Open research questions in Neurogenesis and neuroplasticity mechanisms

What the literature leaves open

• Although altered C4 expression has been associated with disease risk, it remains unclear whether localized C4 elevation in a small neuronal population is sufficient to reshape broader cortical gene-regulatory programs and cellular phenotypes.

  Sparse Neuronal C4 Elevation Induces Network-Wide Transcriptomic and Lipid-Droplet Remodeling in the Cortical Microenvironment · 2026 · DOI

• Although excessive GC exposure during early life adversity has been linked to changes in OPC development, the physiological role of GR signaling specifically within OPCs remains unclear.

  Glucocorticoid receptors in oligodendrocyte precursor cells regulate hippocampal network plasticity and stress-induced behavior in mice · 2026 · DOI

• Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear.

  Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD · 2026 · DOI

• Significance StatementNeuronal loss is a defining feature of neurodegenerative diseases, yet its underlying mechanisms remain incompletely understood.

  Masking phosphatidylserine prevents neuronal loss in two distinct Drosophila models of neurodegeneration · 2026 · DOI

• While LS results from mutations in the OCRL gene, which encodes an inositol polyphosphate 5-phosphatase, the cellular mechanisms driving neuronal dysfunction remain poorly understood.

  Defective Neuronal Differentiation in Lowe Syndrome is Associated with Mitochondrial Dysfunction and Impaired Cilia-related Sonic Hedgehog Signaling · 2026 · DOI

• Abstract Subarachnoid haemorrhage (SAH) is a life-threatening cerebrovascular event frequently accompanied by consciousness disturbances, yet the underlying mechanisms remain poorly defined.

  Oligodendrocyte prosaposin restores subarachnoid haemorrhage-induced consciousness impairment · 2026 · DOI

• While LFB staining provides a sensitive and wellestablished histochemical measure of myelin content, it has important limitations. LFB intensity re- (cid:192)(cid:72)(cid:70)(cid:87)(cid:86)(cid:3)(cid:74)(cid:85)(cid:82)(cid:86)(cid:86)(cid:3)(cid:80)(cid:92)(cid:72)(cid:79)(cid:76)(cid:81)(cid:3)(cid:68)(cid:69)(cid:88)(cid:81)(cid:71)(cid:68)(cid:81)(cid:70)(cid:72)(cid:3)(cid:69)(cid:88)(cid:87)(cid:3)(cid:71)(cid:82)(cid:72)(cid:86)(cid:3)(cid:81)(cid:82)(cid:87)(cid:3)(cid:85)(cid:72)(cid:86)(cid:82)(cid:79)(cid:89)(cid:72)(cid:3) ultrastructural features, such as myelin thickness, internodal length, nodal organization, or axonal in- (cid:87)(cid:72)(cid:74)(cid:85)(cid:76)(cid:87)(cid:92)(cid:17)(cid:3) (cid:38)(cid:82)(cid:81)(cid:86)(cid:72)(cid:84)(cid:88)(cid:72)(cid:81)(cid:87)(cid:79)(cid:92)(cid:15)(cid:3) (cid:81)(cid:82)(cid:85)(cid:80)(cid:68)(cid:79)(cid:76)(cid:93)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3) (cid:82)(cid:73)(cid:3) (cid:47)(cid:41)(cid:37)(cid:3) (cid:86)(cid:76)(cid:74)(cid:81)(cid:68)(cid:79)(cid:3) after cuprizone withdrawal should not be interpreted as proof of complete structural or functional recovery. To determine whether remyelination restores normal myelin architecture and conduction, complementary (cid:68)(cid:81)(cid:68)(cid:79)(cid:92)(cid:86)(cid:72)(cid:86)(cid:3)(cid:68)(cid:85)(cid:72)(cid:3)(cid:85)(cid:72)(cid:84)(cid:88)(cid:76)(cid:85)(cid:72)(cid:71)(cid:29)(cid:3)(cid:72)(cid:79)(cid:72)(cid:70)(cid:87)(cid:85)(cid:82)(cid:81)(cid:3)(cid:80)(cid:76)(cid:70)(cid:85)(cid:82)(cid:86)(cid:70)(cid:82)(cid:83)(cid:92)(cid:3)(cid:87)(cid:82)(cid:3)(cid:68)(cid:86)(cid:86)(cid:72)(cid:86)(cid:86)(cid:3) g-ratio and internodal structure, immunohistochemistry for axonal and nodal markers, and electrophysiological measurements to test conduction velocity. Moreover, biochemical or imaging measures that distinguish newly formed versus residual/compacted (cid:80)(cid:92)(cid:72)(cid:79)(cid:76)(cid:81)(cid:3)(cid:90)(cid:82)(cid:88)(cid:79)(cid:71)(cid:3)(cid:86)(cid:87)(cid:85)(cid:72)(cid:81)(cid:74)(cid:87)(cid:75)(cid:72)(cid:81)(cid:3)(cid:70)(cid:82)(cid:81)(cid:70)(cid:79)(cid:88)(cid:86)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:68)(cid:69)(cid:82)(cid:88)(cid:87)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:84)(cid:88)(cid:68)(cid:79)- ity of repair.

