搜索结果：Developmental neurobiology

Lead (Pb) is a persistent environmental neurotoxicant with particular hazard during developmental periods. This study investigated the mechanistic effects of developmental Pb exposure (100 ppm; 5 mg/kg/day, administered to dams from GD5-PND14) on maternal neurobiology and reproductive function. All endpoints were assessed in dams' plasma and tissues collected at PND14. Pb accumulated significantly in the brain, ovary, and uterus, establishing a systemic toxic burden. Exposure induced severe oxidative stress, evidenced by elevated malondialdehyde and depletion of antioxidant defences (CAT, GSH, GST, GR, GPx), alongside increased neuroinflammatory mediators (IL-1β, TGF-β), cholinergic dysregulation, and glial activation (elevated AChE, GFAP, and Iba-1). Cerebral glucose metabolism was markedly impaired, with GLUT-1 overexpression and downregulation of key glycolytic enzymes (HK, PFK-1, PK, G6PD), indicating bioenergetic failure. Pb exposure disrupted the hypothalamic-pituitary axis, reducing GnRH and GnRHR expression while paradoxically elevating Fshβ and Lhβ mRNA and corresponding plasma gonadotropins in dams. Epigenetic dysregulation was characterised by miR-34a upregulation and miR-144 suppression, with pathway enrichment analysis implicating apoptosis, inflammation, and metabolic signalling networks. Collectively, these findings demonstrate that developmental Pb exposure induces convergent oxidative, neuroinflammatory, metabolic, and epigenetic disturbances that underlie dams neuroendocrine and reproductive dysfunction.

Prenatal alcohol exposure (PAE) is recognized as a major public health concern due to its profound and lasting effects on the central nervous system (CNS) and its ability to induce fetal alcohol spectrum disorders (FASD), which encompass a wide range of cognitive, behavioural, and neuropsychiatric disorders that persist throughout life. Experimental and clinical studies have identified several mechanisms underlying ethanol impairing brain development, including apoptosis, oxidative stress, disruption of morphogen and growth factor signalling pathways, impaired neuronal proliferation and migration, neurotransmitter systems' dysfunction, glial cells damage associated with deficient myelination, vascular and blood-brain barrier (BBB) alterations, and lasting epigenetic reprogramming. However, to date no widely accepted integrative framework explaining how these impairments underline the heterogeneous phenotype observed in FASD is available. The present brings together developmental neurobiology and computational neuroscience to conceptualize PAE as a disorder of emerging neural and functional architecture. Here, we summarize the pharmacokinetics of ethanol in pregnancy, critical windows of vulnerability, and the classical pathways of alcohol teratogenesis affecting neuronal survival, migration, synaptogenesis, myelination, and gene regulation. We have also reviewed MRI, diffusion imaging, and EEG/MEG evidence showing altered brain volumes, white matter microstructure, functional connectivity, and network organization in individuals with PAE. Finally, we propose a systems-level model that conceptualizes PAE as a disorder of emerging neuro-computational architecture, in which ethanol-induced cellular and molecular perturbations collectively alter the building blocks and self-organization rules of brain network assembly.

The circadian system synchronizes physiology, improving the adaptation to daily environmental changes. In mammals, the central pacemaker, in the suprachiasmatic nuclei (SCN) of the hypothalamus, coordinates "wake" functions by inducing the circadian release of glucocorticoids (GCs). GCs entrain the clocks of a wide variety of tissues through GC receptor (GR) activation, however, the influence of GCs on the SCN is unclear and seems to depend on the maturity of the circuit. During the perinatal period, the mouse SCN express GR and respond directly to GCs while the adult SCN express low GR and have been traditionally considered resistant to GCs. To understand the change of sensitivity to GCs we followed the developmental trajectory of the mouse SCN, and found that while GR is expressed in all SCN cells early in life, it remains expressed mainly in astrocytes in the adult. Using a model of prenatal exposure to GCs, we found that offspring from treated mothers, adapt slower to shifted light-dark cycle and shows reduced expression of GR in SCN astrocytes. The adult SCN astrocytes can indeed sense and respond to GCs with rapid astrocytic Ca2+ events that propagate across neighboring cells, an effect that is prevented by the specific inhibition of astrocyte-astrocyte communication. Our findings provide a conceptual advance on how the mouse clock develops and on the influence that GCs have on the SCN. This might be relevant to understand how circadian synchrony is restored in conditions of temporal misalignment, such as jet lag.

