Search Results (5,996)

Animal studies have shown that early life exposure to general anesthetics may impair brain development. However, the implications of this phenomenon in human patients remain unclear. In this study, we use an induced pluripotent stem cell (iPSC)-derived human brain microphysiological system (bMPS) to investigate the effects of early sevoflurane (SEV) exposure on human brain development. Human iPSCs were cultured and differentiated into neural progenitor cells (NPCs) and then into bMPS. At week 8, bMPSs were exposed to 2.4% SEV for 4 h. Four weeks after exposure, immunofluorescence (IF), Western blotting (WB), and quantitative real-time polymerase chain reaction (qPCR) were conducted to evaluate the alteration of nerve cells in bMPS. After SEV exposure, the number of apoptotic cells increases, and the level of neural differentiation markers decreases. The ratios of mature neurons over NPCs and mature oligodendrocytes over oligodendrocyte progenitor cells (OPCs) are reduced, which leads to a reduction in myelination. SEV also impedes the development of astrocytes and synaptogenesis, especially the formation of excitatory synapses. Meanwhile, SEV increases the expression of molecules in the mammalian target of rapamycin (mTOR) signal pathway. In conclusion, early SEV exposure substantially disrupts the development of human brain tissue, and the mTOR signal pathway is likely to be involved in this alteration. Full article

Neuropathic pain represents a complex, prolonged pain state arising from lesions within the somatosensory nervous system. Despite significant advances in elucidating its pathophysiology, current therapeutic approaches remain largely symptomatic and frequently inadequate. MicroRNAs, a class of small non-coding RNAs that regulate gene expression post-transcriptionally, have recently emerged as critical modulators of neuronal excitability, neuroinflammation, and synaptic plasticity, which are crucial processes in the development and maintenance of neuropathic pain. This review summarizes the current evidence linking specific miRNAs to the onset and maintenance of neuropathic pain, with an emphasis on their roles in peripheral and central sensitization. The potential of miRNA-based biomarkers for diagnosis and prognostic evaluation is also highlighted. A thorough understanding of the complex miRNA regulatory networks underlying neuropathic pain could facilitate the development of novel, mechanism-based therapies and ultimately improve clinical outcomes. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder first described more than one century ago. Over this time, many features of the disease have been discovered and, consequently, many different approaches in the diagnosis and treatment of AD have been developed. A major assumption has guided research on AD in the past: this fatal form of cognitive decline is believed to have a pathogenic basis in the deposition of amyloid beta (Aβ) aggregates throughout the brain. Consequently, a main goal of AD therapy is to reduce Aβ load, and several monoclonal antibodies targeting amyloid are among the most recent approaches to AD treatment. However, the effectiveness of these drugs is limited, as they cannot block the progression of the disease; they only slow it down in certain conditions. Many other causative factors are known to promote the development of the disease, with immune system involvement being the most investigated. Indeed, it has been well documented that the microglial response enhances the deposition of other altered proteins, such as Tau, and induces a neurotoxic microenvironment that promotes neuronal loss. In this scenario, the interaction between microglia and astrocytes is known to accelerate pathogenic processes, and a possible role for peripheral T lymphocytes in AD pathology has also been described. An interesting hypothesis is that immune cells driving chronic inflammation might worsen AD progression and, therefore, could represent a target for treatment strategies in this disease. Thus, this review article aims to summarise the role of brain and peripheral immune molecules and cells in AD. Also, immune-based treatments for AD are described, including those targeting microglia and T cells. Full article

