2026-04-02
Aniella Vanessa Bak, Karen M. J. van Loo, Deborah Kronenberg-Versteeg, Henner Koch
Preclinical research in neuroscience has traditionally relied on animal models to investigate disease mechanisms and develop new therapeutic strategies. While these models are valuable to gain mechanistic insights, their translational power remains limited due to interspecific differences and, hence, frequent failures in clinical translation. The uniqueness of the human brain calls for alternative approaches in neuroscientific research that more faithfully capture human physiology and pathology. In recent years, a variety of human-based model systems have emerged, ranging from dissociated neuronal cultures and stem cell-derived platforms, including organoids, to micro-engineered devices and human brain slice approaches. Each model offers distinct advantages and limitations in recapitulating neural circuits, disease mechanisms, and therapeutic responses. In this review, we critically discuss the merits and drawbacks of animal models, outline the historic development and current applications of human-based systems, and highlight their potential to complement or replace animal-based models. We further explore current challenges in human brain research, including human variability, technical challenges, as well as ethical considerations and regulatory hurdles. Together, these advances represent a shift toward more predictive, human, and ethically responsible neuroscientific research that could aid in decreasing the translational gap.
DOI: 10.3389/fncel.2026.17764392026-04-01
Claudia F. Kirsch, Mackenzie Herb, Guarav Verma, Priti Balchandani
The abundant capillary network penetrating the brain parenchyma is surrounded by potential tubular, fluid-filled regions referred to as perivascular spaces (PVSs). PVSs have a unique and complex history and are believed to act as a pathway for the drainage of waste products from brain interstitial and cerebrospinal fluid (CSF) as part of the glymphatic clearance system. The unique perivascular “gap” spaces are eponymously linked to Virchow and Robin, who argued vigorously in the 1800s over PVSs’ exact location and physiology. Currently, debates are ongoing regarding whether PVSs are predominantly periarteriolar, perivenular, or both and how they aid in clearing fluids from the brain parenchyma. In neurodevelopmental, neuropsychiatric, and neuropathological conditions, PVS can enlarge, a phenomenon referred to as enlarged perivascular spaces (ePVSs), which are identifiable on magnetic resonance imaging (MRI), with improved detection and resolution at higher magnetic field strengths. Quantification of ePVS enlargement on MRI using artificial intelligence (AI) imaging algorithms may serve as a potential non-invasive imaging biomarker for impaired glymphatic clearance and brain disorders. This mini-review presents the historical background and pathophysiology of PVSs and ePVSs, current debates regarding their exact location, their potential as neuroimaging biomarkers, and how AI may aid in ePVS quantification.
DOI: 10.3389/fncel.2026.17411152026-03-27
Yara Izhiman, Charitha Anamala, Eric A. Nauman, Volha Liaudanskaya
Assembloids, engineered fusions of region-specific brain 3D constructs, have emerged as powerful platforms to study neurodevelopment and neurological diseases. Unlike first-generation organoids, assembloids enable direct modeling of interregional communication, allowing investigation of higher-order brain functions that depend on circuit-level interactions. Over the past 5 years, rapid advances in human-derived assembloid systems have demonstrated their ability to recapitulate key features of human brain organization, including long-range projection formation, region-specific signaling, neurovascular coupling, and progressive network dysfunction. The primary application of assembloid modeling remains the study of neurodevelopment, specifically focusing on mapping biological mechanisms driving the human brain development. Another major application of assembloids is the study and modeling of neurological diseases. Recent studies have integrated multiple neural regions, alongside vascular and glial components, and disease-relevant genetic backgrounds to recreate circuit-level interactions underlying pathology. These approaches have further highlighted the importance of neuroglial interactions in shaping development, connectivity, and disease progression in the human brain. Across models and disease contexts, a consistent theme has emerged: pathological phenotypes arise primarily from disrupted intercellular communication rather than isolated cellular and more purely neuronal, defects. Despite these strengths, current assembloid platforms remain limited by incomplete maturation, variability in reproducibility, and challenges in modeling long-term disease trajectories. Together, existing evidence positions assembloids as a promising next-generation platform for studying human brain development and neurodegeneration, while highlighting the need for continued refinement to improve physiological relevance as model complexity increases.