Most widely studied option evaluation strategies rely on knowledge accumulated across repeated experiences. But how should options be evaluated in unfamiliar environments, in which knowledge is sparse? In these situations, how do decision makers make efficient use of limited past experience to guide their choices? One possible strategy is episodic sampling, in which a decision maker retrieves a small number of past decisions from memory to estimate the value of present options. By virtue of their age, children and adolescents have less experience than adults, making episodic sampling a particularly useful strategy for them. At the same time, the effectiveness of episodic sampling derives from memory's precision and context sensitivity-properties that continue to develop into adolescence and young adulthood. This tension raises a key question: are developmental differences in episodic memory associated with differences in episodic sampling? To address this question, 106 participants, ages 8 to 25, completed a 2-d choice task that dissociated the influence of a single episodic memory from the influence of multiple episodes sharing a common context. At all ages, single episodes biased choices. But, only adults were sensitive to the broader evoked context. Further clarifying the relationship between episodic memory and decision making, differences in memory precision predicted differences in episodic sampling, even after taking into account age, while episodic sampling, in turn, accounted for individual differences in forward planning. Together, these findings suggest that episodic memory guides decision making throughout development, but the character of its influence evolves as memory becomes more precise and richly structured.

Brain lesions can unlock latent neurogenic potential in parenchymal astrocytes, but the identity of their neuronal progeny has remained unclear. Here, we show that neurons generated by striatal astrocytes after excitotoxic lesions are transient, yet reach advanced morphological and functional maturation and integrate into cortico-striatal-thalamic circuits. Single-cell RNA-seq mapping onto an embryonic reference revealed these cells are not fated to adult striatal neuron types but belong to the LGE-MEIS2/PAX6 interneuron class. Reanalysis of neuroblasts from cortical and striatal astrocytes after Notch abrogation revealed shared commitment of rostral telencephalic astrocytes to this class. Public spatial transcriptomics datasets revealed these cells are widely distributed throughout the mouse telencephalon during embryonic and postnatal development. Thus, unlike other vertebrates in which adult telencephalic astroglia preserve the potential to generate resident, regionally appropriate neuronal types, homologous mammalian cells converge on a specific transient neuron class, possibly representing a reservoir for circuit plasticity in adult life.

The RAC subfamily of Rho family small GTPases plays a crucial role in neurodevelopment by regulating cellular signaling pathways and the actin cytoskeleton. The activity of RAC is controlled by guanine nucleotide exchange factors (GEFs), which facilitate the transition from an inactive GDP-bound form to an active GTP-bound form. A novel de novo variant, NM_020820.4:c.572 A > G p.(Y191C), was identified in PREX1, which encodes a RAC-specific GEF, by whole-exome sequencing of a patient with epilepsy. Biochemical analysis using recombinant proteins demonstrated that the p.Y191C variant reduced the GDP/GTP exchange activity of PREX1 toward RAC1 and attenuated RAC1-PAK1 signaling compared with wild-type PREX1, suggesting that the p.Y191C variant is hypofunctional. To explore its neurodevelopmental consequences in vivo, we performed in utero electroporation-mediated RNA interference targeting PREX1 in cerebrocortical progenitor cells in mice at embryonic day 14 (E14). While no significant effects on radial migration or morphological development were observed at E17, PREX1-knockdown neurons were located more apically within layer II/III than controls at postnatal day 0 (P0). By P7, these neurons showed aberrant dendritic arborization with a significant increase in apical dendritic branching. Likewise, dendritic overgrowth was observed in granule cells of the hippocampal dentate gyrus following PREX1 knockdown at P0, with minimal effects on dendritic spine morphology. Functionally, PREX1 knockdown enhanced spontaneous Ca²⁺ activity in cultured hippocampal neurons and depolarization-evoked Ca²⁺ responses in layer II/III cortical neurons in acute brain slices. These findings indicate that reduced PREX1-RAC1 signaling leads to mislocalization, dendritic overgrowth, and neuronal hyperexcitability, which may underlie epilepsy in the human case.

