Search Results (64)

One major challenge in cellular neuroscience is to elucidate how the accurate alignment of presynaptic release sites with postsynaptic densely clustered ligand-gated ion channels at chemical synapses is achieved upon synapse assembly. The clustering of neurotransmitter receptors at postsynaptic sites is a key moment of synaptogenesis and determinant for effective synaptic transmission. The number of the ionotropic neurotransmitter receptors at these postsynaptic sites of both excitatory and inhibitory synapses is variable and is regulated by different mechanisms, thus allowing the modulation of synaptic strength, which is essential to tune neuronal network activity. Several well-regulated processes seem to be involved, including lateral diffusion within the plasma membrane and local anchoring as well as receptor endocytosis and recycling. The molecular mechanisms implicated are numerous and were reviewed recently in great detail. The role of pre-synaptically released neurotransmitters within the complex regulatory apparatus organizing the postsynaptic site underneath presynaptic terminals is not completely understood, even less for inhibitory synapses. In this mini review article, we focus on this aspect of synapse formation, summarizing and contrasting findings on the functional role of the neurotransmitters glycine and γ-aminobutyric acid (GABA) for initiation of postsynaptic receptor clustering and regulation of Cl⁻ channel receptor numbers at inhibitory synapses gathered over the last two decades. Full article

The common gardening herbicides and fertilizers are crucial for weed control and plant growth, yet they may have potentially harmful impacts on neurological health. This review explored the possible effects of these chemicals on neurodegenerative disorders, especially Alzheimer’s disease (AD) and Parkinson’s disease (PD). The mode of action of several frequently used gardening chemicals (paraquat, glyphosate, 2,4-dichlorophenoxyacetic acid: 2,4-D, and ammonium chloride) in AD and PD has been highlighted. The mechanisms involved are glutamate excitotoxicity, dopaminergic pathway disruption, oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic dysfunction, and gut–brain-axis dysregulation, crucial in the pathophysiology of AD and PD. Although the links between these substances and neurodegenerative conditions remained to be seen, growing evidence indicated their detrimental effects on brain health. This highlights the need for further research to understand their long-term consequences and develop effective interventions to mitigate the adverse effects of commonly used chemicals on human health and the environment. Full article

Retinal ribbon synapses are continuously active chemical synapses. The eponymous synaptic ribbon is anchored to the active zone neurotransmitter release sites of ribbon synapses, recruits synaptic vesicles and guides ribbon-associated synaptic vesicles to the release sites. RIBEYE is the major protein component of synaptic ribbons. But likely, additional proteins contribute to ribbon synapse function. The synaptic ribbon of photoreceptor synapses is embedded into a highly polarized microtubule cytoskeleton. Interestingly, proteins of the photoreceptor primary cilium, such as NPHP4 and other ciliary proteins, including KIF3A, were shown to be localized to photoreceptor synaptic ribbons. Previous studies demonstrated that the microtubule motor protein KIF13B catalyzes secretory vesicle transport to the plus ends of microtubules and identified an interaction of KIF13B with NPHP4 at primary cilia. However, the localization of KIF13B, a kinesin-3 family motor protein, in the retina is still unknown. In the present study, we used two different antibodies against KIF13B and high-resolution confocal microscopy, super-resolution structured illumination microscopy (SR-SIM), and post-embedding immunogold electron microscopy to determine the localization of KIF13B in retinal photoreceptors. Apart from its localization at the primary photoreceptor cilium, we found a strong enrichment of KIF13B at photoreceptor synaptic ribbons. The synaptic ribbon is needed for the synaptic enrichment of KIF13B as shown by analyses of synaptic ribbon-deficient RIBEYE knockout mice. These findings suggest that KIF13B performs vesicle trafficking functions at the photoreceptor synaptic ribbon complex at the interface between the synaptic ribbon and the presynaptic microtubule transport system. Full article

