Search Results (231)

Glaucoma is recognized as a chronic optic neuropathy marked by progressive optic nerve degeneration, loss of retinal ganglion cells (RGCs, the neurons responsible for transmitting visual information from the eye to the brain), disruptions in optic disc blood supply, and changes in glial cell activation. It ranks as the second most prevalent cause of irreversible visual impairment worldwide and is a resultant of increased intraocular pressure (IOP). Addressing this condition proves complex due to the inherent hindrances posed by ocular barriers, which curtail the entry of drugs into the eye. Diverse carriers such as inorganic nanoparticles, polymeric nanocarriers, hydrogels, and contact lens-based systems with distinct physical and chemical attributes are being studied for drug delivery. They have shown enhanced ocular drug bioavailability through higher penetration across ocular tissues, prolonged retention in the precorneal space, sustained drug release, and targeted delivery to specific tissues. These ingenious delivery systems can be deployed through various administration routes—intravitreal or periocular injections or systemic administration—enabling the drugs to reach affected areas, aiding in the regeneration of compromised optical nerves. This review presents a comprehensive exploration of contemporary strides in ocular delivery formulations pertaining to glaucoma. This encompasses an examination of various nanocarrier typologies, delivery routes, in vitro and in vivo effectiveness, clinical applicability, and a forward-looking perspective into potential future developments. Full article

An important disadvantage of plastics is their fragmentation into smaller particles, classified according to size as microplastics and nanoplastics. These plastic particles persist for extended periods in aerial, terrestrial, and aquatic ecosystems and can be incorporated into animal bodies through various routes, including inhalation, dermal contact, and the food chain. The accumulation of these debris generates toxicity on several organs, including the nervous system. In this review article, I will cover the detrimental consequences of plastic exposure on the nervous system, the impact of microplastics and nanoplastics on the genesis of neurons both in the embryonic period as well as in adulthood, and the reliability of 5-bromo-2′-deoxyuridine (BrdU) labeling as a tool to analyze the effect of microplastic and nanoplastic exposure on the proliferative behavior of neuronal precursors. BrdU is a marker of DNA synthesis. It is widely used to identify proliferating neuroblasts and follow their fate during embryonic, perinatal, and adult neurogenesis. However, the use of BrdU labeling for analyzing neurogenesis may be inaccurate due to pitfalls and limitations. This is because BrdU exposure can induce apoptosis, cellular senescence, and alterations in DNA methylation. Interestingly, these cellular events also occur following exposure to plastic particles. Full article

Accurate calibration of mesoscopic contact model parameters is essential for ensuring the reliability of Particle Flow Code in Three Dimensions (PFC3D) simulations in geotechnical engineering. Trial-and-error approaches are often used to determine the parameters of the contact model, but they are time-consuming, labor-intensive, and offer no guarantee of parameter validity or simulation credibility. Although conventional machine learning techniques have been applied to invert the contact model parameters, they are hampered by the difficulty of selecting the optimal hyperparameters and, in some cases, insufficient data, which limits both the predictive accuracy and robustness. In this study, a total of 361 PFC3D uniaxial compression simulations using a linear parallel bond model with varied mesoscopic parameters were generated to capture a wide range of rock and geotechnical material behaviors. From each stress–strain curve, eight characteristic points were extracted as inputs to a multi-objective Automated Machine Learning (AutoML) model designed to invert three key mesoscopic parameters, i.e., the elastic modulus (E), stiffness ratio (k_s/k_n), and degraded elastic modulus (E_d). The developed AutoML model, comprising two hidden layers of 256 and 32 neurons with ReLU activation function, achieved coefficients of determination (R²) of 0.992, 0.710, and 0.521 for E, k_s/k_n, and E_d, respectively, demonstrating acceptable predictive accuracy and generalizability. The multi-objective AutoML model was also applied to invert the parameters from three independent uniaxial compression tests on rock-like materials to validate its practical performance. The close match between the experimental and numerically simulated stress–strain curves confirmed the model’s reliability for mesoscopic parameter inversion in PFC3D. Full article

