Complex neural activity in the mammalian central nervous system are achieved through the coordinated function of diverse neuronal subtypes. The sequential generation of distinct types of neurons from neural progenitor cells during development is a key process in establishing this complexity. However, how this temporal specification of neuronal identities is regulated across different brain regions during development remains only partially understood. Here, we identify PHF21B, ZFP7, and ZFP57 as critical regulators that control the transition from the generation of early-born to late-born neurons by neural progenitor cells in the developing mouse cortex and ganglionic eminence. Combinatorial overexpression of these factors in developmentally advanced progenitors that normally generate late-born neurons led to a prolonged generation of early-born neuronal subtypes. Conversely, simultaneous knockdown of these genes markedly reduced generation of early-born neurons. Because these factors are predicted to function as transcriptional regulators involved in heterochromatin formation at their target genomic loci, our findings suggest the presence of a shared epigenetic mechanism that governs the temporal specification of neurons across multiple regions of the developing brain.

Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuronal degeneration in the substantia nigra, in which lysosomal dysfunction and impaired autophagy-lysosome pathway activity are increasingly recognized as important pathogenic mechanisms. However, disease-modifying therapies targeting this pathway remain unavailable. Here, we generated induced pluripotent stem cells (iPSCs) from a PARK9 patient carrying an ATP13A2 mutation and established mutation-corrected isogenic control iPSCs. PARK9 iPSC-derived neurons recapitulated lysosomal dysfunction-associated cellular phenotypes, including impaired lysosomal acidification, reduced mature cathepsin D levels, CD63-positive vesicle accumulation, LC3B-positive autophagosome accumulation, cytoplasmic pSer129 α-synuclein accumulation, and increased cleaved caspase-3 signals. These phenotypes were ameliorated in mutation-corrected neurons, supporting the contribution of ATP13A2 dysfunction to these abnormalities. We then performed high-content imaging-based compound screening targeting LC3B-positive autophagosome accumulation in PARK9 neurons. A three-step workflow identified 19 candidate compounds that reduced autophagosome accumulation consistent with partial improvement of lysosome-dependent downstream autophagosome processing rather than simple suppression of autophagosome formation. Among these, paroxetine, Ro 25-6981, amisulpride, and PK11195 showed additional, compound-dependent effects on PARK9-associated phenotypes, including lysosomal acidification, CD63-positive vesicle accumulation, cytoplasmic pSer129 α-synuclein signals, and cleaved caspase-3 signals. These findings establish PARK9 iPSC-derived neurons as a useful model of lysosomal dysfunction-associated PD pathology and provide a practical screening platform for identifying candidate compounds that modulate autophagy-lysosome pathway-related cellular phenotypes.

Clarifying the relationship between structure and function is important for understanding the brain. In Drosophila melanogaster, FlyEM and FlyWire electron microscopy-based connectome data and whole-brain calcium imaging data are available. We applied pre-processing methods from fMRI to whole-brain calcium imaging data and comprehensively investigated the optimal parameters. Then, we found that the FC-SC (functional and structural connectivity) correlation decreased linearly with region of interest count, and this trend was the same in flies and humans. We also developed a new, more robust method to quantify the degree of pre– and post-synaptic segregation and investigated this in the fly whole-brain. This revealed that many neurons have unsegregated synapses. We extracted highly unsegregated synapses and compared them with random-extracted null SC matrices. Their FC-SC correlation was significantly higher, indicating that these synapses contribute to FC well. Conversely, highly segregated-synapses showed significantly lower FC-SC correlation and contribute less to FC. Neurons with unsegregated synapses like non-spiking neurons are spread throughout the whole-brain, and they are thought to have a significant influence on FC.