Primary cultures of neural cells are important key tools for basic and translational neuroscience research. These primary cell cultures are classically generated from the rodent brain hippocampus or cortex and optimized for enrichment in neurons at the expense of glial cells. Importantly, considerable differences exist in neuronal cell populations and in glial cell contribution between different brain regions. Because many basic and translational research projects aim to identify mechanisms underlying brainstem neuronal networks that affect major vital functions, primary cultures representative of cell populations present in the hindbrain are required. However, the preparation of primary cultures of brainstem/hindbrain neurons is scarcely described in the literature, limiting the possibilities for studying the development and physiology of these brain regions in vitro. The present report describes a reliable protocol to dissociate and culture in vitro embryonic mouse fetal hindbrain neurons in a defined culture medium, while control of astrocytes’ expansion was attained by using a chemically defined, serum-free supplement, namely CultureOne™. The neuronal cells maintained according to this protocol differentiate and, by 10 days in vitro, they develop extensive axonal and dendritic branching. Using immunofluorescence, we further characterized the different cell populations and neuronal subtypes. Patch–clamp recordings demonstrate the excitable nature of these neurons, while colocalization of pre- and postsynaptic neuronal markers showed that neurons form mature synapses, suggesting the establishment of functional networks in vitro. The cultures produced by this method show excellent reproducibility and can be used for molecular, biochemical, and physiological analyses, as illustrated here for tamoxifen-induced Cre recombination in genetically-modified neural cells. Full article

Ganoderma capense, a member of the Ganoderma genus within the Polyporaceae family, has long been recognized for its high nutritional value and extensive use in traditional medicine. Its primary distribution is in China and South Africa, with the type locality being South Africa. This species is rich in a diverse array of bioactive compounds, including various polysaccharides, glycopeptide macromolecules, and various small-molecule compounds, such as sesquiterpenes, triterpenes, steroids, and alkaloids. Research indicates that these chemical constituents exhibit numerous pharmacological properties, including antioxidant, anti-inflammatory, and anti-tumor activities, as well as inhibition of acetylcholinesterase, reduction in blood lipids, and promotion of neural synapse growth. Apart from its use in traditional Chinese medicine, the components of G. capense are utilized globally for the treatment of a wide range of diseases, including Alzheimer’s disease, febrile convulsions, HIV, and diabetes. This underscores the extensive medical applications of G. capense, emphasizing its significance in contemporary and traditional healthcare. This review summarizes the latest research findings on the bioactive compounds and pharmacological effects of G. capense, compiled from databases such as PubMed, Web of Science, and Elsevier. This study aimed at providing researchers in this field with in-depth scientific insights and guidance, promoting further application and development in the pharmaceutical and food industries, and serving as a reference for subsequent exploration of active substances and the development of new disease treatments. Full article

Background/Objectives: High-altitude environments have a significant detrimental impact on the cognitive functions of the brain. Qi Jing Wan (QJW), a traditional herbal formula composed of Angelica sinensis, Astragalus membranaceus, and Rhizoma Polygonati Odorati, has demonstrated potential efficacy in treating cognitive disorders. However, its effects on cognitive dysfunction in plateau hypoxic environments remain unclear. Methods: In this study, acute and chronic plateau cognitive impairment mouse models were constructed to investigate the preventive and therapeutic effects of QJW and its significant active ingredient, diosgenin (Dio). Behavioral experiments were conducted to assess learning and memory in mice. Morphological changes in hippocampal neurons and synapses were assessed, and microglial activation and inflammatory factor levels were measured to evaluate brain damage. Potential active ingredients capable of crossing the blood–brain barrier were identified through chemical composition analysis and network database screening, followed by validation in animal and brain organoid experiments. Transcriptomics analysis, immunofluorescence staining, and molecular docking techniques were employed to explore the underlying mechanisms. Results: QJW significantly enhanced learning and memory abilities in plateau model mice, reduced structural damage to hippocampal neurons, restored NeuN expression, inhibited inflammatory factor levels and microglial activation, and improved hippocampal synaptic damage. Transcriptomics analysis revealed that Dio alleviated hypoxic brain damage and protected cognitive function by regulating the expression of PDE4C. Conclusions: These findings indicate that QJW and its significant active ingredient Dio effectively mitigate hypoxic brain injury and prevent cognitive impairment in high-altitude environments. Full article