Background: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons, with bulbar dysfunction manifesting in up to 80% of patients. Dysarthria, characterized by impaired speech production, is common in ALS and often correlates with disease severity. Voice analysis has emerged as a promising tool for detecting disease progression and monitoring functional status. Methods: This study investigates acoustic and biomechanical voice alterations in ALS patients and their association with clinical measures of functional independence. A descriptive observational case series study was conducted, involving 43 ALS patients and 43 age and sex matched controls with non-neurological voice disorders. Sustained vowel /a/ recordings were obtained and analyzed using Voice Clinical Systems^® and Praat software (version 6.2.22). Biomechanical and acoustic parameters were correlated with ALS Functional Rating Scale-Revised (ALSFRS-R) and Barthel Index scores. Results: Significant differences were observed between ALS and control groups (elevated muscle force and tension and interedge distance in non-ALS individuals). Between bulbar and spinal ALS subtypes, elevated values were observed in certain parameters in Bulbar ALS patients, indicating irregular vocal fold contact and weakened phonatory control, while spinal ALS exhibited increased values, suggesting higher phonatory muscle tension. Elevated biomechanical parameters were significantly correlated with low ALSFRS-R scores, suggesting a possible relationship between voice measures and functional decline. However, acoustic measurements showed no relationship with performance status. Conclusions: These results highlight the potential of voice analysis as a non-invasive, objective tool for monitoring ALS stage and differentiating between subtypes. Further research is needed to validate these findings and explore their clinical applications. Full article

In this study, we present a proof-of-concept neuroelectronic interface (NEI) for extracellular stimulation and recording of neurophysiological activity in spiral ganglion neurons (SGNs) cultured in vitro on three-dimensional, micro-patterned substrates with customized microtopographies, integrated within a 196-channel microelectrode array (MEA). This approach enables mechanotaxis-driven neuronal contact guidance, promoting SGN growth and development, which is highly sensitive to artificial in vitro environments. The microtopography geometry was optimized based on our previous studies to enhance SGN alignment and neuron-electrode interactions. The NEI was validated using SGNs dissociated from rat pups in the prehearing period and cultured for seven days in vitro (DIV). We observed viable and proliferative cellular cultures with robust neurophysiological responses in the form of local field potentials (LFPs) resembling action potentials (APs), elicited both spontaneously and through electrical stimulation. These findings provide deeper insights into SGN behavior and neuron-microenvironment interactions, laying the groundwork for further advancements in neuroelectronic systems. Full article

Stainless steel (SS) 316l constitutes a popular biomaterial with various applications as implants in cardiovascular and orthopedic surgery, as well as in dentistry. Nevertheless, its cytocompatibility against neuronal cells has not been investigated, a feature that is important for the construction of implants that require contact with neurons, e.g., neuronal electrodes. In addition, most cytocompatibility studies have focused on decorated or surface-modified SS 316l. On the other hand, SH-SY5Y cells are an established cellular model for cytocompatibility studies of potential biomaterials given their ability to differentiate into neuron-like cells. Here, we used retinoic-acid-differentiated SH-SY5Y cells and SH-SY5Y controls to investigate the cytocompatibility and biomimetics of uncoated SS 316l. The assessment of cytocompatibility was based on the determination of differentiation markers by immunofluorescence, RT-qPCR, and the neurite growth of these cells attached on SS 316l and standard tissue culture polystyrene (TCP) surfaces. Even though the neurite length was shorter in differentiated SH-SY5Y cells grown on SS 316l, no other significant changes were found. In conclusion, our results suggest that the uncoated SS 316l mimics a natural bio-surface and allows the adhesion, growth, and differentiation of SH-SY5Y cells. Therefore, this alloy can be directly applied in the emerging field of biomimetics, especially for the development of implants or devices that contact neurons. Full article

Allergic contact dermatitis (ACD) is a skin condition characterized by inflammation resulting from hypersensitivity upon contact with certain allergens. Although ACD is characterized by an immune-mediated pathomechanism, the involvement of the nervous system in this condition has increasingly been considered, particularly in the amplification and persistence of inflammation. This paper aims to present a comprehensive overview of the mechanisms involved in neurogenic inflammation in ACD, focusing on the role of sensory neurons, the release of neuropeptides, their interaction with immune cells, and the potential therapeutic implications related to neurogenic pathways, diversified by age and gender. Innovative therapies for ACD, including topical formulations, may target the mass-bound X2 G-protein-coupled receptor (MRGPRX2) and endocannabinoid systems. Full article

