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On the road to the brain-on-a-chip: a review on strategies, methods, and applications.
The brain is the most complex organ of our body. Such a complexity spans from the single-cell morphology up to the intricate connections that hundreds of thousands of neurons establish to create dense neuronal networks. All these components are involved in the genesis of the rich patterns of electrophysiological activity that characterize the brain. Over the years, researchers coming from different disciplines developedin vitrosimplified experimental models to investigate in a more controllable and observable way how neuronal ensembles generate peculiar firing rhythms, code external stimulations, or respond to chemical drugs. Nowadays, suchin vitromodels are namedbrain-on-a-chippointing out the relevance of the technological counterpart as artificial tool to interact with the brain: multi-electrode arrays are well-used devices to record and stimulate large-scale developing neuronal networks originated from dissociated cultures, brain slices, up to brain organoids. In this review, we will discuss the state of the art of the brain-on-a-chip, highlighting which structural and biological features a realisticin vitrobrain should embed (and how to achieve them). In particular, we identified two topological features, namely modular and three-dimensional connectivity, and a biological one (heterogeneity) that takes into account the huge number of neuronal types existing in the brain. At the end of this travel, we will show how 'far' we are from the goal and how interconnected-brain-regions-on-a-chip is the most appropriate wording to indicate the current state of the art.
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New perspective on central nervous system disorders: focus on mass spectrometry imaging.
An abnormally organized brain spatial network is linked to the development of various central nervous system (CNS) disorders, including neurodegenerative diseases and neuropsychiatric disorders. However, the complicated molecular mechanisms of these diseases remain unresolved, making the development of treatment strategies difficult. A novel molecular imaging technique, called mass spectrometry imaging (MSI), captures molecular information on the surface of samples in situ. With MSI, multiple compounds can be simultaneously visualized in a single experiment. The high spatial resolution enables the simultaneous visualization of the spatial distribution and relative content of various compounds. The wide application of MSI in biomedicine has facilitated extensive studies on CNS disorders in recent years. This review provides a concise overview of the processes, applications, advantages, and disadvantages, as well as mechanisms of the main types of MSI. Meanwhile, this review summarizes the main applications of MSI in studying CNS diseases, including Alzheimer's disease (AD), CNS tumors, stroke, depression, Huntington's disease (HD), and Parkinson's disease (PD). Finally, this review comprehensively discusses the synergistic application of MSI with other advanced imaging modalities, its utilization in organoid models, its integration with spatial omics techniques, and provides an outlook on its future potential in single-cell analysis.
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Human Cortex Spheroid with a Functional Blood Brain Barrier for High-Throughput Neurotoxicity Screening and Disease Modeling.
The integral selectivity characteristic of the blood brain barrier (BBB) limits therapeutic options for many neurologic diseases and disorders. Currently, very little is known about the mechanisms that govern the dynamic nature of the BBB. Recent reports have focused on the development and application of human brain organoids developed from neuro-progenitor cells. While these models provide an excellent platform to study the effects of disease and genetic aberrances on brain development, they may not model the microvasculature and BBB of the adult human cortex. To date, most in vitro BBB models utilize endothelial cells, pericytes and astrocytes. We report a 3D spheroid model of the BBB comprising all major cell types, including neurons, microglia and oligodendrocytes, to recapitulate more closely normal human brain tissue. Spheroids show expression of tight junctions, adherens junctions, adherens junction-associated proteins and cell specific markers. Functional assessment using MPTP, MPP+ and mercury chloride indicate charge selectivity through the barrier. Junctional protein distribution was altered under hypoxic conditions. Our spheroid model may have potential applications in drug discovery, disease modeling, neurotoxicity and cytotoxicity testing.
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Integrated biocircuits: engineering functional multicellular circuits and devices.