Graphene oxide (GO)–lipid hybrid nanostructures represent a promising class of multifunctional platforms for drug delivery and fluorescence-guided cellular imaging. In this study, we developed a graphene oxide-supported lipid bilayer system composed of rhodamine-labeled phosphatidylcholine (POPC-Rhod) for the delivery of the repurposed antispasmodic drug alverine citrate (ALV) to neuroblastoma cells. The hybrid nanostructures were assembled using two drug-loading strategies and characterized by UV–Vis spectroscopy, fluorescence analysis, dynamic light scattering, and atomic force microscopy to evaluate molecular interactions, vesicle size distribution, and nanomechanical properties. In vitro studies were performed using human neuroblastoma SH-SY5Y cells and their retinoic acid-differentiated neuronal-like counterparts. Confocal microscopy confirmed efficient cellular uptake of the fluorescent lipid–graphene hybrids, while viability and mitochondrial reactive oxygen species assays revealed differentiation-dependent cellular responses. ALV-loaded hybrids induced cytotoxic effects in proliferating neuroblastoma cells, whereas differentiated neuron-like cells exhibited greater tolerance and, at moderate concentrations, preserved viability despite increased oxidative stress. These findings demonstrate that graphene oxide–lipid hybrids can act as fluorescence-traceable drug delivery platforms and highlight the potential of alverine as a candidate for repurposing in neural cancer models. The system presented here provides a proof-of-concept framework for the development of multifunctional nanocarriers integrating therapeutic delivery with imaging capabilities. Full article

Arsenic induces apoptosis in both cancerous and non-cancerous cells. The mechanism of arsenic-induced apoptosis is complex. We previously demonstrated that the antioxidant acetyl L-carnitine prevented sodium arsenite-induced apoptosis in zebrafish embryos. To gain more insight into the mechanism of arsenic-induced apoptosis, we explored the effect of another antioxidant, N-acetylcysteine (NAC). Co-treatment of sodium arsenite with 1 or 2 mM NAC had no effect on zebrafish development. There was a significant but partial reduction in apoptosis in the embryos co-treated with sodium arsenite and 1 mM NAC, while embryos treated with 1 mM NAC alone showed the loss of normal apoptosis that was observed in the control embryos. Complete abolition of apoptosis occurred in embryos co-treated with sodium arsenite and 2 mM NAC; however, 2 mM NAC alone resulted in 100% mortality, indicating antioxidant toxicity at high doses. NAC (1 mM) did not prevent sodium arsenite-induced increase in motor neurons, suggesting that arsenic-induced apoptosis and supernumerary motor neuron development are mediated via distinct pathways. To determine whether NAC prevented arsenic-induced apoptosis via reactive oxygen species (ROS) signaling, we assessed ROS levels and oxidative modification of proteins (carbonylation) using an OxyBlot assay. Neither sodium arsenite nor NAC altered protein oxidation, ROS levels, or p53, a pro-apoptotic protein, transcript levels. Additionally, dicoumarol, an inducer of p53 protein degradation, did not inhibit sodium arsenite-induced apoptosis. These results indicate that protein oxidation and p53 signaling are not involved in arsenic-induced apoptosis and that NAC prevents arsenic toxicity in zebrafish embryos through a hitherto unknown mechanism. Full article

Background: Translational circuit neuroscience delivers many candidate neurons whose manipulation could ameliorate psychiatric symptoms. However, the translation of these cellular targets into molecular targets—proteins selectively expressed in those neurons that could be pharmacologically manipulated for treatment—remains scarce. To what extent such a translation is possible or is actually impeded by a lack of highly cell type-specific expression of druggable proteins is unknown. Methods: We performed combinatorial differential expression analysis for over 7200 putatively druggable genes (Illuminating the Druggable Genome database) on large-scale single-cell RNAseq datasets from mouse and human cortex (Allen Institute Cell Types Database) to identify selectively expressed genes in important cellular candidates: several pyramidal cell types and parvalbumin, somatostatin and VIP interneurons of the prefrontal and anterior cingulate cortex and hippocampus in mice, and the cingulate cortex in humans. Results: We identified dozens of targets, including some with psychiatric relevance and/or suitability to modulate neural activity, like ion channels, GPCRs and transporters. However, none of them were expressed with absolute specificity in any of the analysed target cell types but only stood out in some comparisons, not others. Generally, results depended strongly on selectivity criteria: less conservative approaches (such as moderate p-value adjustment or grouping of contrast cell sets) yielded more targets, whereas the introduction of additional plausible constraints (difference in proportion of expressing cells, beta; absence of expression in contrast cell type) drove numbers towards zero. Generally, interneurons showed more selectively expressed targets in comparison to cells of the same region compared to excitatory ones (intra-regional comparisons), whereas the reverse was found in inter-regional contrasts comparing the same cell type across regions. Conclusions: The lack of high selectivity in the expression of genes encoding druggable targets constitutes a principal biological limit for manipulating cortical neurons of one type, specifically to leverage therapeutic action. While, currently, this conclusion is limited to the investigated neocortical and hippocampal regions, it highlights the need to develop biological heuristics for identifying targets expressed with relative specificity. Full article