Sensory signals generated by peripheral nociceptors are transmitted by peptidergic and nonpeptidergic nociceptive primary afferents to the superficial spinal dorsal horn, where their central axon terminals establish synaptic contacts with secondary sensory spinal neurons. In the case of suprathreshold activation, the axon terminals release glutamate into the synaptic cleft and stimulate postsynaptic spinal neurons by activating glutamate receptors located on the postsynaptic membrane. When overexcitation is evoked by peripheral inflammation, neuropathy or pruritogens, peptidergic nociceptive axon terminals may corelease various neuropeptides, neurotrophins and endomorphin, together with glutamate. However, in contrast to glutamate, neuropeptides, neurotrophins and endomorphin are released extrasynaptically. They diffuse from the site of release and modulate the function of spinal neurons via volume transmission, activating specific extrasynaptic receptors. Thus, the released neuropeptides, neurotrophins and endomorphin may evoke excitation, disinhibition or inhibition in various spinal neuronal populations, and together with glutamate, induce overall overexcitation, called central sensitization. In addition, the synaptic and extrasynaptic release of neurotransmitters is subjected to strong retrograde control mediated by various retrogradely acting transmitters, messengers, and their presynaptic receptors. Moreover, the composition of this complex chemical apparatus is heavily dependent on the actual patterns of nociceptive primary afferent activation in the periphery. This review provides an overview of the complexity of this signaling apparatus, how nociceptive primary afferents can activate secondary sensory spinal neurons via synaptic and volume transmission in the superficial spinal dorsal horn, and how these events can be controlled by presynaptic mechanisms. Full article

Non-invasive, non-contact, and painless methods of electrical stimulation to enhance neural function have been widely studied in recent years, particularly in the context of neurodegenerative diseases such as Alzheimer’s disease (AD) and related dementias, which cause cognitive decline and other neurological symptoms. Radiofrequency (RF), which is a rate of oscillation in the range of 3 kHz to 300 GHz (3 THz), has been suggested as one potential non-contact neuronal stimulation (NCNS) technique for improving brain function. A new type of electrical stimulation uses a radiofrequency electromagnetic field (RF-EMF). RF exposure has been shown to modulate neural stimulation and influence various brain activities in in vitro and in vivo models. Recent studies have explored the effects of RF-EMF on human physiology, particularly in areas such as brain activity, cognition, and sleep behavior. In this review, we summarize recent findings about the effects of non-contact stimulations in in vitro studies, in vivo animal models, and human clinical cases. Full article

Unsatisfactory sleep is a worldwide concern, as evidenced by the high prevalence of insomnia symptoms and diagnosis in the general population, and an issue that has also risen among adolescents. These circumstances are a cause of worry due to, among other factors, the observed bidirectional association of sleep disturbances and the risk of substance use disorder development. In this regard, across the globe, several reports indicate that substance consumption is at an all-time high, with alcohol, nicotine, and cannabis leading the charts. Additionally, the age of onset has dropped, with reports suggesting that first contact is usually during adolescence. Although the nature of the link between poor sleep and substance use disorder development is still not fully understood, it is possible that an overactive orexinergic system could play a role, as it has been observed that treatment with orexinergic antagonists improves insomnia symptoms and that postmortem studies show an increase in orexin immunoreactive neurons in sections obtained from habitual opioid consumers. We further argue that it is during adolescence that this maladaptive loop can be established, priming for the development of substance use disorders. Full article

