lamina X was seen around the central canal. Laminae varied in cell size and thickness between regions of the cord. Development of laminae and nuclei of spinal gray in fetuses corresponded to the progressive growth of muscles and skeleton. All the ten laminae were together present in the spinal gray matter by the end of gestation.

Populations of Hindbrain Glucagon-Like Peptide 1 (GLP1) Neurons That Innervate the Hypothalamic PVH, Thalamic PVT, or Limbic Forebrain BST Have Axon Collaterals That Reach All Central Regions Innervated by GLP1 Neurons.

Neurons in the caudal nucleus of the solitary tract (cNTS) and intermediate reticular nucleus (IRt) that express the glucagon gene (Gcg) give rise to glucagon-like peptide 1 (GLP1)-immunopositive axons in the spinal cord and many subcortical brain regions. Central GLP1 receptor signaling contributes to motivated behavior and stress responses in rats and mice, in which hindbrain GLP1 neurons are activated to express c-Fos in a metabolic state-dependent manner. The present study examined whether GLP1 inputs to distinct brain regions arise from distinct subsets of Gcg-expressing neurons, and mapped the distribution of axon collaterals arising from projection-defined GLP1 neural populations. Using our Gcg-Cre knock-in rat model, Cre-dependent adeno-associated virus (AAV) tracing was conducted in adult male and female rats to compare axonal projections of IRt versus cNTS GLP1 neurons. Overlapping projections were observed in all brain regions that receive GLP1 input, with the caveat that cNTS injections produced Cre-dependent labeling of some IRt neurons, and vice versa. In additional experiments, specific diencephalic or limbic forebrain nuclei were microinjected with Cre-dependent retrograde AAVs (AAVrg) that expressed reporters to fully label the axon collaterals of transduced GLP1 neurons. AAVrg injected into each forebrain site labeled Gcg-expressing neurons in both the cNTS and IRt. The collective axon collaterals of labeled neurons entered the spinal cord and every brain region previously reported to contain GLP1-positive axons. These results indicate that the axons of GLP1 neural populations that innervate the thalamic paraventricular nucleus, paraventricular nucleus of the hypothalamus, and/or bed nucleus of the stria terminalis collectively innervate all central regions that receive GLP1 axonal input.

Investigating Descending Pain Regulation in Fibromyalgia and the Link to Altered Autonomic Regulation by Means of Functional MRI Data.

Fibromyalgia syndrome (FM) is a chronic pain condition that affects a significant portion of the population; yet, this condition is still poorly understood. Prior research has suggested that individuals with FM display a heightened sensitivity to pain and signs of autonomic dysfunction. Recent advances in functional MRI analysis methods to model blood-oxygenation-level-dependent (BOLD) responses across networks of regions, and structural and physiological modeling (SAPM) have shown the potential to provide more detailed information about altered neural activity than was previously possible. Therefore, this study aimed to apply novel analysis methods to investigate altered neural processes underlying pain sensitivity in FM in functional magnetic resonance imaging (fMRI) data from the brainstem and spinal cord. Prior fMRI studies have shown evidence of functional differences in fibromyalgia (FM) within brain regions associated with pain's motivational aspects, as well as differences in neural activity related to pain regulation, arousal, and autonomic homeostatic regulation within the brainstem and spinal cord regions. We, therefore, hypothesized that nociceptive processing is altered in FM compared to healthy controls (HCs) in the brainstem and spinal cord areas linked to autonomic function and descending pain regulation, including the parabrachial nuclei (PBN) and nucleus tractus solitarius (NTS). We expected that new details of this altered neural signaling would be revealed with SAPM. The results provide new evidence of altered neural signaling in FM related to arousal and autonomic homeostatic regulation. This further advances our understanding of the altered neural processing that occurs in women with FM.

A patterned human neural tube model using microfluidic gradients.

The human nervous system is a highly complex but organized organ. The foundation of its complexity and organization is laid down during regional patterning of the neural tube, the embryonic precursor to the human nervous system. Historically, studies of neural tube patterning have relied on animal models to uncover underlying principles. Recently, models of neurodevelopment based on human pluripotent stem cells, including neural organoids1-5 and bioengineered neural tube development models6-10, have emerged. However, such models fail to recapitulate neural patterning along both rostral-caudal and dorsal-ventral axes in a three-dimensional tubular geometry, a hallmark of neural tube development. Here we report a human pluripotent stem cell-based, microfluidic neural tube-like structure, the development of which recapitulates several crucial aspects of neural patterning in brain and spinal cord regions and along rostral-caudal and dorsal-ventral axes. This structure was utilized for studying neuronal lineage development, which revealed pre-patterning of axial identities of neural crest progenitors and functional roles of neuromesodermal progenitors and the caudal gene CDX2 in spinal cord and trunk neural crest development. We further developed dorsal-ventral patterned microfluidic forebrain-like structures with spatially segregated dorsal and ventral regions and layered apicobasal cellular organizations that mimic development of the human forebrain pallium and subpallium, respectively. Together, these microfluidics-based neurodevelopmentmodels provide three-dimensional lumenal tissue architectures with in vivo-like spatiotemporal cell differentiation and organization, which will facilitate the study of human neurodevelopment and disease.