Precise regulation of neural progenitor states and neuronal positioning is essential for cortical development. Here, we identified Sox2 regulatory region 42 (SRR42), a regulatory region located 42 kb downstream of the Sox2 transcription start site that exhibits open chromatin, active histone modifications, and bidirectional transcription of enhancer RNAs (eRNAs). Using transgenic reporter mice, we found that SRR42 is active in neural progenitor cells in the developing cortex. CRISPR-Cas9-mediated deletion of SRR42 combined with single-cell multiome analysis revealed alterations in progenitor-state dynamics, neuronal migration, and cortical lamination without detectable changes in Sox2 expression. Furthermore, in vivo knockdown of SRR42-derived eRNAs impaired neuronal migration. These findings identify SRR42-derived RNAs as regulators of neuronal migration during cortical development and highlight enhancer-associated transcription as a functional component of neurodevelopmental gene regulation.

Spinal cord injury (SCI) causes irreversible motor and sensory deficits, and no therapy currently restores the damaged neural circuitry. Previous work has shown that transplantation of induced pluripotent stem cell (iPSC)-derived neural stem/progenitor cells (NS/PCs) restored motor function in preclinical models of subacute SCI; however, the safety of this approach in humans remains unknown. Here we report results from a first-in-human, open-label study of iPSC-NS/PC transplantation in four patients with subacute cervical complete SCI. The primary safety end point was achieved, with no tumor formation or graft-related adverse events observed during 2-4 years of follow-up and stable graft sites on imaging. Exploratory efficacy was assessed as a secondary end point. Median improvement in the International Standards for Neurological Classification of Spinal Cord Injury motor score from baseline (2 weeks after injury) to week 52 was 13 points (range 10-40), with two patients improving in American Spinal Injury Association Impairment Scale (grade A → C and A → D). These gains were numerically greater than spontaneous recovery observed in a registry-based cohort. This study provides clinical evidence that transplantation of human iPSC-NS/PCs into the injured spinal cord is feasible and safe under short-term immunosuppression, with findings supporting further clinical evaluation. The trial is registered at UMIN000035074 , UMIN000050104 and jRCTa031190228 .

Spinal cord injury (SCI) causes irreversible neurological damage and remains a major clinical challenge due to the lack of effective regenerative therapies. Human-induced pluripotent stem cells (hiPSCs) and their derivatives, hiPSC-derived neural stem/progenitor cells (hiPSC-NS/PCs), have demonstrated potential to promote neural repair and functional recovery. The world’s first clinical trial using hiPSC-NS/PCs in the subacute phase of SCI has already been initiated. In contrast, chronic SCI—despite accounting for the majority of clinical cases—remains difficult to treat due to pathological barriers such as widespread demyelination, cavitation, scar formation, and persistent inflammation. Recent efforts to overcome these obstacles include combinatorial strategies incorporating rehabilitation, biomaterial scaffolds, pharmacological adjuvants, and robotic-assisted therapy as well as gliogenic or regionally patterned hiPSC-NS/PCs. Preclinical models have demonstrated that such multifaceted approaches can enhance graft survival, axonal regeneration, and functional recovery. In this review, we provide an overview of the biological characteristics, mechanisms of action, and recent advances in preclinical and clinical research on hiPSC-NS/PCs transplantation for SCI. We also discuss future perspectives and challenges toward clinical application. Collectively, these efforts underscore the diverse, innovative, and translational potential of hiPSC-based regenerative medicine for SCI.

The mammalian brain orchestrates the processing and integration of information to guide behaviour. Here, to characterize mammalian information-processing architecture, we combine functional neuroimaging and anaesthesia in humans, macaques, marmosets and mice. We show that breakdown of information integration is a convergent effect of diverse anaesthetics across mammalian species. As the system disintegrates, brain dynamics become more difficult to control. Both effects are reversed upon re-awakening induced by thalamic deep-brain stimulation in the macaque. Regional breakdown of integrated information coincides with the species-specific spatial topography of PVALB/Pvalb gene expression. To provide mechanistic insight beyond correlation, we develop computational models for humans, macaques and mice that integrate species-specific connectivity and transcriptomic gradients, demonstrating their respective roles for controlling brain dynamics and information integration. We reveal evolutionarily conserved controllers of information integration in the mammalian brain.