Computational models of the MLG1 neurons in crab Neohelice granulata have been developed to detect and spatially localize looming stimuli. However, existing models suffer from significant performance degradation in dim scenarios, primarily due to visual signal corruption from stochastic noise such as photon shot noise. To address this challenge, we propose a computational framework that embeds Daubechies wavelet directly into ON/OFF visual pathways. The ON/OFF mechanism separates the input signals in parallel based on luminance changes to capture dynamic differences between target and background. Embedding Daubechies wavelet enables multi-scale frequency decomposition, allowing the model to suppress high-frequency noise while enhancing low-frequency looming trends. This process extracts low-frequency components and high-frequency details, providing the MLG1 neuron with more discriminative feature inputs. Experimental results demonstrate that the model achieves reliable looming spatial localization under extremely low contrast conditions, offering a robust methodology for bionic vision in extreme dim light environments. Full article

Botulinum neurotoxin injections are used off-label to treat chronic pain, but their efficacy is limited and paralytic effects restrict clinical utility in these applications. Here, we investigated whether combining the light chain and translocation domains of botulinum neurotoxin A (BoNT/A) with the GM1-binding B subunit of cholera toxin would be beneficial in silencing pain-associated sensory neurons. Chimeric ChoBot was assembled via a coiled-coil linking technology and was shown to retain the enzymatic activity of BoNT/A in vitro and in vivo. In cultured dorsal root ganglion neurons, ChoBot cleaved SNAP25 in a calcitonin gene-related peptide (CGRP)-rich subpopulation of sensory neurons, resulting in marked inhibition of CGRP release. ChoBot had a lesser effect on the compound muscle action potentials of the rat gastrocnemius muscle than BoNT/A following subcutaneous injections. In rat models of pain, including chemotherapy-induced peripheral neuropathy, intraplantar administration of ChoBot significantly attenuated mechanical allodynia. Immunohistochemical analysis confirmed SNAP25 cleavage in NF200- and CGRP-expressing sensory fibres in the epidermis following a single injection. ChoBot also mediated SNAP25 cleavage in human neuroblastoma cells in culture. Together, these findings indicate that ChoBot enables a silencing of pain-associated sensory pathways, providing a new strategy for the development of new long-lasting analgesics for chronic pain. Full article

Thyroid hormones (THs) and estrogen (E2) play essential roles in neuronal differentiation and plasticity during brain development. S-equol, a plant-derived isoflavone metabolite, is a selective E2 receptor (ER) ligand that exhibits neurotrophic effects; however, its interaction with TH receptor (TR) signaling remains unclear. In this study, we investigated the effects of S-equol on TRβ-associated transcriptional activity and neuronal morphogenesis in mouse neuroblastoma-derived Neuro-2a cells or rat C6 glioma cells. Luciferase reporter assays demonstrated that S-equol significantly enhanced T3-induced TRβ transcriptional activity in a concentration- and time-dependent manner. Additionally, exposure to S-equol or T3 alone promoted neurite outgrowth and wound closure, whereas co-exposure to both compounds resulted in a more significant enhancement of these processes. Furthermore, mRNA expression levels of synapse-related genes (Dlg4, Syn1, Syp, Camk2b, and Bdnf) were significantly increased by S-equol co-exposure in the presence of T3. In silico docking analysis revealed that S-equol exhibited moderate to high binding affinity for TRβ (−8.7 kcal/mol), ERα, and ERβ, suggesting a structural basis for TR–ER crosstalk. Collectively, these findings indicate that S-equol functions as a dual-acting modulator that may modulate T3 signaling involving TR–ER interaction. Although S-equol may exert beneficial effects on neurodevelopment, it may also act as an endogenous endocrine modulator that alters the fine regulation of TH action during development, warranting careful evaluation from physiological and toxicological perspectives. Full article