Rapid industrialization has introduced a range of chemicals into the environment, posing significant risks to fetal and child brain development. Using the Comparative Toxicogenomics Database (CTD), we constructed chemical exposome frameworks for seven neurodevelopmental disorders (NDDs) and identified chemical pollutants of epidemiological concern, including air pollutants (n = 8), toxic elements (n = 14), pesticides and related compounds (n = 18), synthetic organic chemicals (n = 16), and solvents (n = 5). Gene set enrichment analysis validated and revealed significant toxicogenomic associations between these chemical pollutants and NDDs, including autism spectrum disorder (ASD) (12 pollutants, proportional reporting ratio (PRR) 3.56–7.21) and intellectual disability (ID) (9 pollutants, PRR 3.13–5.59). Functional annotation of pollutant-specific gene sets highlighted shared biological processes, such as metabolic processes (e.g., xenobiotic metabolic process, xenobiotic catabolic process, and cytochrome P450 pathway) for ASD and cognitive processes (e.g., cognition, social behavior, and synapse assembly) for ID (Bonferroni-corrected p-values < 0.05). Time trajectory analysis of developmental transcriptomic data from the BrainSpan database for ASD (275 genes) and ID (93 genes) revealed three distinct expression patterns of chemical-pollutant-associated genes—higher prenatal, postnatal, and perinatal expression—indicating common and divergent underlying mechanisms across critical windows of chemical pollutant exposure. Full article

Valerian possesses a multitude of pharmacological effects, including sedative and hypnotic properties, antihypertensive effects, antibacterial activity, and liver protection. Insomnia, one of the most prevalent disorders in contemporary society, significantly impacts people’s daily lives. This study aims to explore the anti-insomnia effects of valerian volatile oil (VVO) and investigate its potential mechanism of action through chemical analysis, network pharmacology, molecular docking, molecular dynamics simulations, and experimental validation. Through gas chromatography–mass spectrometry (GC-MS) analysis and drug-likeness screening, we identified 38 active compounds. Network pharmacology studies revealed that these 38 compounds might affect 103 targets associated with insomnia, such as monoamine oxidase B (MAOB), dopamine receptor D2 (DRD2), monoamine oxidase A (MAOA), interleukin 1β (IL1B), solute carrier family 6 member 4 (SLC6A4), prostaglandin-endoperoxide synthase 2 (PTGS2), and 5-hydroxytryptamine receptor 2A (HTR2A), which contribute to regulating the neuroactive ligand–receptor interaction, 5-hydroxytryptaminergic synapse, and calcium signaling pathways. The results of the molecular dynamics simulations indicated that bis[(6,6-dimethyl-3-bicyclo[3.1.1]hept-2-enyl)methyl] (E)-but-2-enedioate exhibited a stabilizing interaction with MAOB. The animal studies demonstrated that gavage administration of a high dose (100 mg/kg) of VVO significantly diminished autonomous activity, decreased sleep latency, and extended sleep duration in mice. Furthermore, the results of the Western blot experiment indicated that VVO interacts with MAOB, resulting in decreased expression levels of MAOB in the cerebral cortex. This study demonstrates the protective mechanism of VVO against insomnia through chemical analysis, network pharmacology, and experimental validation and extends the possible applications of VVO, which is a potential therapeutic ingredient for use in insomnia treatment. Full article