The striatum plays a central role in motor control, cognition, reward processing, and habit formation, and its dysfunction is implicated in a broad spectrum of neurological and psychiatric disorders. Although animal models have provided important insights into striatal development and disease mechanisms, species-specific differences in cellular composition, developmental timing, and circuit organization limit their translational relevance to the human brain. In this context, human pluripotent stem cells (PSCs), including embryonic stem cells and induced pluripotent stem cells, have emerged as valuable platforms for modeling human striatal development and pathology in vitro. In this review, we summarize current approaches for generating striatal cell types from PSCs, with a particular focus on medium spiny neurons (MSNs), the principal projection neurons of the striatum. We discuss key developmental principles underlying dorsal and ventral striatal specification and highlight the protracted maturation of human MSNs, which may contribute to human-specific disease vulnerability. Advances in differentiation strategies, including small molecule-based patterning, transcription factor-driven induction, and three-dimensional organoid and assembloid systems, have progressively improved the efficiency, reproducibility, and cellular complexity of PSC-derived striatal models. We further review applications of PSC-derived striatal systems in disease modeling, noting that most studies to date have focused on Huntington’s disease, where these models have revealed early developmental, transcriptional, synaptic, and network-level abnormalities. More recent studies have begun to extend these approaches to other neurological conditions and to incorporate circuit-level analyses using cortico-striatal assembloids. In parallel, the growing availability of single-cell and single-nucleus transcriptomic datasets from the human striatum provides powerful reference frameworks for benchmarking the identity and maturation state of PSC-derived striatal cells. Finally, we discuss current challenges and limitations of PSC-based striatal models, including incomplete maturation, limited representation of non-neuronal cell types, and restricted applicability to psychiatric disorders. We propose that continued integration of developmental biology, public multi-omics resources, and advanced in vitro modeling strategies will be essential for advancing human striatal models and expanding their utility in translational neuroscience.

Ex vivo brain studies are essential in neuroscience research, yet the effects of perfusion fixation on structural connectivity remain poorly understood. We previously demonstrated that axial diffusivity is most sensitive to regional volume changes following fixation at the local tissue level. However, how these microstructural changes affect whole-brain network organization remains unclear. To investigate changes in whole-brain structural connectivity following perfusion fixation, advancing our understanding from local microstructural alterations to macroscopic network-level changes. Twelve common marmosets underwent 9.4T MRI scanning both in vivo and following perfusion fixation (ex vivo). Diffusion-weighted imaging was performed with optimized parameters for each condition. Whole-brain tractography was generated using constrained spherical deconvolution and anatomically-constrained tractography framework. Structural connectivity matrices were compared between conditions using the SIFT2 algorithm for quantitative assessment. We identified 799 connections showing significant differences between in vivo and ex vivo conditions (p < 0.05, Bonferroni corrected), 14.9

Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) cause progressive loss of specific neuronal populations and currently lack curative therapies. Animal models and immortalized cell lines incompletely recapitulate human pathology and genetic heterogeneity, limiting drug discovery. Human induced pluripotent stem cells (iPSCs) provide a patient‑specific platform for disease modelling, drug screening and studying individual responses. Translational research (TR) uses iPSC models to identify candidate therapies that are subsequently tested in clinical trials, while reverse translational research (rTR) feeds clinical observations back to the bench by analyzing iPSCs derived from trial participants and integrating molecular data with patient phenotypes. This review summarizes recent advances in iPSC‑based TR and rTR for ALS and extends the discussion to other neurodegenerative diseases. Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases.

