bims-adhine 2026-10-11 papers

Issue of 2026–10–11
seven papers selected by
Tamara J. Buijs, Universiteit van Amsterdam

Commun Biol. 2026 Oct 07. pii: 1307. [Epub ahead of print]9(1):

Adult hippocampal neurogenesis shapes ideomotor action control in mice.

Warsha Barde, Gerd Kempermann, Christian Beste.

Humans select and learn goal-directed actions through the anticipation of their outcomes. While this ideomotor principle is well established in humans, its biological instantiation and relevance for organizing naturalistic behavior remain unclear, including its neurobiological substrates such as hippocampal plasticity. Here, we leverage high-resolution, continuous behavioral tracking in mice across a month-long series of automated learning tasks to test whether ideomotor principles generalize to naturalistic behavior and how they relate to adult hippocampal neurogenesis. Mice lived in a shared enriched environment and engaged in self-initiated learning tasks, allowing us to quantify how action-outcome associations are formed, maintained, and updated. Despite identical genetic background and environment, animals showed stable individual differences in how these associations were organized. These differences correlated with levels of adult hippocampal neurogenesis: higher neurogenesis was associated with broader, more variable exploration and greater flexibility in updating action-outcome relations, whereas lower neurogenesis was linked to more rigid behavior. Together, these findings link ideomotor theory to a cellular plasticity mechanism supporting flexible action control.

DOI: https://doi.org/10.1038/s42003-026-11112-z

Aging Cell. 2026 Oct;25(10): e70663

Sex-Specific Neurogenic and Cognitive Responses in a Murine Model of Accelerated Aging.

Ricardo Gómez-Oliva, Andrea Chamorro-Francisco, Isabel Atienza-Navarro, Livia Carrascal, María D Freire-Aragón, Rosario Hernández-Galán, Pedro Nunez-Abades, Mónica García-Alloza, Carmen Castro.

Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer's disease-like neuropathology, and an initial increase in hippocampal neurogenesis that ultimately depletes the neural stem cell pool. Notably, most studies using murine models of aging or neurodegeneration have focused on males or mixed-sex cohorts, leaving sex-specific differences in neurogenesis and cognitive decline largely unexplored. Recent evidence indicates that diterpenoid treatment is associated with improved cognitive performance and enhanced neurogenesis in 6-month-old male SAMP8 mice. However, whether females exhibit similar responses remains unknown. In this study, we characterized sex differences in hippocampal neurogenesis in 6-month-old SAMP8 mice and examined potential sex-dependent effects of diterpenoid therapy. Our findings reveal sex-specific differences in physiological and pathological hippocampal neurogenesis and in responsiveness to ER272 treatment. Male SAMR1 mice displayed higher baseline neurogenesis than females, while male and female SAMP8 mice followed distinct neurogenic aging trajectories. ER272 was associated with improved cognitive performance and preservation of multiple neurogenic parameters in males but showed limited effects in females. These results suggest sex-specific mechanisms of brain aging and indicate that mixed-sex analyses may mask biologically relevant differences, highlighting the importance of considering sex in aging studies and therapeutic development.

Keywords: aging; cognitive performance; neurogenesis; sex‐differences; therapy

DOI: https://doi.org/10.1111/acel.70663

Brain Res. 2026 Oct 03. pii: S0006-8993(26)00438-5. [Epub ahead of print]1893 150576

Early-life maternal separation induces anxiety-like behavior in male mice associated with reduced dentate gyrus neurogenesis and hippocampal inflammatory remodeling.

Xixia Li, Jiayu Liang, Feijun Huang, Yu Xiong, Jieming Hu, Shujun Sun, Renxi Cai, Yuanchun Feng, Yunyue Hu, Hejian Xiong.