OBJECTIVE: Implantable neurotechnologies have revolutionized neuromodulatory medicine for treating the dysfunction of diseased neural circuitry. However, challenges with biocompatibility and lack of full control over neural network communication and function limits the potential to create more stable and robust neuromodulation devices. Thus, we propose a platform technology of implantable and programmable cellular systems, namely Integrated Biocircuits, which use only cells as the functional components of the device. APPROACH: We envision the foundational principles for this concept begins with novel in vitro platforms used for the study and reconstruction of cellular circuitry. Additionally, recent advancements in organoid and 3D culture systems account for microenvironment factors of cytoarchitecture to construct multicellular circuits as they are normally formed in the brain. We explore the current state of the art of these platforms to provide knowledge of their advancements in circuit fabrication and identify the current biological principles that could be applied in designing integrated biocircuit devices. MAIN RESULTS: We have highlighted the exemplary methodologies and techniques of in vitro circuit fabrication and propose the integration of selected controllable parameters, which would be required in creating suitable biodevices. SIGNIFICANCE: We provide our perspective and propose new insights into the future of neuromodulaion devices within the scope of living cellular systems that can be applied in designing more reliable and biocompatible stimulation-based neuroprosthetics.
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Large-scale single-molecule analysis of tau proteoforms.
Proteins exist as diverse proteoforms resulting from a combination of genetic variation, alternative splicing and post-translational modifications. Current methods struggle to capture this complexity at the single-molecule level. Here we introduce Iterative Mapping of proteoforms, a method that enables massively parallel interrogation of millions to billions of single-protein molecules through iterative probing with fluorescently labeled antibodies. We applied Iterative Mapping to tau, a key protein in neurodegenerative diseases, using 12 site-specific antibodies. The tau proteoform assay demonstrates high sensitivity (detecting proteoforms at 0.1% abundance), high reproducibility (median coefficient of variation <5.5%) and broad dynamic range (>3 orders of magnitude), outperforming conventional techniques in resolving closely related proteoform groups. Analysis of relevant biological samples, including organoids, mouse brains and human Alzheimer's disease samples, revealed 130 distinct tau proteoform groups with as many as six phosphorylation events. The nonrandom distribution of these phosphorylation events suggests ordered and site-specific modification processes rather than random, stochastic accumulation. Iterative Mapping provides insights into proteoform complexity at the single-molecule level, with implications for understanding protein regulation in neurodegenerative diseases and beyond.
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Neuroteratogenic mechanisms of Zika virus (ZIKV) infection: Insights into fetal brain development disruption and congenital Zika syndrome: A systematic review.
The Zika virus (ZIKV), a mosquito-borne Flavivirus, has emerged as a global health threat due to its severe neuroteratogenic effects, particularly during pregnancy. This mechanistic-to-translational synthesis examines how ZIKV disrupts fetal brain development and links molecular events to clinical manifestations of Congenital Zika Syndrome (CZS). Our review advances prior summaries by presenting a unifying neural progenitor cell (NPC)-centric pathway framework that integrates viral entry, host signaling disruption, cell fate outcomes, and imaging correlates. Once transmitted vertically, the virus targets NPCs, impairing proliferation, triggering apoptosis, and halting the cell cycle. It modulates host pathways such as PI3K-Akt-mTOR and p53 to enhance autophagy, avoid immune detection, and sustain replication. ZIKV also interferes with RNA interference and synaptic formation, contributing to cortical thinning, ventriculomegaly, and agenesis of the corpus callosum. Inflammatory responses further exacerbate tissue damage as ZIKV activates TLRs and inflammasomes, increasing proinflammatory cytokines and pyroptosis. Brain organoid and imaging studies highlight the virus's NPC tropism and capacity for lasting neurodevelopmental impairment-even in normocephalic infants. Importantly, ZIKV exhibits SOX2-dependent permissiveness with integrin αvβ5 functioning as a key dependency/attachment factor in neural and glioblastoma stem cells, distinguishing transcriptional state from receptor function. This intersection of neurotropism and potential oncolytic activity underscores the dual pathogenic and therapeutic implications of ZIKV. Literature was synthesized according to a predefined search strategy, with evidence appraised for quality, strengths, and limitations. This review highlights mechanistic pathways linking viral replication, immune modulation, and disrupted neurodevelopment, emphasizing implications for surveillance, therapeutic targets, and maternal-fetal health preparedness.
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Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability.
Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction. This study examines how a single disorder differentially affects distinct brain regions using induced pluripotent stem cell (iPSC)-derived cortical- and hippocampal-ganglionic eminence assembloids to model developmental and epileptic encephalopathy 13, a condition arising from gain-of-function mutations in the SCN8A gene encoding the sodium channel Nav1.6. While cortical assembloids showed network hyperexcitability akin to epileptogenic tissue, hippocampal assembloids did not, and instead displayed network dysregulation patterns similar to in vivo hippocampal recordings from epilepsy patients. Predictive computational modeling, immunohistochemistry, and single-nucleus RNA sequencing revealed changes in excitatory and inhibitory neuron organization that were specific to hippocampal assembloids. These findings highlight the unique impacts of a single pathogenic variant across brain regions and establish hippocampal assembloids as a platform for studying neurodevelopmental disorders.