INTRODUCTION:ALS drug discovery has long depended on model systems that incompletely capture human disease heterogeneity, aging, and TDP-43 proteinopathy. Patient-derived platforms have therefore emerged as increasingly important human-relevant complements to animal and molecular models. AREAS COVERED:This Critical Perspective examines when patient-derived ALS models genuinely change therapeutic decision-making rather than merely add mechanistic insight. The authors then propose a heuristic framework based on disease-relevant phenotype recapitulation, capture of patient-to-patient heterogeneity, and generation of findings that influence therapeutic prioritization or clinical translation. Furthermore, the authors evaluate iPSC-derived motor neurons, directly reprogrammed neurons, glial co-cultures, organoids, neural networks, and organ-chip systems against these conditions, while also addressing aging fidelity, reproducibility, upper motor neuron modeling, and regulatory implementation. EXPERT OPINION:Patient-derived models are not yet standalone decision-grade tools for ALS drug development. Their present value lies in functioning as a human-biology filter for target discovery, reverse translation, biomarker development, and patient stratification when used within rigorous, standardized, and clinically linked workflows. The strongest current evidence supports proof-of-principle rather than generalized predictive validity.

Benign adult familial myoclonus epilepsy (BAFME) is caused by intronic TTTCA and TTTTA repeat expansions in SAMD12 and other genes; the neuronal basis of cortical hyperexcitability, however, remains unclear. We generated induced pluripotent stem cell (iPSC)-derived glutamatergic and GABAergic neurons from three BAFME1 patients and examined functional and transcriptomic phenotypes. Patient-derived neurons retained the pathogenic repeat expansions and showed a tendency toward upstream intronic RNA accumulation. Calcium imaging revealed increased spontaneous Ca2 + transient frequency in both neuronal subtypes, indicating heightened activity. Pharmacological profiling demonstrated attenuated responses to calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor (CP-AMPAR) blockade and GABAA receptor antagonism in GABAergic neurons, suggesting altered inhibitory signaling. RNA sequencing revealed transcriptomic alterations without differential expression of ion channels and neurotransmitter receptors. In glutamatergic neurons, ATF4-regulated genes, including SLC7A5 encoding LAT1, a Kv1.2 channel modulator, were downregulated. Reduced SLC7A5 expression was validated at both mRNA and protein levels. In GABAergic neurons, synapse-associated genes PTPRD and GPC6 were upregulated. TCERG1L and NLRP2 were suppressed across both neuronal subtypes. These findings suggest subtype-specific alterations may contribute to neuronal hyperexcitability in BAFME and provide a platform for mechanistic studies of repeat expansion-associated epilepsies.

BackgroundPeripheral nerve injuries often cause persistent sensory and motor deficits, and autologous nerve grafting, the current standard, is limited by donor site morbidity and tissue availability. Human induced pluripotent stem cells (hiPSCs)-derived neural crest-like cells (NCLCs) have shown potential for nerve regeneration, but achieving high purity and safety remains a challenge.MethodsUsing a mouse model of large sciatic nerve defects, we evaluated the efficacy of transplanting NCLCs triple-positive for low-affinity nerve growth factor receptor (LNGFR), thymocyte antigen 1 (THY-1), and neural cell adhesion molecule (NCAM). Purified triple-positive cells induced from hiPSC-derived neural crest lineage were seeded in the conduit with collagen gel in the transplantation group and compared the regeneration with the autograft group and the negative control group without cells.ResultsNCAM-positive NCLCs promoted robust angiogenesis and recruited host Schwann cells, thereby establishing a supportive regenerative microenvironment. This facilitated axonal regrowth, thick myelination, and organized nerve architecture comparable to that of autografts. Functional recovery, assessed by electrophysiological conduction and motor performance, eventually matched autografts, with earlier improvement observed in the transplantation group. No tumor formation was detected, and the proliferative activity of transplanted cells declined over time. Selective marker-based purification likely contributed to the favorable safety profile.ConclusionNCAM-positive NCLCs derived from hiPSCs enhance peripheral nerve regeneration through vascularization and Schwann cell-mediated remyelination, resulting in structural and functional recovery equivalent to autografts. This strategy offers a safe, scalable alternative to donor nerve harvest, and integration with bioengineered conduits could further expand clinical applicability in peripheral nerve reconstruction.