Early-life adversity increases vulnerability to affective disorders, but the neural alterations underlying sex-dependent susceptibility remain unclear. Here, C57BL/6J mouse pups underwent maternal separation (MS) for 3 h daily from postnatal day 1 to 10, and adult male and female offspring were assessed behaviorally. MS induced significant anxiety-like behavioral alterations in male offspring, whereas comparable anxiogenic changes were not detected in females. c-Fos-based regional screening identified the hippocampus as a candidate region. In males, the reduction in c-Fos-positive cells was further localized to the dorsal and ventral dentate gyrus (DG), whereas females showed no significant change in overall hippocampal c-Fos expression. Transcriptomic analysis of the hippocampus revealed enrichment of inflammation-related pathways and downregulation of neurogenesis-related signatures, whereas histological analyses demonstrated reduced adult DG neurogenesis, including decreased quiescent and activated neural stem cells and reduced DCX immunoreactivity. These neurogenic alterations were accompanied by microglial activation, increased hippocampal pro-inflammatory cytokine expression, reduced IL-10 expression, and increased microglia-neural stem cell proximity. Together, these findings indicate that early-life maternal separation is associated with anxiety-like behavioral alterations in male offspring accompanied by reduced DG neurogenesis and hippocampal inflammatory alterations.

Keywords: Anxiety-like behavior; Dentate gyrus; Maternal separation; Neurogenesis; Neuroinflammation; Sex differences

DOI: https://doi.org/10.1016/j.brainres.2026.150576

Glia. 2026 Dec;74(12): e70234

Molecular Control of Neural Stem Cell Quiescence in the Adult Zebrafish Telencephalon: Established Mechanisms and an Integrative Hypothesis.

Mathilde Hoareau, Nicolas Diotel, Sepand Rastegar.

The zebrafish telencephalon is an excellent model for adult neurogenesis under physiological and regenerative conditions, as many pathways regulating neural stem cell behavior are conserved with mammalian neurogenic niches. Resident radial glial cells (RGCs) serve as neural stem cells in the adult brain and are readily accessible in vivo, because forebrain eversion repositions the ventricular zone to the dorsal surface. Recent studies have revealed substantial heterogeneity among RGCs, including activation-primed cells and deeply quiescent states during homeostasis. Here, we first review the evidence that four mechanisms control quiescence in pallial RGCs: Notch3-mediated lateral inhibition, the neuronal bone morphogenetic protein (BMP)-Id1 axis, the nuclear receptor Nr2f1b, and the secreted factor Midkine-a. The evidence supporting them is unequal, and we state its level for each before asking whether they act together. Notch-mediated lateral inhibition and neuronal BMP-Id1 signaling converge on her4.1, the clearest documented interaction among them, whereas Nr2f1b establishes a deeper dormancy program that resists Notch and BMP inhibition and protects a reserve stem cell pool. Midkine-a is proposed to reinforce quiescence, pending functional validation. Finally, we propose as a hypothesis that these mechanisms act as partially redundant inputs whose relative contributions determine quiescence depth and vary along the antero-posterior axis of the pallium. Together, these findings reframe quiescence as a spectrum of actively maintained conditions rather than a passive default state. These mechanisms are conserved across vertebrates, with implications for understanding why mammalian neural stem cell pools decline with age and injury.

Keywords: adult neurogenesis; neural stem cell; quiescence; radial glial cell; telencephalon; zebrafish

DOI: https://doi.org/10.1002/glia.70234

Life Sci. 2026 Oct 03. pii: S0024-3205(26)00529-1. [Epub ahead of print]406 124720

Loss of Cotl1 disrupts mitochondrial fission and impairs learning and memory in mice.

Eunkuk Park, Min Jun Jang, Jae Hyouk Choi, Gyu-Sang Hong, Hyun Goo Woo, Hyun-Seok Jin, Min Soo Kim, Seon-Yong Jeong.

Mitochondrial morphology dynamics are essential for neuronal function and are regulated by fission and fusion machinery, in which the actin cytoskeleton plays a crucial role. Coactosin-like F-actin-binding protein 1 (Cotl1), a key component of the actin cytoskeleton, is gaining attention for its profound pathophysiological implications in human neurodegenerative disorders. However, its role in neuronal function remains unclear. Therefore, we aimed to explore the role of Cotl1 in mitochondrial morphology and neuronal dysfunction. We generated Cotl1-knockdown and Cotl1-K75E mutants to examine mitochondrial structure and produced Cotl1-knockout (Cotl1-/-) mice to assess learning and memory-related phenotypes. Both Cotl1 knockdown and Cotl1-K75E overexpression induced mitochondrial elongation and disrupted F-actin organization by inhibiting fission. In silico analysis of differentially expressed genes in Cotl1-/- hippocampal tissue revealed a link between Cotl1 and neuronal function. Cotl1-/- mice further exhibited impaired learning and memory, accompanied by decreased doublecortin (Dcx) expression in the hippocampal dentate gyrus (DG). Notably, restoration of Cotl1 expression in the DG recovered both Dcx expression and cognitive functions. These results highlight the crucial role of Cotl1 in mitochondrial fission through its regulation of F-actin and Drp1 assembly in the mitochondria, and they link Cotl1 loss to impaired learning and memory and to reduced Dcx expression in the hippocampal DG. Collectively, these findings suggest an important role of Cotl1 in maintaining developing granule neurons in the dentate gyrus, a process closely linked to mitochondrial fission and cognitive function.