  Spatial Dynamics of Cuprizone-Induced Myelin Loss and Recovery in the Mouse Corpus Callosum · 2026 · DOI

• Furthermore, the divergent patterns of GPR54 expression raise the possibility that KISS1–GPR54 signaling may differentially modulate SuM function across models, although its causal role remains to be determined.

  Reduced SuM Activation Accompanies Impaired Social Novelty Recognition in Mouse Models of Neurodevelopmental Disorders · 2026 · DOI

• The supramammillary nucleus (SuM) has been implicated as a key region involved in processing novelty-related information and associated with hippocampal CA2 activity; however, whether SuM dysfunction occurs in neurodevelopmental disorder models with impaired social novelty recognition remains unclear.

  Reduced SuM Activation Accompanies Impaired Social Novelty Recognition in Mouse Models of Neurodevelopmental Disorders · 2026 · DOI

• 48,49 As a result, given the neural crest origin of jaw-derived BMSCs, a fundamental but understudied question remains: Do jaw bone-derived BMSCs retain ancestral neurogenic functions inherited from their progenitors, unlike mesoderm-derived BMSCs from long bones? In this study, we have compared the features of jaw bone-derived BMSCs in comparison to those derived from other mesodermal origins (rib marrow-derived BMSCs).

  ANKRD1 sustains a neurogenic BMSC niche and counters cognitive aging · 2026 · DOI

• While much attention has been focused on postnatally-born neurons, their presumed progenitor -- the postnatal neural stem cell (NSC) -- remains poorly characterized.

  Isolation of postnatal human neural stem cells · 2026 · DOI

• However, little is known about the molecular alterations that occur during brain development in SCZ, particularly regarding the role of microRNA (miRNA) mediated regulatory mechanisms.

  Dysregulation of miRNAs Drives Premature GABAergic Maturation and Early Neurodevelopmental Defects in Schizophrenia · 2026 · DOI

• In this review, we synthesize disease-specific oligodendrocyte pathological signatures and context-dependent cellular responses, focusing on underrecognized OL-intrinsic pathogenic mechanisms: endogenous Aβ production, aberrant protein aggregation, disrupted cholesterol turnover, and excessive neuroinflammatory amplification.

  Oligodendrocyte dysfunction in neurodegenerative diseases: pathological features, underlying mechanisms and therapeutic targeting · 2026 · DOI

• Circulating IgG antibodies against myelin-associated glycoprotein (MAG) have been reported in individuals with ASD and their mothers; however, the pathogenic relevance of these antibodies and the contribution of MAG signaling to neurodevelopment remain unclear.

  Disruption of Myelin-Associated Glycoprotein Activity Drives Aberrant Cerebellar Neurodevelopment and Autism-Like Behaviors. · 2026 · DOI

• Genome-wide association studies have identified protective variants in the phosphoinositide-metabolising enzyme PLCG2 that modify Alzheimers disease risk, but how PLCG2-dependent phosphoinositide signalling regulates glial engulfment remains unclear.

  Phosphoinositide turnover through PLCγ regulates Draper-dependent engulfment in glia · 2026 · DOI

• During CNS development, oligodendrocytes wrap spirally around axons while compacting membranes, yet how cytoskeletal remodeling is coupled to these events remains unclear.

  Actin disassembly triggers CNS myelin compaction and wrapping · 2026 · DOI

• The basal ganglia (BG) form anatomically and functionally segregated yet integrative parallel circuits, but the molecular mechanisms specifying them remain unclear.

  Complementary δ2-protocadherin expression delineates parallel basal ganglia circuits in primates · 2026 · DOI

• Although remyelination, a central nervous system (CNS) regenerative process mediated by oligodendrocyte progenitor cells (OPCs), takes place in an inflammatory environment the long-term impact of inflammation on OPC remyelination capacity remains unclear.

  Inflammation-induced epigenetic memory restores oligodendrocyte progenitor cell regenerative capacity in the aged central nervous system · 2026 · DOI

• Harnessing the stem cell potential in the human hippocampus to limit cognitive aging Susmit Mhatre1,2, Darcie L. Moore 1* 1 Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 2 Cell and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America * [email protected] The field of human adult neurogenesis has been controversial despite mounting evidence. The authors propose moving beyond debating the existence of adult neurogenesis and towards discovering strategies to harness endogenous stem cell potential for resilience against cognitive aging. OPEN ACCESS Citation: Mhatre S, Moore DL (2026) Harnessing the stem cell potential in the human hippocampus to limit cognitive aging. PLoS Biol 24(5): e3003787. https://doi.org/10.1371/ journal.pbio.3003787 Academic Editor: William B. Mair, Harvard University T H Chan School of Public Health, UNITED STATES OF AMERICA Published: May 22, 2026 Copyright: © 2026 Mhatre, Moore.