The acute management of traumatic spinal cord injury (SCI) continues to lack a universally accepted pharmacological intervention. We developed a novel therapeutic strategy, intrathecal administration of pharmaceutical recombinant human hepatocyte growth factor (KP-100), based on translational research using a non-human primate model of cervical SCI. A Phase I/II trial (multi-center, randomized, double-blind study including subjects with cervical SCI with modified Frankel grade A/B1/B2 at 72 h post-injury) demonstrated the safety and efficacy of intrathecal KP-100. A greater proportion of Frankel grade A subjects achieved ≥1 point improvement on their lower-extremity motor score (33.3% [KP-100] vs. 6.3% [placebo]). This study aimed to confirm these findings by including only subjects with the American Spinal Injury Association (ASIA) impairment scale (AIS) grade A. This open-label, non-randomized, single-group interventional Phase III study enrolled subjects with AIS grade A at 72 h post-injury. KP-100 was administered intrathecally immediately after enrollment. Subsequent doses were given once weekly, for a total of five administrations. Subjects were followed up for 168 days after the first administration. The primary end-point was the proportion of subjects who demonstrated improvement from AIS grade A at baseline to C or higher at day 168, compared with subjects with AIS grade A at 72 h post-injury in the General Spinal Cord Injury Center Data Bank in Japan (n = 81, the DB group). Additionally, we utilized data from modified Frankel grade A subjects in the PI/II study (n = 16, the PI/II Placebo group; n = 15, the PI/II KP-100 group) for post hoc analyses of therapeutic effects. Of the 31 pre-registered participants, 6 were excluded due to ineligibility, and 25 were included in the efficacy analysis (the PIII group). The primary end-point was not achieved (8.6% [DB, 95% confidence interval [CI]: 4.2-16.8] vs. 12.0% [PIII, 95% CI 4.2-30.0]). However, in post hoc exploratory comparisons, the PIII group tended to have greater proportion of subjects who improved to AIS grade B or higher (56.0% [37.1-73.3]) than the DB group (19.8% [12.5-29.7]). Whereas SCIs without fracture at the C3/4 level were more common in the PI/II KP-100 group, the PIII group tended to have more SCIs with fractures or dislocations and below C3/4. Accordingly, in exploratory comparisons, the proportion of subjects who improved to modified Frankel grade C1 or higher tended to be highest in the PI/II KP-100 group (6.3% in the PI/II Placebo, 26.7% in the PI/II KP-100, 12.0% in the PIII group). Conversely, ≥5 points of improvement on the upper-extremity motor score tended to be most frequent in the PIII group (31.3% in the PI/II Placebo, 20.0% in the PI/II KP-100, 56.0% in the PIII group). These results showed exploratory signals of neurological recovery in this highly impaired population, providing supportive evidence for potential biological activity of KP-100.

How the activity and connectivity of the brain support consciousness remains a central question in neuroscience. Recent progress driven by the use of functional MRI has seen growing recognition that large-scale distributed functional organisation of the human and non-human primate brain are systematically and consistently reshaped by anaesthetic-induced unconsciousness, across anaesthetics and across human and macaque. Here, we generalise these results to a different primate species that is gaining traction as model organism in neuroscience, the marmoset ( Callithrix jacchus ). We also generalise results to an additional anaesthetic, isoflurane, which we compare with propofol and sevoflurane. We report that under anaesthesia with propofol, sevoflurane, or isoflurane, distributed brain activity from functional MRI is increasingly constrained by the underlying structural connectivity across scales. Anaesthesia also induces a collapse of the principal gradient and intrinsic functional geometry of the marmoset brain, coinciding with a breakdown of hierarchical integration. Altogether, the present results indicate generalisable signatures of anaesthesia in the large-scale organisation of the primate brain.