Learning and memory formation rely on synaptic plasticity, the process that changes synaptic strength in response to neuronal activity. In the tripartite synapse concept, molecular signals that affect synapse strength and morphology originate not only from the pre- and post-synaptic neuronal terminals but also from astrocytic processes ensheathing many synapses. Despite significant progress made in understanding astrocytic contribution to synaptic plasticity, only a few astrocytic plasticity-related proteins have been identified so far. In this study, we present evidence indicating the role of astrocyte-secreted Lipocalin-2 (Lcn2) in neuronal plasticity. We show that Lcn2 expression is induced in hippocampal astrocytes in a kainate-evoked aberrant plasticity model. Next, we demonstrate that chemically induced long-term potentiation (cLTP) similarly increases Lcn2 expression in astrocytes of neuronal–glial co-cultures, and that glutamate causes the immediate release of Lcn2 from these cultures. Additionally, through experiments in primary astrocytic cultures, we reveal that Lcn2 release is triggered by calcium signaling, and we demonstrate that a brief treatment of neuronal–glial co-cultures with Lcn2 alters the morphology of dendritic spines. Based on these findings, we propose Lcn2 as an activity-dependent molecule released by astrocytes that influences dendritic spine morphology. Full article

V-type nerve agents are exceedingly toxic chemical warfare agents that irreversibly inhibit acetylcholinesterase (AChE), leading to acetylcholine accumulation in synapses and the disruption of neurotransmission. VG or O.O-diethyl S-(diethylamino)ethyl phosphorothiolate was the first compound of this class that was synthesized. The selenocholines (-Se-), cholines (-O-), and methylene-cholines (-CH₂-) analogs of V-agents have been synthesized and their anti-AChE activities reported. Nevertheless, the aminocholine derivatives have not been pursued. Here, we have designed and synthesized a series of phosphorylated aminocholines analogs of VG that were characterized by NMR spectroscopy (H1, C13, P31, and TOCSY). Their pharmacological properties were analyzed in silico, while their toxicological properties were in vitro investigated using the SH-SY5Y cellular model. Despite the drug likeness of the new compounds, these fail to inhibit AChE in vitro and in cellulo. This may be partially explained by the fact that aminocholine is not a good leaving group compared to thiocholine. Remarkably, one of the compounds (P4) was found to even increase the activity of AChE. These compounds may serve as new nerve agent mimics that are safer alternatives for testing countermeasures. Importantly, P4 may act as a lead compound for developing a new class of alternative nerve agent pretreatments that are safer from pyridostigmine. Full article

One of the most significant applications of mathematical numerical methods in biology is the theoretical description of the convectional reaction–diffusion of chemical compounds. Initial biological objects must be appropriately mimicked by digital domains that are suitable for further use in computational modeling. In the present study, an algorithm for the creation of a digital phantom describing a local part of nervous tissue—namely, a synaptic contact—is established. All essential elements of the synapse are determined using a set of consistent Boolean operations within the COMSOL Multiphysics software 6.1. The formalization of the algorithm involves a sequence of procedures and logical operations applied to a combination of 3D Voronoi diagrams, an experimentally defined inner synapse area, and a simple ellipsoid under different sets of biological parameters. The obtained digital phantom is universal and may be applied to different types of neuronal synapses. The clear separation of the designed domains reveals that the boundary’s conditions and internal flux dysconnectivity functions can be set up explicitly. Digital domains corresponding to the parts of a synapse are appropriate for further application of the derived numeric meshes, with various capacities of the included elements. Thus, the obtained digital phantom can be effectively used for further modeling of the convectional reaction–diffusion of chemical compounds in nervous tissue. Full article

Fifty-two years have passed since President Nixon launched the “War on Cancer”. Despite unparalleled efforts and funds allocated worldwide, the outlined goals were not achieved because cancer treatment approaches such as chemotherapy, radiation therapy, hormonal and targeted therapies have not fully met the expectations. Based on the recent literature, a new direction in cancer therapy can be proposed which targets connections between cancer cells and their microenvironment by chemical means. Cancer–stromal synapses such as immunological synapses between cancer and immune cells provide an attractive target for this approach. Such synapses form ligand–receptor clusters on the interface of the interacting cells. They share a common property of involving intercellular clusters of spatially proximate and cooperatively acting proteins. Synapses provide the space for the focused intercellular signaling molecules exchange. Thus, the disassembly of cancer–stromal synapses may potentially cause the collapse of various tumors. Additionally, the clustered arrangement of synapse components offers opportunities to enhance treatment safety and precision by using targeted crosslinking chemical agents which may inactivate cancer synapses even in reduced concentrations. Furthermore, attaching a cleavable cell-permeable toxic agent(s) to a crosslinker may further enhance the anti-cancer effect of such therapeutics. The highlighted approach promises to be universal, relatively simple and cost-efficient. We also hope that, unlike chemotherapeutic and immune drugs that interact with a single target, by using supramolecular large clusters that include many different components as a target, the emergence of a resistance characteristic of chemo- and immunotherapy is extremely unlikely. Full article

