Developmental Neuroscience最新文献

The gut microbiota plays a vital role in shaping brain development through complex bidirectional communication within the microbiota-gut-brain axis. Emerging evidence highlights neural, immune, endocrine, metabolic, and epigenetic pathways by which gut microbes influence neurodevelopmental processes. This review synthesizes current knowledge on the temporal dynamics of gut colonization and brain maturation. Drawing on mechanistic insights from animal models, we emphasize the central role of the maternal microbiota and particularly, microbially derived metabolites that cross the feto-placental barrier and shape fetal brain development. We also discuss molecular and cellular targets of microbial influence, implications for neurodevelopmental disorders, and potential therapeutic strategies. Understanding these interactions opens new avenues for early-life interventions aimed at optimizing neurodevelopment and preventing neuropsychiatric conditions.

Introduction: Neonatal hypoxic-ischemic (HI) brain injury is a major cause of mortality and long-term neurological disability, yet effective neuroprotective strategies remain limited. Microglia are central mediators of injury and repair, with arginase-1 (ARG1) marking anti-inflammatory, reparative states. However, the functional roles of ARG1⁺ microglia in tissue remodeling after HI are poorly understood.

Methods: Neonatal mice (P10) underwent HI using the Vannucci procedure. ARG1 activity was inhibited pharmacologically using N-omega-hydroxy-nor-L-arginine (Nor-NOHA). ARG1 expression, microglial morphology, efferocytosis, tissue scar, and injury volume were assessed via immunohistochemistry, Western blotting, and arginase activity assays at 1 and 5 days post-injury.

Results: ARG1⁺ microglia rapidly engaged apoptotic neurons, exhibiting phagocytic activity confirmed by CD68 expression. Nor-NOHA treatment reduced ARG1 enzymatic activity, impaired microglial process extension, attenuated efferocytosis, and increased injury volume. ARG1⁺ microglia persisted in the glial scar and co-localized with collagen I alpha 1 (Col1a1), suggesting a role in extracellular matrix (ECM) deposition. Inhibition of ARG1 decreased Col1a1 expression, highlighting its contribution to tissue remodeling.

Conclusions: ARG1⁺ microglia are pivotal in neonatal HI, mediating early efferocytosis and later ECM remodeling, thereby limiting injury and shaping scar architecture. Pharmacological blockade of ARG1 exacerbates injury, underscoring its reparative function. These findings establish ARG1 as a critical regulator of microglial-mediated neuroprotection and tissue repair, providing a potential therapeutic target for neonatal HI brain injury.

Precise regulation of neurite initiation, elongation, and branching is critical for neuronal network formation. Rac1, a key regulator of cytoskeletal remodeling, influences neurite morphogenesis through protein phosphorylation-mediated signaling, but the global phosphorylation landscape that governs Rac1-mediated morphogenesis remains unknown. To address this knowledge gap, we performed phosphoproteomics profiling of primary rat cortical neurons treated with 3, 10, or 30 µM of a Rac1 inhibitor for 48 hours to evaluate phosphoprotein dynamics. Phosphorylation levels of 167 signaling proteins were quantified using a targeted phospho-antibody array, and correlated with neurite count, length, and branch point count. Correlation analysis identified morphology-specific phosphoproteins, such as Tau, CREB, CaMK2, and GAP43, whose phosphorylation levels were significantly associated with neurite morphology features at specific inhibitor concentration. These results define a correlation-based framework linking phosphoprotein signaling to neurite morphology and offer novel insights into neurodevelopmental processes, neuronal disorders, and developmental neurotoxicity.

Introduction: The long-term neurological consequences of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, are an area of growing concern, particularly for prenatally exposed individuals. Prior research has shown that APOE4, the leading genetic risk factor for late-onset Alzheimer's disease, is associated with increased COVID-19 severity and enhanced SARS-CoV-2 neurotropism. However, whether the interaction between APOE4 and SARS-CoV-2 infection leads to adverse neurodevelopmental outcomes remains unclear. Using human induced pluripotent stem cell derived cortical and ganglionic eminence organoids (COs and GEOs) to model neurodevelopment, we have previously reported that SARS-CoV-2 preferentially infects glial cells, and that APOE4 promotes gliogenesis in COs and accelerates GABAergic neuron differentiation in GEOs. Here, we build upon our previous work by using COs and GEOs to examine how APOE4 modifies cellular responses to SARS-CoV-2 during late gestational development.

Methods: Using low viral titers to better mimic natural infection, COs and GEOs were infected at 220-270 DIV, aligning with the third trimester, and were analyzed 7 days post infection.

Results: We observed region-specific, APOE4-dependent changes. In infected COs, APOE4 elevated immature astrocyte marker, suggesting a genotype-dependent glial response. Additionally, infected GEOs exhibited reduced marker expression for mature neurons within both genotypes. Notably, APOE4 and infection interacted to modulate immature neuron expression in a region-specific manner.

Conclusion: Taken together, this study suggests that APOE4 modulates region-specific responses to low-grade SARS-CoV-2 infection, underscoring the importance of exploring how genetic risk factors alter neurodevelopmental vulnerability to prenatal viral infection.

Introduction: We recently identified variants in 10 genes that are members of either the p53 pathway or Fanconi Anemia Complex (FAC), regulators of DNA repair (DNA damage response [DDR]) in 17 cases with pediatric acute-onset neuropsychiatric syndrome (PANS) or regression in autism spectrum disorder and other neurodevelopmental disorders (NDD). We aimed to identify additional cases with genetic vulnerabilities in DDR and related pathways.

Methods: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) data from 32 individuals were filtered and analyzed to identify ultrarare pathogenic or likely pathogenic variants.