Introduction Jean Piaget's theory of cognitive development posits that human intelligence progresses through four distinct, sequential stages. While modern neurobiology recognizes a general posterior-to-anterior gradient in brain maturation consistent with Piaget's proposal, the specific correspondence between structural cortical reorganization and these discrete psychological transitions remains a subject of investigation. Here we examine the temporal correspondence between cortical shape change and Piaget's cognitive stages by analyzing ontogenetic trajectories and introducing a novel approach to quantify developmental alignment, with applicability to fossil organisms. Methods We examined a cross-sectional dataset of human endocasts derived from CT scans of individuals aged 0 to 18 years. To quantify the brain developmental dynamics, we devised a new method based on a phylogenetic comparative approach, treating chronological age stages as an evolutionary lineage. We applied phylogenetic ridge regression to compute rates of shape change and the charted them on the endocast across age stages to visualize areas of rapid expansion and contraction directly onto the endocast. Results We found significant fluctuations in the rate of endocast shape ontogeny that align well with Piagetian transitions. We observed a rapid phase of growth in all lobes peaking at age 2 (transition to preoperational stage), followed by a distinct reorganization at age 7 involving parietal and occipital expansion (at the onset of concrete operational stage). A subsequent shift in frontal and parietal dynamics occurred at age 11, corresponding to the onset of the formal operational stage. The temporal lobe is the last to develop. Extensive endocast contraction occurs in frontal and parietal lobes around age 15, consistent with the operation of synaptic pruning. Conclusion These findings provide quantitative evidence that the emergence of complex cognitive faculties is biologically paced by discrete waves of cortical restructuring. Furthermore, the efficacy of this morphometric approach on endocasts validates its potential for reconstructing the evolutionary ontogeny of intelligence in extinct Homo species, offering a bridge between developmental psychology and paleoanthropology.

The targeted differentiation of stem cell-like cells into functional neurons is a central goal in developmental biology and comparative neurobiology. In this study, we report for the first time on the successful neuronal remodeling of cell line derived from the Atlantic sturgeon larvae (Acipenser oxyrinchus; AOXlar7y) under defined in vitro conditions. The cells were cultured on poly-D-lysine-coated surfaces and exposed to a reduced-serum medium supplemented with nerve growth factor-β to induce neuronal differentiation. Morphologically, time-dependent formation of neurite-like processes and network structures was observed over a period of 14 days. The neuronal identity of the differentiated cells was confirmed by immunocytochemistry with the neuronal marker NeuN. Functional maturation was examined by measurement of cytoplasmatic calcium activity. After stimulation with 200 µM ATP, cells with neuronal morphology showed distinct intracellular calcium transients, indicating functional purinergic signaling pathways. AOXlar7y thus represents a novel in vitro model for studying neurogenesis and neuronal function in a cellular model of ancient fish species and provides a valuable basis for future studies in comparative neurobiology, neurotoxicology, and evolutionary developmental biology.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by persistent deficits in social communication and interaction, alongside restricted and repetitive behaviors. Despite substantial advances in genetics, neurobiology and neuroimaging, no pharmacological treatment currently addresses the core symptoms of ASD. Existing medications primarily target associated behavioral disturbances such as irritability, aggression and hyperactivity. This narrative review synthesizes contemporary neurobiological findings, methodological challenges and evolving clinical trial frameworks relevant to the evaluation of emerging pharmacotherapies in ASD. Particular emphasis is placed on biomarker-informed stratification, rigorous trial design and developmental timing as critical determinants of therapeutic success. Advances in molecular genetics, systems neuroscience and multimodal biomarker integration highlight the need for precision medicine approaches that align pharmacological targets with underlying neurodevelopmental mechanisms. Strengthening methodological rigor while maintaining ethical and neurodiversity-affirming principles will be essential to advancing effective pharmacological interventions for ASD.

The Activity-Dependent Neuroprotective Protein (ADNP) is an important regulator of early brain development, especially during cortical neurogenesis and neurite formation. De novo point mutations or haploinsufficiency of the ADNP gene result in ADNP syndrome, which is also known as Helsmoortel-Van der Aa syndrome, a complex neurodevelopmental disorder recognized as a leading single-gene cause of syndromic autism spectrum disorder (ASD) and intellectual disability. ADNP works as both a transcription factor and a microtubule (MT) regulator. As a transcription factor, ADNP is a key component of chromatin remodeling complexes such as ChAHP (CHD4 (Chromodomain Helicase DNA-binding Protein 4)-ADNP-HP1 (Heterochromatin Protein 1)) and SWI/SNF (Switch/Sucrose Non-Fermentable), and it tightly regulates the expression of numerous essential developmental genes. ADNP also modulates the Wnt/β-catenin signaling pathway. During neural differentiation, ADNP is redistributed from the nucleus to the cytoplasm, and this redistribution is regulated by binding to 14-3-3 proteins, which are phosphorylated by protein Kinase C (PKC). After relocating to the cytoplasm, ADNP functions as an MT regulator by binding to microtubule end-binding proteins (EB1 and EB3) and Tau to control neurite formation. Previous studies have focused on NAP (also known as Davunetide, a peptide derived from ADNP) in MT regulation and its therapeutic potential for autism spectrum disorder (ASD) and neurodegenerative diseases, such as Alzheimer's disease. This review highlights the functions of full-length ADNP and NAP in early brain development, particularly in neurogenesis and neurite formation during cortical development. We will also discuss the potential of NAP as a therapeutic medication for neurodevelopmental disorders, especially ASD and ADNP syndrome.