Oligodendrocyte progenitor cells (OPCs) generated in the ventricular-subventricular zone (V-SVZ) migrate long distances to sites of brain injury to contribute to remyelination, but the mechanisms guiding their efficient recruitment remain unclear. Using a neonatal cortical injury model combined with live imaging and three-dimensional culture, we show that V-SVZ-derived OPCs migrate toward lesions by interacting with migrating neuroblasts that share the same route. Neuroblast contact significantly enhances OPC motility even in the absence of external scaffolds. High-resolution imaging reveals that these heterotypic interactions are associated with punctate adherens junctions that form and dissolve dynamically during migration. These findings uncover a previously unrecognized mechanism in which transient, dynamic adherens junctions support cooperative migration between neuronal and glial progenitors to facilitate efficient recruitment of OPCs to injured brain tissue.

Importance:Blood-based neural biomarkers linked to aging may provide insights into the biological end point of the human lifespan. However, the key biomarker associated with cognition and mortality in centenarians remains unclear. Objective:To investigate the associations between 3 neural biomarkers-amyloid-β42 and amyloid-β40 ratio (Aβ42/40), phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL)-and both cognitive function and all-cause mortality in centenarians. Design, Setting, and Participants:This population-based cohort study included Japanese centenarians aged 100 years or older who were enrolled between September 2000 and January 2021. Participants underwent baseline cognitive assessments and blood sampling and were followed up for 17 years for mortality. Data analysis was performed in February 2026. Exposures:Baseline plasma levels of Aβ42/40, p-tau181, and NfL measured using ultrasensitive immunoassays. Main Outcomes and Measures:Cognitive function at baseline, measured using the Mini-Mental State Examination (MMSE), and all-cause mortality. Results:Of 495 participants (398 [80.4%] women; mean [SD] age 104.1 [3.0] years), 419 completed a cognitive assessment (mean [SD] MMSE, 14.9 [6.9]). During 17 years of follow-up, 466 participants (95.5%) died. Lower Aβ42/40 (β = 0.99; 95% CI, 0.46 to 1.52) and higher NfL levels (β = -0.92; 95% CI, -1.62 to -0.23) were significantly associated with lower MMSE scores after adjusting for confounders. Higher NfL levels were also associated with increased mortality (hazard ratio, 1.36; 95% CI, 1.17 to 1.57), showing the greatest point estimate among the biomarkers, all of which were standardized and statistically significant (change in Akaike Information Criterion, likelihood ratio test, χ2 = 30.16; P < .001). Aβ42/40 and p-tau181 were not statistically significant after full adjustment. Conclusions and Relevance:In this cohort study of centenarians, higher plasma NfL levels were associated with lower cognitive function and increased all-cause mortality, whereas Aβ42/40 and p-tau181 showed no associations. These findings suggest that plasma NfL was associated with neurodegeneration in extreme aging. Further studies are needed to confirm its clinical utility before routine implementation.

This commemorative article reflects on a research journey spanning neural development, stem cell biology, regenerative medicine, and iPSC-based drug discovery. My early work focused on RNA-mediated regulation in the nervous system, including studies on myelin basic protein gene regulation and the identification and functional characterization of the RNA-binding protein Musashi. These studies contributed to the conceptual foundation of neural stem cell biology and helped establish methods for identifying and isolating neural stem/progenitor cells, including those present in the adult human brain. Building on this foundation, my colleagues and I pursued translational research in spinal cord injury, ranging from analyses of injury pathophysiology and molecular interventions to preclinical studies using rodent and non-human primate models. These efforts ultimately led to the first-in-human clinical study of induced pluripotent stem cell-derived neural stem/progenitor cell transplantation for subacute spinal cord injury. In parallel, we developed patient-derived iPSC platforms for neurological disease modeling and drug discovery, particularly for amyotrophic lateral sclerosis, where iPSC-based screening identified Ropinirole as a therapeutic candidate and enabled reverse translational research linking cellular phenotypes with clinical responses. Looking ahead, I argue that the future of regenerative therapy will depend on the continued integration of developmental biology, stem cell science, disease modeling, rehabilitation, and clinical translation to address unmet medical needs in disorders of the central nervous system.