Abstract Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Recent advances in human-induced pluripotent stem cell-derived brain organoids offer an innovative platform to model amyotrophic lateral sclerosis in a human-specific context. These three-dimensional organoid systems allow for the study of neuronal circuit-level dysfunction, which is central to amyotrophic lateral sclerosis pathogenesis, by incorporating multiple neuronal subtypes and supporting glial populations. In particular, the integration of region-specific brain organoids into assembloid models has enabled the reconstruction of functional long-range projections and cortico-motor circuits, closely resembling human neural connectivity. This review summarizes the generation and application of human induced pluripotent stem cell-derived brain organoids for amyotrophic lateral sclerosis research, with a focus on the reconstruction of neural circuits, multi-omics profiling, and functional assays. We also discuss how organoid systems can be leveraged for drug discovery and personalized medicine in amyotrophic lateral sclerosis, highlighting their potential to unveil human-specific disease mechanisms. Lastly, we address the current challenges and future directions for improving the physiological relevance of organoid models in amyotrophic lateral sclerosis research.
Abstract Cooperation is a fundamental form of social behavior that promotes collective benefits and group survival. Although considerable progress has been made in understanding cooperation from behavioral and theoretical perspectives, the neural activities underlying cooperative behavior remain incompletely understood. In the present study, we established a cooperative behavioral paradigm in pairs of mice using a Skinner box, with the protocol spanning 22 days. Mice were retrospectively classified into high-, middle-, and low-performance groups based on their performance in the cooperation task. In vivo local field potential recordings from the nucleus accumbens and ventral hippocampus were then conducted in the three groups. High-cooperation mice showed significantly increased delta and low-gamma power in the nucleus accumbens, as well as enhanced delta, theta, beta, and low-gamma power in the ventral hippocampus, compared to low-cooperation mice. Meanwhile, nucleus accumbens–ventral hippocampus coherence within the beta and low-gamma frequency bands was significantly reduced in high-cooperation animals. Behaviorally, high-cooperation mice exhibited social dysfunction as shown by reduced social interaction and more pronounced anxiety-like behaviors compared with low-cooperation mice after training. Collectively, these findings provide early evidence that individual differences in cooperative behavior are associated with distinct patterns of neural oscillatory activity within the nucleus accumbens–ventral hippocampus circuit. Moreover, enhanced cooperative performance was correlated with alterations in social and affective behavior, such as increased social avoidance and anxiety-like behavior. The results suggest that nucleus accumbens–ventral hippocampus oscillatory dynamics may represent a neural correlate of cooperative behavior, and that training-induced differences in cooperative performance are associated with subsequent changes in social and affective functioning.
Abstract Poststroke depression critically hampers neurological recovery, and although transcutaneous auricular vagus nerve stimulation exhibits antidepressant potential, its mechanistic basis remains incompletely defined. Given that activin receptorlike kinase 5 (ALK5) regulates neuroplasticity through the Smad2/3/growth arrest and DNA-damage-inducible 45β (Gadd45b) axis, we postulated that transcutaneous auricular vagus nerve stimulation alleviates poststroke depression via this cascade. Using a rat poststroke depression model established by middle cerebral artery occlusion combined with chronic unpredictable mild stress, we knocked down ALK5 in hippocampal CA1 area and administered 14-day transcutaneous auricular vagus nerve stimulation. Behavioral assessments, histopathological and ultrastructural analyses, neurotransmitter measurements, and immunoblotting for neuroplasticity markers revealed that transcutaneous auricular vagus nerve stimulation reversed post-stroke depression-induced ALK5 downregulation and concurrently ameliorated depressive-like behaviors, restored monoamine levels, and enhanced neuronal survival, dendritic arborization, and synaptic integrity. Crucially, ALK5 knockdown abolished all these beneficial effects and blocked transcutaneous auricular vagus nerve stimulationmediated activation of the Smad2/3/Gadd45b pathway. Collectively, our findings demonstrate that transcutaneous auricular vagus nerve stimulation exerts its anti-depressant and proneuroplastic actions in poststroke depression by engaging the hippocampal ALK5 signaling cascade, thereby supporting transcutaneous auricular vagus nerve stimulation as a promising therapeutic strategy for poststroke affective and functional recovery.
Abstract Transcending the paradigm of passive structural support, contemporary peripheral nerve repair pivots decisively toward the deliberate spatiotemporal programming of instructive microenvironments. Integrative evidence, synthesized from bibliometric landscapes and high-resolution single-cell transcriptomic atlases, has firmly established mechanotransduction as a preeminent regulatory hub, while concurrently resolving the injury-elicited mechanosensitive phenotypic landscapes. This evidence informs a mechano-adaptive niche-engineering framework that systematically deciphers how biophysical cues govern Schwann cell plasticity, directed axonal navigation, macrophage phenotypic re-polarization, vascular integration, and global tissue homeostasis. In this context, advanced additive manufacturing platforms, notably three- and four-dimensional biofabrication, serve as foundational cornerstones for constructing biomimetic niches endowed with spatiotemporally programmable and dynamically interactive features. Collectively, these mechanistic insights are rigorously codified into rational design blueprints, wherein stiffness gradients, topographical anisotropy, and dynamic mechanical actuation converge to define next-generation neural guidance conduits. In their clinical translation, adaptive, patient-conformal, and context-responsive biofabrication ecosystems constitute transformative modalities, propelling mechano-regenerative biomaterials toward a new vanguard in neural reinnervation.
Abstract Macrophages are essential for myelin clearance following peripheral nerve injury, yet the mechanisms linking their functional heterogeneity to metabolic regulation remain unclear. Single-cell RNA sequencing was combined with functional assays to characterize macrophage heterogeneity and investigate the relationship between metabolic reprogramming and myelin clearance after peripheral nerve injury. A distinct macrophage subset enriched was identified after injury that exhibited elevated expression of glycolysis-related and phagocytosis-associated genes. Functional analyses demonstrated that glycolytic activity was positively associated with macrophage-mediated myelin clearance. Among candidate regulators, solute carrier family 2 member 6 was highly expressed in this subset, and its knockdown impaired glycolysis, lactate production, histone lactylation and myelin clearance capacity, effects that were partially rescued by metabolic intervention or lactate supplementation. In vivo , lactate administration was associated with enhanced myelin clearance and improved nerve structural and functional recovery. These findings provide new insights into the interplay between metabolic reprogramming and immune function in nerve injury. These results provide a mechanistic foundation for the development of metabolism-targeted therapeutic strategies to enhance peripheral nerve regeneration.