DOI: 10.3389/fncel.2026.17871732026-03-26
Muhammad Abdullah, Anam Naz, Leah R. Reznikov, Javed Anver Qureshi, Ammarah Hasnain, Ayesha Obaid, Amjed Ali
BackgroundLong COVID-19 causes neurophysiological, cardiopulmonary, and musculoskeletal issues. Increased neuropeptides and cytokines lead to neuroinflammation, resulting in neurocognitive impairments, fatigue, depression, anxiety, and severe cognitive deficits. The Neurokinin 1 receptor (NK1R) is a cellular receptor for the neuropeptide Substance P, and its dysregulation links to neuropsychological issues despite antipsychotic use.ObjectivesIn the present study, neuropsychological sequelae related to long COVID-19 were screened and the expression of related neuropeptides and cytokines was evaluated. Additionally, potential drugs have been evaluated computationally to reduce neuroinflammation in long COVID-19.MethodsAfter informed consent, subjects were screened by a medical physician for long COVID-19 in an outdoor patient clinic. Various biological scales were used to assess and categorize the severity of neuropsychological symptoms related to long COVID-19. After that, peripheral blood samples were collected from subjects using ELISA and RT-qPCR. Nine drugs were selected and subjected to virtual screening to identify potential drug antagonists for NK1R. The key drug-like properties, safety profile, pharmacokinetic analysis, and biological activity of the identified hits were assessed.ResultsIn this study the mean age of 90 patients (60% males and 40% females), was 33 ± 5 years in the symptomatic group and 31 ± 6 years in the asymptomatic long COVID-19 group for 40 years age-group was 58 ± 10 years in the symptomatic group and 54 ± 11 years in the asymptomatic long COVID-19 group. The minimum persistence of duration of long COVID-19 related symptoms in the 30 weeks group of symptomatic long COVID-19. A total of 48% patients had fatigue, 47% complained about headache, 28% had anxiety, 25% faced depression, 20% had psychosocial distress, 20% felt discomfort, and 13% had cognitive impairment. A total of 10% had reported dizziness sequelae among long COVID-19 survivors. Experimental data showed upregulation of IL-6, IL-10, and SP in both symptomatic and asymptomatic individuals compared with controls (p < 0.001). Drug screening analyses revealed aprepitant (−9.3 kcal/mol) and N- acetyl- L- tryptophan (−8.7 kcal/mol) stable interactions with NK1R and maintaining molecular dynamics stability (RMSD: 1.5–2.2 Å; RMSF 0.8–1.4 Å; Rg approximately 21.6 Å). These compounds also demonstrated favorable blood-brain barrier permeability and pharmacokinetic profiles, suggesting their potential as therapeutic antagonists for treating prolonged COVID-related neuroinflammation.ConclusionIL-6, IL-10, and SP are found to be deregulated in long COVID-19 leading to neurophysiological sequelae. To overcome neuropsychological sequelae, binding of SP to NK1R can be hindered using aprepitant and N-Acetyl-L tryptophan which has been evaluated computationally and may require further in vivo and in vitro studies for validation.