  Harnessing the stem cell potential in the human hippocampus to limit cognitive aging · 2026 · DOI

• Chemical screening in zebrafish has potential to identify in vivo promyelinating molecules before transitioning to rodent models, but this screening approach has not been systematized for oligodendrocyte differentiation. Comprehensive chemical screens could reveal novel small molecules that promote oligodendrocyte myelination capacity in living zebrafish before expensive rodent validation.

  Oligodendrocyte differentiation · 2016 · DOI

• Cell type-specific CRISPR/Cas9 knockout studies for oligodendrocyte development in zebrafish have not been extensively utilized. Reverse genetic approaches using cell type-specific CRISPR/Cas9 knockouts would enable systematic investigation of gene function in oligodendrocyte lineage progression and axonal myelination.

  Oligodendrocyte differentiation · 2016 · DOI

• Proteomic analysis of oligodendrocyte differentiation in zebrafish remains an understudied area. Proteomic profiling is needed to identify new molecular targets in CNS myelination and remyelination pathways that could complement existing genomic screening approaches.

  Oligodendrocyte differentiation · 2016 · DOI

• Essential molecules involved in axo-glial signaling that mediate oligodendrocyte behavior in vivo remain unidentified. Future genetic screens in zebrafish are needed to systematically discover these critical axo-glial signaling factors that regulate oligodendrocyte differentiation and myelination.

  Oligodendrocyte differentiation · 2016 · DOI

• The transcriptional mechanisms that maintain adult Parvalbumin (PV) interneuron function and cortical network stability remain poorly understood.

  Dlx5/6 regulate perineuronal net-synapse coupling and stabilize adult cortical Parvalbumin neurons networks · 2026 · DOI

• However, the molecular logic that underlies the cell type specification of the IC remains unknown.

  Molecular and cell type-specific determinants of inferior colliculus development and auditory function · 2026 · DOI

Most-cited papers in Neurogenesis and neuroplasticity mechanisms

• Mapping gene transcription and neurocognition across human neocortex · Nature Human Behaviour · 2021 · 207 citations
• An epigenetic barrier sets the timing of human neuronal maturation · Nature · 2024 · 201 citations
• Neuropsychological profile of patients with first-episode of schizophrenia. · Neuropsychopharmacologia Hungarica · 2004 · 105 citations
• Derivation and transcriptional reprogramming of border-forming wound repair astrocytes after spinal cord injury or stroke in mice · Nature Neuroscience · 2024 · 78 citations
• Border Lines: The Partition of Judaeo-Christianity · The Journal of Theological Studies · 2006 · 77 citations
• Functional myelin in cognition and neurodevelopmental disorders · Cellular and Molecular Life Sciences · 2024 · 73 citations
• Breast cancer exploits neural signaling pathways for bone-to-meninges metastasis · Science · 2024 · 72 citations
• Oligodendrocytes and myelin limit neuronal plasticity in visual cortex · Nature · 2024 · 65 citations
• "Do I still want to play?" Parents' and peers' influences on girls' continuation in sport. · Journal of sport behavior · 2013 · 64 citations
• CRISPR–Cas9 screens reveal regulators of ageing in neural stem cells · Nature · 2024 · 62 citations

Most recent work

• Dopamine drives persistent remodelling of the maternal brain · Nature · 2026
• The sodium channel SCN2A regulates cortical excitatory and inhibitory neurogenesis · bioRxiv · 2026
• Harnessing the stem cell potential in the human hippocampus to limit cognitive aging · PLOS Biology · 2026
• Defective ventral neurogenesis due to midfetal Chd8 mutation drives autistic-like behavior in mice · Nature Communications · 2026
• Dysregulation of miRNAs Drives Premature GABAergic Maturation and Early Neurodevelopmental Defects in Schizophrenia · bioRxiv · 2026
• ANKRD1 sustains a neurogenic BMSC niche and counters cognitive aging · International Journal of Oral Science · 2026
• Confined migration induces non-lethal DNA damage in developing neurons · Nature · 2026
• High dopamine impairs early neuronal identity and morphology in human hippocampal progenitor cells · Frontiers in Cell and Developmental Biology · 2026
• Perinatal brain developmental transition revealed by transcriptomic and proteomic analyses of Bama miniature pigs · Nature Communications · 2026
• Adrenomedullin restores the human cortical interneurons migration defects induced by hypoxia · eLife · 2026

Related topics in Neuroscience