Background/Objectives: Autophagy is an evolutionarily conserved degradation and recycling pathway through which cells deliver cytoplasmic components, including toxic or damaged proteins and organelles, to lysosomes for clearance. In neurons, which are largely post-mitotic, degradative pathways are essential to prevent the accumulation of cellular waste and to maintain nutrient and energy homeostasis. Increasing evidence suggests that autophagy plays a critical role during early brain development, when neuronal circuits are established, synaptic connections are refined, and activity-dependent mechanisms shape network architecture. However, the developmental regulation of autophagy-related genes and the composition of the autophagic machinery at synapses remain poorly understood. This study aimed to characterize the maturation-dependent dynamics of autophagy–lysosomal genes and to investigate the synaptic autophagy-associated proteome during cortical development. Methods: Genome-wide transcriptomic analyses were performed in the cortical brain region across developmental stages to assess changes in the expression of autophagy–lysosomal genes. In parallel, synaptosomes were isolated and subjected to proteomic analysis to identify autophagy-related proteins associated with synaptic compartments. Results: Transcriptomic profiling revealed stage-dependent regulation of autophagy–lysosomal genes during cortical maturation. Proteomic analysis of synaptosomes identified multiple autophagy-associated proteins enriched at synaptic sites, suggesting that components of the autophagic machinery are present at synapses and may participate in synaptic remodeling and function during key phases of neuronal network formation. Conclusions: These findings provide new insights into the developmental regulation of autophagy in the brain and highlight the potential contribution of synaptic autophagy to neuronal circuit maturation. Understanding these mechanisms may help identify novel therapeutic targets for neurological disorders associated with impaired synaptic and cellular homeostasis. Full article

Sleep disturbances are early hallmarks of Alzheimer’s disease (AD) and other dementias, yet the molecular mechanisms remain poorly understood. We previously showed that dipeptidyl aminopeptidase-like protein 6-knockout (DPP6-KO) mice exhibit accelerated neurodegeneration with synaptic loss, neuronal death, and circadian dysfunction resembling AD pathology. Here, we investigate whether DPP6 deficiency directly causes sleep dysregulation and assess age-dependent effects using wireless EEG/EMG telemetry, behavioral monitoring, and body temperature recordings. We found striking age-dependent sleep phenotypes in DPP6-KO mice. Adult (3-month) DPP6-KO mice showed hyperactivity-driven REM sleep increases, while aged (12-month) DPP6-KO mice developed insomnia with fragmented sleep architecture. Critically, aged DPP6-KO mice exhibited decreased REM latency, a biomarker of depression, which we confirmed by behavioral assays. Conversely, DPP6 overexpression in aged wild-type mice increased NREM duration and reduced sleep fragmentation, demonstrating a protective effect. Throughout aging, DPP6-KO mice showed dysregulated locomotor activity and body temperature rhythms, suggesting broader disruption of circadian and metabolic homeostasis. These findings establish DPP6 as a critical regulator of sleep architecture whose loss recapitulates key sleep disturbances observed in AD/dementia. The progressive nature of sleep dysfunction in DPP6-KO mice, from REM abnormalities to insomnia, parallels human disease progression and positions DPP6 as a potential therapeutic target for sleep-related symptoms in neurodegenerative disorders. Full article