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The e-Flower: A hydrogel-actuated 3D MEA for brain spheroid electrophysiology.
Traditional microelectrode arrays (MEAs) are limited to measuring electrophysiological activity in two dimensions, failing to capture the complexity of three-dimensional (3D) tissues such as neural organoids and spheroids. Here, we introduce a flower-shaped MEA (e-Flower) that can envelop submillimeter brain spheroids following actuation by the sole addition of the cell culture medium. Inspired by soft microgrippers, its actuation mechanism leverages the swelling properties of a polyacrylic acid hydrogel grafted to a polyimide substrate hosting the electrical interconnects. Compatible with standard electrophysiology recording systems, the e-Flower does not require additional equipment or solvents and is ready to use with preformed 3D tissues. We designed an e-Flower achieving a curvature as low as 300 micrometers within minutes, a value tunable by the choice of reswelling media and hydrogel cross-linker concentration. Furthermore, we demonstrate the ability of the e-Flower to detect spontaneous neural activity across the spheroid surface, demonstrating its potential for comprehensive neural signal recording.
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Hyaluronic acid conjugated gold nanoparticles/chitosan/4-aminopyridine intranasal nanocomposites for myelin repair in multiple sclerosis.
Exploiting the therapeutic advantages of 4-Aminopyridine (4AP) in neurological conditions like multiple sclerosis (MS) are limited due to toxicity concerns and blood-brain barrier when administered through intraperitoneal or oral routes. Alternatively, intranasal delivery, which allows direct access to brain, would require 4AP to be encapsulated and stabilised. To meet this, a carrier based on hyaluronic acid (HA) conjugated to chitosan (C) with gold nanoparticles (G) for 4AP has been prepared (HA@G-C-4AP). Firstly, efficacy of G-C-4AP studied on C57BL/6 mouse model, where cuprizone was used to induce demyelination. Initially, significance of each nanocomposite component was studied; for example, G-C-4AP showed a T-maze alteration with significance at P < 0.01 when compared to induced alone group and promoted myelination as evidenced by increase in myelin markers, viz., myelin basic protein and proteolipid protein (P < 0.001, P < 0.01). Later, to prove higher localisation of nanocomposite in the presence of HA in brain tissue, HA@G-C (without 4AP) was encapsulated with fluorescent label 5-aminofluorescein (5AF) (HA@G-C-5AF), and brain tissue was observed through imaging system. Our studies indicate that HA-functionalised gold-chitosan nanocomposites can improve myelin repair owing to improved bioavailability of 4AP. Further long-term therapeutic studies on intranasal administration of HA@G-C-4AP nanocomposite in organoid and animal models are required for its use in clinical settings.
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The CUL4B-based E3 ubiquitin ligase regulates mitosis and brain development by recruiting phospho-specific DCAFs.
The paralogs CUL4A and CUL4B assemble cullin-RING E3 ubiquitin ligase (CRL) complexes regulating multiple chromatin-associated cellular functions. Although they are structurally similar, we found that the unique N-terminal extension of CUL4B is heavily phosphorylated during mitosis, and the phosphorylation pattern is perturbed in the CUL4B-P50L mutation causing X-linked intellectual disability (XLID). Phenotypic characterization and mutational analysis revealed that CUL4B phosphorylation is required for efficient progression through mitosis, controlling spindle positioning and cortical tension. While CUL4B phosphorylation triggers chromatin exclusion, it promotes binding to actin regulators and to two previously unrecognized CUL4B-specific substrate receptors (DCAFs), LIS1 and WDR1. Indeed, co-immunoprecipitation experiments and biochemical analysis revealed that LIS1 and WDR1 interact with DDB1, and their binding is enhanced by the phosphorylated N-terminal domain of CUL4B. Finally, a human forebrain organoid model demonstrated that CUL4B is required to develop stable ventricular structures that correlate with onset of forebrain differentiation. Together, our study uncovers previously unrecognized DCAFs relevant for mitosis and brain development that specifically bind CUL4B, but not the CUL4B-P50L patient mutant, by a phosphorylation-dependent mechanism.