DOI: 10.3389/fncel.2026.17630292026-03-23
Chao Guo, Song Liu
BackgroundPeripheral nerve injury (PNI) presents a significant clinical challenge due to limited endogenous regenerative capacity. The translocator protein (TSPO) ligand etifoxine (ETX) has shown promise in promoting nerve repair, but the underlying cellular and molecular mechanisms remain incompletely understood.MethodsUtilizing in vitro co-culture systems with human Schwann cells (HSCs) and THP-1-derived macrophages, TSPO-knockdown HSCs, conditioned medium experiments, and an in vivo rat sciatic nerve crush injury model, we investigated the effects of ETX on cellular crosstalk and macrophage polarization. Molecular analyses included RNA sequencing, western blotting, fatty acid oxidation (FAO) assays, and a Mito-QC reporter system to assess mitophagy. Functional recovery was evaluated through behavioral tests (hindlimb grip strength, mechanical pain threshold), immunofluorescence, and retrograde tracing.ResultsETX specifically activated TSPO on Schwann cells, stimulating progesterone synthesis and secretion. This Schwann cell-derived progesterone acted as a paracrine signal on macrophages, activating the PPARγ–PGC1α axis. This activation triggered dual reprogramming in macrophages: a metabolic shift toward FAO and induction of BNIP3L-mediated mitophagy, both essential for sustaining a pro-regenerative M2 phenotype. These effects were significantly attenuated by the progesterone receptor antagonist RU486 or the PPARγ antagonist GW9662. In vivo, ETX treatment accelerated functional recovery, enhanced axonal regeneration, and increased infiltration of M2 macrophages at the injury site, effects that were partially reversed by RU486 or GW9662 co-administration.ConclusionETX facilitates peripheral nerve repair by promoting Schwann cell-derived progesterone, which drives macrophage PPARγ pathway activation, orchestrating metabolic-autophagic reprogramming necessary for sustained M2 polarization. These findings identify a novel Schwann cell–macrophage metabolic crosstalk mechanism and support the therapeutic potential of targeting this axis in PNI.
DOI: 10.3389/fncel.2026.17894502026-03-23
Srdjan D. Antic, Katarina D. Milicevic, William W. Lytton
In cortical and hippocampal pyramidal neurons, backpropagating action potentials (bAPs) play a central role in dendritic signaling, synaptic integration, and spike-timing-dependent plasticity (STDP). In most experimental and theoretical frameworks, bAPs are implicitly treated as reliable signals that faithfully inform dendritic synapses of somatic spiking. Here, we review experimental evidence demonstrating that this assumption is often violated. In large portions of the pyramidal neuron dendritic tree, particularly in distal apical branches and apical tuft dendrites, bAP amplitude exhibits pronounced spatial and temporal variability, including: (i) activity-dependent attenuation, (ii) frequency-dependent amplification, (iii) branch-specific propagation failures, and (iv) trial-to-trial stochastic AP flickering. We summarize five experimentally documented forms of bAP variability and discuss how stochastic backpropagation may shape synaptic plasticity in computational neuroscience, especially STDP, by introducing probabilistic gates that limit the coincidence of: (i) dendritic depolarization (bAP) and (ii) synaptic input (EPSP). Finally, we consider broader implications of the AP flickering in dendrites for cortical information processing, including redundancy, averaging, evidence accumulation, and error-correcting strategies in cortical circuits.
DOI: 10.3389/fncel.2026.18032622026-03-19
Zhirui Jiang, Ce Zhang, Zejing Zhao, Bin Ning
The blood–spinal cord barrier (BSCB) is a specialized vascular interface that preserves spinal cord homeostasis by regulating molecular and cellular trafficking between blood and neural tissue. Disruption of BSCB integrity is a critical pathological event follow-ing spinal cord injury (SCI), leading to increased permeability, inflammatory cell infil-tration, and secondary neurodegeneration. Increasing evidence indicates that BSCB breakdown is not a single event but a dynamic, time-dependent process. In this review, we summarize the molecular and cellular mechanisms responsible for BSCB disruption after SCI in a chronological manner. Key pathological events occurring during the acute, subacute, and chronic phases are discussed, including pathological hemody-namic changes, endothelial stress responses, epigenetic regulation, inflammatory me-diators, immune cell–endothelial interactions, and extracellular matrix remodeling. We further highlight endogenous protective and reparative mechanisms that emerge at later stages. A comprehensive understanding of the temporal characteristics of BSCB disruption may facilitate the development of phase-specific therapeutic strate-gies aimed at preserving barrier integrity, limiting secondary injury, and improving neurological recovery after SCI. This temporal perspective underscores the need for stage-specific interventions to preserve BSCB integrity and improve outcomes after SCI.
DOI: 10.3389/fncel.2026.1805529