Diabetes Mellitus is a chronic metabolic disorder characterized by impaired insulin production and/or action, leading to persistent hyperglycemia and insulin resistance. It has been associated with several comorbidities, including cognitive dysfunction, affecting functions such as attention, memory, and processing speed. Mounting evidence indicates a complex relationship between type 2 Diabetes Mellitus (DM2) and neurodegenerative disorders such as mild cognitive impairment and Alzheimer’s disease (AD). Beyond the conventional hallmarks of each pathology, patients with DM2 face an increased risk of neuronal degeneration, while AD is characterized by a marked reduction in insulin receptor density. Although aging, neuroinflammation, and vascular dysfunction have been recognized as key risk factors in AD, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. Various studies have been conducted to identify reliable biomarkers that elucidate the connection between DM2 and AD, including insulin dysregulation, neuroinflammation, amyloid-β aggregation, and tau hyperphosphorylation. Investigation of these biomarkers is still ongoing, and they may serve not only as diagnostic tools but also as therapeutic targets. Here, we review the current evidence supporting a convergent biological framework between DM2 and AD. Clarifying these shared pathways may improve early detection and guide the development of targeted therapeutic strategies aimed at reducing neurodegeneration in metabolically vulnerable populations. Full article

The widespread development of medium-voltage and high-voltage direct current transmission systems has highlighted the modular multilevel converter (MMC) as a crucial enabling technology. However, the overall performance and lifetime of the MMC strongly depend on the integrity of its submodules (SMs), making online capacitance condition monitoring a critical requirement. Unlike recent related studies that rely on computationally heavy matrix-based algorithms or “black-box” artificial neural networks requiring massive offline training datasets, this paper proposes a parametric, adaptive linear neuron network. Mapped directly to the physical equations of the MMC, the method simultaneously exploits the arm current, SM switching state, and capacitor voltage to identify online parametric variations caused by aging or harsh conditions. The proposed scheme is fully non-intrusive, requiring no additional hardware sensors or signal injections, thereby reducing implementation complexity. The simulation results obtained in MATLAB/Simulink (vR2024b) demonstrate the method’s fast convergence and a quantified steady-state estimation error within ±1%. Furthermore, the estimator exhibits strong robustness under severe operating conditions, successfully maintaining accuracy during a 20% capacitance reduction, a 100% active power step variation, dc-link voltage fluctuations, measurement noise, grid unbalances, and harmonic perturbations. Full article

The convergence of sensing and processing is a critical frontier in the development of energy-efficient spiking edge intelligence. This paper presents a novel hardware implementation of a sensory neuron evolving from the leaky integrate-and-fire (LIF) model by coupling a volatile memristor with an LC tank circuit. The proposed memristor–resistor–inductor–capacitor (MRLC) neuron embeds electromagnetic sensing directly into neuronal dynamics, enabling direct transduction of proximity information into spike trains. We demonstrate that the circuit functions as a metal-sensitive proximity sensor with spiking output in both simulation and physical experiments. Moreover, the MRLC neuron exhibits rich dynamical regimes, including regular spiking, bursting with 2–5 spikes per burst, and quasi-chaotic behavior, as well as sensing memory provided by hysteresis-like multistability, which is a notable advancement over simple rate-encoding LIF neurons. Full article

Inflammasomes are cytosolic multiprotein complexes that detect pathogens, cellular stress, and damage-associated molecular signals, thereby orchestrating innate immune responses. Increasing evidence suggests that dysregulated inflammasome activation contributes to persistent neuroinflammation and to a wide range of neuropsychiatric disorders, including mood disorders, schizophrenia, Alzheimer’s disease, and autism spectrum disorders. Together, these findings emphasize the critical role of neuroimmune interactions in the pathophysiology of mental disorders. Recent molecular studies have substantially advanced our understanding of the crosstalk among neurons, microglia, astrocytes, and peripheral immune cells, uncovering complex regulatory networks mediated by cytokines, neurotrophins, and neurotransmitters. By examining key inflammatory mediators and cell type-specific mechanisms, this review consolidates current knowledge and proposes conceptual frameworks to guide future investigations and facilitate the development of targeted therapeutic strategies for neuropsychiatric disorders. Full article