Keywords: Cotl1; Dentate gyrus; Doublecortin; F-actin; Memory; Mitochondrial fission

DOI: https://doi.org/10.1016/j.lfs.2026.124720

Nature. 2026 Oct;658(8135): 308-310

Can your brain grow new neurons? How researchers are solving a century-old puzzle.

Mariana Lenharo.

Keywords: Brain; Neuroscience; Regeneration

DOI: https://doi.org/10.1038/d41586-026-03132-w

Brain Res. 2026 Oct 08. pii: S0006-8993(26)00432-4. [Epub ahead of print] 150570

A comprehensive single-cell transcriptomic atlas of hippocampal microglia in a mouse model of traumatic brain injury.

Wenbin Dong, Yinuo Jia, Ruilin Wang, Mingxuan Yu, Ying Bai, Wei Pang, Renjie Wang.

BACKGROUND: Traumatic brain injury (TBI) triggers microglial activation and disrupts the inflammatory microenvironment in the hippocampus, which are key contributors to neuroinflammation and subsequent secondary brain damage. Nevertheless, the cellular heterogeneity of microglia, their pro-inflammatory activation mechanisms, and microenvironmental regulatory networks have not been fully characterized.
METHODS: By integrating multi-source single-cell transcriptomic datasets and establishing a mouse TBI validation model, we constructed a high-resolution cellular atlas of hippocampal microglia. Through comprehensive re-analysis of single-cell RNA-sequencing (scRNA-seq) datasets, bioinformatic approaches, high-dimensional weighted gene co-expression network analysis (hdWGCNA), cell-cell communication profiling, and in vivo behavioral and in vivo pathological evaluations, we thoroughly explored the subpopulation diversity, functional features, and regulatory mechanisms of hippocampal microglia following TBI.
RESULTS: TBI elicited extensive phenotypic diversification in hippocampal microglia, and five major subpopulations were identified, among which disease-associated microglia (DAM) were further classified into four distinct subclusters. A distinct inflamed DAM subset (Inflam-DAM) was found to highly express canonical pro-inflammatory signature genes. Transcriptomic profiling revealed enrichment of AP-1 family transcription factors and the IL-17 signaling pathway in this subset, confirming its robust pro-inflammatory phenotype. hdWGCNA demonstrated that the pro-inflammatory state of Inflam-DAM was tightly linked to transcriptional and translational regulation. Cell-cell communication analysis indicated that meningeal macrophages, B cells and fibroblasts acted as upstream regulators and selectively interacted with DAM subclusters in the inflammatory niche. In turn, activated DAM communicated with neurons in an injury-dependent manner, eventually impairing neurogenesis. In vivo experiments validated that TBI mice displayed severe neurological dysfunction, elevated expression of pro-inflammatory microglial markers and signaling molecules in the hippocampus, and fewer newborn mature neurons - all findings consistent with our single-cell data.
CONCLUSION: In summary, this work constructs a full-scale single-cell transcriptomic landscape of hippocampal microglia in TBI mice. We systematically delineated the heterogeneity of DAM subsets, the pro-inflammatory regulatory mechanism of Inflam-DAM, and the multi-layered intercellular network within the inflammatory microenvironment. Our results deepen the mechanistic understanding of TBI-associated neuroinflammation and offer valuable clues for the development of targeted anti-inflammatory therapies.

Keywords: Disease-associated microglia; Inflammatory microenvironment; Microglial heterogeneity; Single-cell RNA sequencing; Traumatic brain injury

DOI: https://doi.org/10.1016/j.brainres.2026.150570