High Mobility Group A (HMGA) proteins function as non-histone chromatin-associated architectural regulators that modulate gene transcription by modifying chromatin structure rather than binding DNA in a sequence-specific manner. By altering chromatin conformation, HMGA proteins coordinate complex transcriptional programs essential in both physiological and pathological conditions. This review highlights their emerging roles in the context of the nervous system, brain tumorigenesis, and neurodegeneration. We discuss how HMGA-mediated chromatin remodeling and transcriptional regulation influence neurodevelopmental processes, regulating neural stem cell proliferation, differentiation, and lineage specification. We also highlight evidence linking HMGA dysregulation to malignant transformation and progression of brain tumors, where these proteins support oncogenic transcriptional networks. Finally, we explore their possible involvement in molecular pathways associated with neurodegenerative disorders. By integrating findings from developmental neurobiology, oncology, and neurodegeneration research, we aim to provide a comprehensive overview of HMGA proteins as pivotal regulators of neural homeostasis and highlights their potential as biomarkers and therapeutic targets in neurological diseases.

KIF1A-associated neurological disorder (KAND) encompasses a broad neurodevelopmental and neurodegenerative spectrum in which motor and movement disorders are common but incompletely defined. To systematically characterize motor and movement disorder phenotypes in KAND. In this cross-sectional study, 51 individuals with likely-pathogenic or pathogenic KIF1A variants underwent standardized neurological assessment using the Spastic Paraplegia Rating Scale (SPRS), SPATAX disability scale, Gross Motor Function Classification System (GMFCS), and Modified Ashworth Scale. A history of global developmental delay was present in 96.1% and neonatal or infantile hypotonia in 62.7%. Progressive spasticity occurred in 72.5%, predominantly affecting the lower extremities and correlated with age (β = 0.45, odds ratio [OR] = 1.56, 95% confidence intervals [95% CI] 1.09-2.25, P = 0.016). Lower extremity weakness was nearly universal (88.2%) and inversely related with age (β = -0.08, OR = 0.93, 95% CI 0.86-0.99, P = 0.032). Independent walking was achieved by 62.7% at a median age of 24 months, but only 31.4% retained independent ambulation at last evaluation. Movement disorders included motor stereotypies (43.1%), ataxia (19.6%), action tremor (15.6%), and dystonia (3.9%). Cerebellar signs were present in 37.2%. The p.Glu253Lys variant was associated with the most severe phenotype. KAND encompasses a continuous spectrum of motor and movement disorders that integrates developmental and neurodegenerative features. These findings inform clinical management, genetic counseling, and the design of future clinical trials. © 2026 International Parkinson and Movement Disorder Society.

Over the past ∼25 years, our understanding of neural circuit development in the central nervous system has shifted. Once considered passive supporters, glial cells, namely, astrocytes, oligodendrocyte lineage cells, and microglia, are increasingly recognized as active regulators of developmental circuit formation and maturation. In this review, we synthesize evidence for the multifaceted functions by which glial cells instruct neuronal circuit establishment and maturation across developmental stages and in both vertebrate and invertebrate nervous systems. We describe the programs deployed to guide successive phases of synapse formation, refinement, plasticity, and stabilization in a circuit- and experience-dependent manner. We also highlight how an extensive glia-glia communication repertoire provides another critical layer of control over development. In summary, glia cooperatively shape circuit development by instructing, stabilizing, or eliminating specific wiring programs. Disruption of this coordinated logic, beyond dysfunction of any single glial or neuronal process, underlies vulnerability to neurodevelopmental and neuropsychiatric disease.

Smith-Magenis syndrome (SMS) is a rare multisystem genetic disorder caused by a 17p11.2 microdeletion or pathogenic variants in the retinoic acid-induced 1 (RAI1) gene. It is characterized by developmental delay, distinctive craniofacial features, behavioral dysregulation, and inverted sleep-wake rhythm. Because early clinical findings are often nonspecific, diagnosis is frequently delayed, and patients may initially present to child psychiatry services with behavioral complaints. We report a 5-year-old girl referred for hyperactivity, severe circadian sleep disturbance with recurrent nocturnal awakenings, self-injurious behaviors, sensory-seeking behaviors, and developmental delay. Comprehensive psychiatric, developmental, neurological, physical, and genetic evaluations revealed a 17p11.2 microdeletion involving both RAI1 and folliculin (FLCN). The diagnosis of SMS was confirmed, and the involvement of FLCN indicated additional potential long-term medical risks. This case underscores the importance of considering genetic etiologies in children presenting with severe behavioral dysregulation and sleep problems and highlights the critical role of comprehensive genetic assessment in guiding diagnosis, management, and long-term follow-up.