Focal swellings of dendrites (“dendritic blebbing”) together with structural damage of mitochondria and the endoplasmic reticulum (ER) are morphological hallmarks of glutamate neurotoxicity, also known as excitotoxicity. These pathological alterations are generally thought to be caused by the so-called “overactivation” of N-methyl-D-aspartate receptors (NMDARs). Here, we demonstrate that the activation of extrasynaptic NMDARs, specifically when forming a protein–protein complex with TRPM4, drives these pathological traits. In contrast, strong activation of synaptic NMDARs fails to induce cell damage despite evoking plateau-type calcium signals that are comparable to those generated by activation of the NMDAR/TRPM4 complex, indicating that high intracellular calcium levels per se are not toxic to neurons. Using confocal laser scanning microscopy and transmission electron microscopy, we show that disrupting the NMDAR/TRPM4 complex using the recently discovered small-molecule TwinF interface inhibitor FP802 inhibits the NMDA-induced neurotoxicity-associated dendritic blebbing and structural damage to mitochondria and the ER. It also prevents, at least in part, the disruption of ER–mitochondria contact sites. These findings establish the NMDAR/TRPM4 complex as the trigger for the structural damage of dendrites and intracellular organelles associated with excitotoxicity. They also suggest that activation of the NMDAR/TRPM4 complex, in addition to inducing high-amplitude, plateau-type calcium signals, generates a second signal required for glutamate neurotoxicity (“two-hit hypothesis”). As structural damage to organelles, particularly mitochondria, is a common feature of many human neurodegenerative diseases, including Alzheimer’s disease and amyotrophic lateral sclerosis (ALS), TwinF interface inhibitors have the potential to provide neuroprotection across a broad spectrum of these diseases. Full article

Background: Epilepsy is a neurological disorder defined by the occurrence of epileptic seizures, which can significantly affect children, often leading to learning and cognitive impairments. Microglia, the resident immune cells of the central nervous system, are essential in clearing damaged neurons through phagocytosis. Notably, GAB_BR-associated microglia have been implicated in regulating phagocytic activity. Since the phagocytic function of microglia is critical in the pathogenesis of epilepsy, this study aims to investigate the role of GAB_BR-associated microglia in the development of the immature brain following epileptic seizures. Methods: Epilepsy was induced in a mouse model by the intraperitoneal injection of KA. Changes in the expression of the GAB_BR-related gene, GAB_BR2, in hippocampal microglia were analyzed using single-nucleus RNA sequencing (snRNA-seq). Cognitive and emotional changes in the mice were assessed through behavioral analyses. The expression of GAB_BR2 was semi-quantitatively measured using Western blotting, quantitative reverse transcription PCR, and immunofluorescence. Additionally, the spatial relationship between GAB_BR2 and hippocampal neurons was evaluated using Imaris software. Results: The snRNA-seq analysis revealed that GAB_BR2 expression was elevated in activated microglia in the hippocampus during chronic epilepsy compared to the early phase of seizures. Behavioral assessments demonstrated heightened anxiety levels and learning and memory impairments in the chronic epilepsy group compared to the control group. GAB_BR2 expression was upregulated in chronic epilepsy. Three-dimensional reconstruction analyses revealed a significantly increased contact volume between GAB_BR-associated microglia and neurons in the chronic epilepsy group compared to the control group. Conclusions: GAB_BR-associated microglia significantly contribute to the progression of immature brain diseases by promoting neuronal phagocytic activity. Full article

Cochlear implants are well established devices for treating severe hearing loss. However, due to the trauma caused by the insertion of the electrode and the subsequent formation of connective tissue, their clinical effectiveness varies. The aim of the current study was to achieve a long-term reduction in connective tissue growth and impedance by combining surface patterns on the electrode array with a poly-L-lactide coating containing 20% diclofenac. Three groups of six guinea pigs each (control, structure, structure with diclofenac in the coating) were implanted for four weeks. The hearing thresholds were measured before implantation and after 28 days, and impedances were monitored over time. After histological preparation, connective tissue growth and spiral ganglion neuron (SGN) survival were quantified. The hearing thresholds and impedances increased over time in all groups, showing no significant differences. The treatment groups showed increased damage in the cochlea, which appeared to be caused by the elevated parts of the microstructures. This seems to be amplified by the trauma model used in the current study. The impedances correlated with connective tissue growth near the electrode contacts. In addition, SGN survival was negatively correlated with the presence of connective tissue, both of which highlight the importance of successfully reducing connective tissue formation after cochlear implantation. Full article

