The Molecular Basis of Maladaptive Neuroplasticity: Pathological Neuronal Epigenetic Remodeling

The study of neuroplasticity at the molecular level is central to understanding how the nervous system adapts to experience and responds to challenges across the lifespan. While neuroplasticity supports learning, circuit refinement, and tissue repair, emerging evidence suggests that the molecular mechanisms that enable plasticity can also contribute to maladaptive outcomes when regulation is disrupted.In particular, epigenetic remodeling plays a central role in coordinating gene expression programs in neurons. Key molecular players such as DNA methylation, histone modification, chromatin dynamics, noncoding RNAs, and three-dimensional genome organization orchestrate developmental and experience-dependent gene regulation. In addition, chromatin organization, enhancer-promoter communication, and higher-order regulatory layers have emerged as crucial determinants of neuronal gene regulatory landscapes and circuit plasticity, with disruptions in these mechanisms being increasingly linked to disease. Recent advances in spatial epigenomics and the study of 3D genome organization in neurons are also illuminating how changes in genome architecture may drive alterations in gene expression and contribute to a variety of neurological and psychiatric disorders. However, when these tightly regulated programs are disrupted, particularly during critical developmental windows or following injury, they may induce maladaptive changes in synapses, cellular architecture, and circuit connectivity. Ongoing work continues to unravel how such pathological epigenetic states alter plasticity thresholds, but significant gaps remain in defining specific molecular mechanisms, timing, and their long-term impact on brain function.This Research Topic aims to dissect how pathological epigenetic remodeling in neuronal populations leads to maladaptive neuroplasticity, focusing on the molecular mechanisms underlying synaptic and circuit alterations during development and adulthood, and their association with neurodevelopmental, neuropsychiatric, or neurodegenerative conditions. By also emphasizing the upstream epigenetic mechanisms, including chromatin structure, enhancer-promoter interaction, and 3D genome architecture, that drive transcriptional regulation, we hope to connect these foundational regulatory events to their downstream effects on synaptic and structural pathology. Through integration of advances in molecular biology, imaging, genomics, and model-based research, we hope to improve understanding of how disrupted epigenetic landscapes give rise to defined pathological phenotypes and to support progress toward molecularly targeted detection and intervention strategies. Both foundational and translational research are encouraged. Topics of interest include, but are not limited to:• Molecular signatures of maladaptive neuroplasticity: aberrant chromatin remodeling, histone/DNA/RNA modifications, and dysregulated noncoding RNA in neural development and disease.• Roles of chromatin organization, enhancer-promoter communication, and transcriptional regulation in shaping gene expression and circuit plasticity.• Spatial epigenomics and 3D genome organization: how altered genome architecture contributes to neurological and psychiatric disorders.• Mapping and manipulating pathological states: molecular imaging, genetically encoded sensors, and precision intervention at the nanoscale.• Glia–neuron signaling and epigenetic interactions: their roles in synaptic remodeling, plasticity regulation, and circuit dysfunction.• Mechanisms of synaptic and structural pathology: phase separation, protein aggregates, cytoskeletal changes, and disrupted local translation in maladaptive outcomes.• Innovative delivery and rescue strategies: nanoparticles, genetically targeted tools, and biomimetic materials for precise correction or modulation of plasticity pathways. Topic editors: Hiroshi Tsubokawa, Yi Liu Source: https://www.frontiersin.org/research-topics/79091/the-molecular-basis-of-maladaptive-neuroplasticity-pathological-neuronal-epigenetic-remodeling