Results: Variants affecting DDR were found in 14 cases diagnosed with PANS or regression (CUX1, USP45, PARP14, UVSSA, EP300, TREX1, SAMHD1, STK19, MYTl1, TEP1, PIDD1, ADNP, FANCD2, and RAD54L). The CUX1 variant is de novo, as are two cases that had mutations in genes that affect mitochondrial functions that are connected directly or indirectly to mitophagy (PRKN and POLG), which can trigger the same innate immune pathways when disrupted as abnormal DDR. We also found pathogenic or likely pathogenic secondary mutations in several genes that are primarily expressed in the gut that have been implicated in gut microbiome homeostasis (e.g., LGALS4, DUOX2, CCR9).

Conclusion: These findings align with previous genetic findings and strengthen the hypothesis that abnormal DDR and mitochondrial dysfunction underlie pathogenic processes in at least some cases of neuropsychiatric decompensation. The potential involvement of genetic variants in gut microbiome homeostasis is a novel aspect of our study. Functional characterization of the downstream impact of DDR deficits may point to novel treatment strategies.

Introduction: According to literature, early stress may lead to a higher susceptibility to the action of various stressors later in life, thus largely contributing to the development of a wide range of affective disorders. Disrupting maternal care is one way to destabilize the environment for pups, which may result in the formation of an altered reaction to acute or moderate stress.

Methods: In this study, we analyzed the effects of limited bedding and nesting material (LBN) in PND2-PND9 on baseline gene expression in the hippocampus and frontal cortex of 1-month-old rats and the expression of the same genes under conditions of 60-min restraint. Among the analyzed genes, some were associated with glucocorticoids (Nr3c1 and Nr3c2), others with the activation of the immune system (Nfkbia, Ccl2, Il1b, Il6, Tnfα, Cx3cl1, Cx3cr1, and Ncf1), and yet others with the activation of neuronal networks under stress (Cfos, Ier-2). Gene expression was assessed using real-time PCR.

Results: Exposure to LBN during early postnatal life significantly increased baseline expression of the Fos gene in the amygdala of adolescent rats. LBN exposure more slightly affected the expression of other analyzed genes (Nr3c1, Cx3cl1, Ier2, Ncf1) or evoked alterations of their expression in this group only after exposure to acute restraint stress. The hyperglycemic response to acute restraint was attenuated in LBN-exposed animals, while corticosterone levels were comparable to controls. Among the studied genes, the expression of Nfkbia, Il6, and Tnf was primarily influenced by acute restraint stress, independently of LBN history. The amygdala and ventral hippocampus were the brain regions where the expression of the analyzed genes appeared most sensitive to the experimental manipulations.

Conclusion: These data indicate that early-life stress induced by LBN leads to a sustained increase in baseline Fos expression in the amygdala and alters the metabolic response to acute stress in adolescence. The findings further suggest that the amygdala and ventral hippocampus are key regions where the expression of a limited set of stress-related genes is modulated by the interplay of early-life adversity and acute stress. These points to a potential role for amygdalar circuits in the altered stress reactivity observed following adverse early-life conditions.

Introduction: Neonatal rats, but not juvenile rats, show spontaneous hindlimb locomotor recovery after complete thoracic spinal cord transection (SCT). Significant increases in parvalbumin-positive proprioceptive nerve terminals are observed on motoneurons in both neonatal and juvenile rats with SCT compared with intact rats.

Methods: In the present study, we focused on Chx10-positive V2a interneurons, which partially comprise the central pattern generator, and examined parvalbumin-positive nerve terminals on Chx10 neurons and the perineuronal net formation around these neurons using Wisteria floribunda agglutinin (WFA) as a marker 2 weeks after SCT on postnatal day 5 (neonatal) or day 20 (juvenile).

Results: Rats with CST during the neonatal period had a significantly greater number of parvalbumin-positive terminals on Chx10 neurons compared to age-matched intact rats, whereas no significant difference was detected between rats with SCT during the juvenile period and age-matched intact rats. Chx10 neurons for which ≥50% of the circumference was surrounded by WFA were identified as WFA-positive. The proportion of WFA-positive neurons among Chx10-positive neurons did not differ significantly between neonatal SCT and age-matched intact rats, but was significantly higher in juvenile SCT and age-matched intact rats.

Conclusion: These findings suggest that SCT promotes the formation of proprioceptive afferent terminals on Chx10-positive neurons. The significant increase in terminals following SCT in neonatal rats might facilitate spontaneous motor recovery, whereas enhanced perineuronal net formation around Chx10 neurons following juvenile SCT might restrict synaptic formation and impair motor recovery.

Background: The proper functioning of the central nervous system depends on the cooperation of distinct neuronal subtypes generated during development.

Summary: Here, we review new insights provided by recent research and technological advances into the mechanisms underlying the generation of the remarkable diversity of inhibitory GABAergic neurons (INs). INs are generated in the ventral telencephalon or subpallium and migrate long distances to populate multiple brain regions. INs exhibit considerable morphological, molecular, and electrophysiological diversity. This diversity is mediated by intrinsic and extrinsic factors, including secreted molecules (such as sonic hedgehog).

Key messages: This review examines the role of extrinsic factors in the establishment of distinct subpallial domains and the subsequent emergence of IN diversity. We begin by summarizing the in vivo morphogenesis of this process and then highlight the new technologies that allow us to revisit the role of morphogens in subpallial development and IN specification.

In the article by Zhou et al. entitled "Caffeine as a Treatment for Perinatal Hypoxic-Ischemic Brain Injury: The Potential Risks and Benefits" [Dev Neurosci. 2025; DOI: 10.1159/000545126] the license was incorrect, and it has changed from CC BY-NC 4.0 to CC BY 4.0.The original article has been updated.