Neural progenitor cells (NPCs) are often used to study the subcellular mechanisms underlying differentiation into neurons in vitro. Works published to date have focused on the pathways that distinguish undifferentiated NPCs from mature neurons, neglecting the earlier and intermediate stages of this process. Current evidence suggests that mitochondria interaction with the ER is fundamental to a wide range of intracellular processes. However, it is not clear whether and how the mitochondria–ER interactions differ between NPCs and their differentiated counterparts. Here we take advantage of the widely used NPC line LUHMES to provide hints on the mitochondrial dynamic trait changes that occur during the first stage of their maturation into dopaminergic-like neurons. We observed that the morphology of mitochondria, their interaction with the ER, and the expression of several mitochondria–ER contact site resident proteins change, which suggests the potential contribution of mitochondria dynamics to NPC differentiation. Further studies will be needed to explore in depth these changes, and their functional outcomes, which may be relevant to the scientific community focusing on embryonic neurogenesis and developmental neurotoxicity. Full article

The ultrastructural organization of the nuclei of the tegmental region in juvenile chum salmon (Oncorhynchus keta) was examined using transmission electron microscopy (TEM). The dorsal tegmental nuclei (DTN), the nucleus of fasciculus longitudinalis medialis (NFLM), and the nucleus of the oculomotor nerve (NIII) were studied. The ultrastructural examination provided detailed ultrastructural characteristics of neurons forming the tegmental nuclei and showed neuro–glial relationships in them. Neurons of three size types with a high metabolic rate, characterized by the presence of numerous mitochondria, polyribosomes, Golgi apparatus, and cytoplasmic inclusions (vacuoles, lipid droplets, and dense bodies), were distinguished. It was found that large interneurons of the NFLM formed contacts with protoplasmic astrocytes. Excitatory synaptic structures were identified in the tegmentum and their detailed characteristic are provided for the first time. Microglia-like cells were found in the NIII. The ultrastructural characteristics of neurogenic zones of the tegmentum of juvenile chum salmon were also determined for the first time. In the neurogenic zones of the tegmentum, adult-type neural stem progenitor cells (aNSPCs) corresponding to cells of types III and IVa Danio rerio. In the neurogenic zones of the tegmentum, neuroepithelial-like cells (NECs) corresponding to cells previously described from the zebrafish cerebellum were found and characterized. In the tegmentum of juvenile chum salmon, patterns of paracrine neurosecretion were observed and their ultrastructural characteristics were recorded. Patterns of apoptosis in large neurons of the tegmentum were examined by TEM. Using immunohistochemical (IHC) labeling of the brain lipid-binding protein (BLBP) and aromatase B (AroB), patterns of their expression in the tegmentum of intact animals and in the post-traumatic period after acute injury to the medulla oblongata were characterized. The response to brainstem injury in chum salmon was found to activate multiple signaling pathways, which significantly increases the BLBP and AroB expression in various regions of the tegmentum and valvula cerebelli. However, post-traumatic patterns of BLBP and AroB localizations are not the same. In addition to a general increase in BLBP expression in the tegmental parenchyma, BLBP overexpression was observed in the rostro-lateral tegmental neurogenic zone (RLTNZ), while AroB expression in the RLTNZ was completely absent. Another difference was the peripheral overexpression of AroB and the formation of dense reactive clusters in the ventro-medial zone of the tegmentum. Thus, in the post-traumatic period, various pathways were activated whose components were putative candidates for inducers of the “astrocyte-like” response in the juvenile chum salmon brain that are similar to those present in the mammalian brain. In this case, BLBP acted as a factor enhancing the differentiation of both radial glia and neurons. Estradiol from AroB+ astrocytes exerted paracrine neuroprotective effects through the potential inhibition of inflammatory processes. These results indicate a new role for neuronal aromatization as a mechanism preventing the development of neuroinflammation. Moreover, our findings support the hypothesis that BLBP is a factor enhancing neuronal and glial differentiation in the post-traumatic period in the chum salmon brain. Full article