In this study, we investigate the impact of O₂ plasma treatment on the performance of Al/TaO_X/Al-based resistive random-access memory (RRAM) devices, focusing on applications in neuromorphic systems. Comparative analysis using scanning electron microscopy and X-ray photoelectron spectroscopy confirmed the differences in chemical composition between O₂-plasma-treated and untreated RRAM cells. Direct-current measurements showed that O₂-plasma-treated RRAM cells exhibited significant improvements over untreated RRAM cells, including higher on/off ratios, improved uniformity and distribution, longer retention times, and enhanced durability. The conduction mechanism is investigated by current–voltage (I–V) curve fitting. In addition, paired-pulse facilitation (PPF) is observed using partial short-term memory. Furthermore, 3- and 4-bit weight tuning with auto-pulse-tuning algorithms was achieved to improve the controllability of the synapse weight for the neuromorphic system, maintaining retention times exceeding 10³ s in the multiple states. Neuromorphic simulation with an MNIST dataset is conducted to evaluate the synaptic device. Full article

The synapse is a piece of information transfer machinery replacing the electrical conduction of nerve impulses at the end of the neuron. Like many biological mechanisms, its functioning is heavily affected by time constraints. The solution selected by evolution is based on chemical communication that, in theory, cannot compete with the speed of nerve conduction. Nevertheless, biochemical and biophysical compensation mechanisms mitigate this intrinsic weakness: (i) through the high concentrations of neurotransmitters inside the synaptic vesicles; (ii) through the concentration of neurotransmitter receptors in lipid rafts, which are signaling platforms; indeed, the presence of raft lipids, such as gangliosides and cholesterol, allows a fine tuning of synaptic receptors by these lipids; (iii) through the negative electrical charges of the gangliosides, which generate an attractive (for cationic neurotransmitters, such as serotonin) or repulsive (for anionic neurotransmitters, such as glutamate) electric field. This electric field controls the flow of glutamate in the tripartite synapse involving pre- and post-synaptic neurons and the astrocyte. Changes in the expression of brain gangliosides can disrupt the functioning of the glutamatergic synapse, causing fatal diseases, such as Rett syndrome. In this review, we propose an in-depth analysis of the role of gangliosides in the glutamatergic synapse, highlighting the primordial and generally overlooked role played by the electric field of synaptic gangliosides. Full article

Biomimetic neuromorphic sensing systems, inspired by the structure and function of biological neural networks, represent a major advancement in the field of sensing technology and artificial intelligence. This review paper focuses on the development and application of electrolyte gated transistors (EGTs) as the core components (synapses and neuros) of these neuromorphic systems. EGTs offer unique advantages, including low operating voltage, high transconductance, and biocompatibility, making them ideal for integrating with sensors, interfacing with biological tissues, and mimicking neural processes. Major advances in the use of EGTs for neuromorphic sensory applications such as tactile sensors, visual neuromorphic systems, chemical neuromorphic systems, and multimode neuromorphic systems are carefully discussed. Furthermore, the challenges and future directions of the field are explored, highlighting the potential of EGT-based biomimetic systems to revolutionize neuromorphic prosthetics, robotics, and human–machine interfaces. Through a comprehensive analysis of the latest research, this review is intended to provide a detailed understanding of the current status and future prospects of biomimetic neuromorphic sensory systems via EGT sensing and integrated technologies. Full article