The present collection of studies highlights major conceptual and translational advances in contemporary neurooncology related to the field of neuropathology. Central themes include the increasing recognition of neuron-tumor interactions, immune microenvironment remodeling, vascular heterogeneity, and epigenetic plasticity as key drivers of brain tumor progression and therapeutic resistance. Glioblastoma emerges as a highly dynamic and synaptically integrated disease entity, while melanoma brain metastases demonstrate profound microglial reprogramming with direct implications for immunotherapy. Novel molecular and spatial profiling approaches further reveal distinct vascular and immune landscapes across gliomas and brain metastases as well as lineage-dependent developmental programs in medulloblastoma. In parallel, rapid advances in artificial intelligence, nanopore sequencing, and real-time molecular diagnostics are reshaping neuropathological workflows and intraoperative decision-making. Proteomic and multi-omics analyses additionally uncover clinically relevant immune-hot glioma subtypes associated with adverse prognosis and spatial immune remodeling. Together, these studies underscore the increasing convergence of molecular neurobiology, immunology, epigenetics, and computational pathology in modern neurooncology and highlight emerging opportunities for precision diagnostics and targeted therapeutic intervention.

The assembly of functional neural circuits relies on the generation of diverse neural types with precise molecular identity and connectivity. Unlocking general principles of neuronal specification and wiring across the nervous system requires a systematic and high-resolution characterization of its diversity, recently enabled by advances in single-cell transcriptomics and connectomics. However, linking the molecular identity of neurons to circuit architecture remains a key challenge. Here we present a high-resolution developmental transcriptional atlas for the Drosophila melanogaster nerve cord, the central hub for sensory-motor circuits. With a considerable 38× aggregate coverage relative to its reference connectome1,2, our atlas captures extensive molecular diversity and enables robust alignment to the adult connectome. We identified three developmental principles underlying neuronal diversity in the nerve cord. First, the timing of neurogenesis shapes diversification of molecular identity: embryonic-born neurons diverge faster than larval-born neurons, as also observed in the adult connectome. Second, 17 transcription factors common to neurons from all lineages provide a global molecular identity code for birth order. Lastly, by mapping sex-specific transcriptional profiles to the connectome, we identified female-specific apoptosis and transcriptional divergence as key global drivers of sex specification. By revealing key organizational axes of molecular identity, this atlas opens avenues to dissect the molecular mechanisms underpinning the development and evolution of neural circuits.

Animals move through their environments using remarkably diverse locomotor behaviors, which are critical for their survival and success. All movement, including locomotion, requires the coordinated function of three components: the central nervous system (CNS), the peripheral nervous system (PNS), and the musculature. Although evolutionary change in any one of these components can alter locomotion, how these changes arise and combine to generate behavioral diversity remains poorly understood. Larval insects are an exceptional system for addressing this question: they combine extensive behavioral and morphological diversity with relatively simple, stereotyped anatomy, enabling cell-level homology inferences and quantitative cross-tissue comparisons. We first review anatomical evidence for the long-standing peripheral change hypothesis, which posits that locomotor diversity is primarily driven by modifications to peripheral structures, such as muscles, while central circuits remain conserved. We then propose an alternative hypothesis, the motor neuron bottleneck hypothesis, which draws on comparative neurodevelopmental data to suggest that motor neurons are disproportionately conserved relative to both upstream sensory neurons and interneurons and downstream muscles. Finally, we consider how connections are maintained between the CNS, PNS, and musculature when these components change in number. Throughout, we assess relative rates of evolutionary change in cell number across nested phylogenetic scales, from the Drosophila genus to the Diptera order to the Holometabola supraorder. By integrating anatomical, developmental, and functional perspectives, larval insects emerge as a powerful comparative model for uncovering general evolutionary principles.

In most animals, a small number of descending neurons (DNs) connect the brain to circuits and motor neurons (MNs) in the nerve cord. To understand how brain signals generate behavior, it is critical to understand the organization of the neural pathways linking DNs to MNs. In companion papers, we introduced a densely reconstructed connectome of the Drosophila Male Adult Nerve Cord (MANC; Takemura et al., 2024), including cell types and developmental lineages (Marin et al., 2024), which provides complete connectivity of the ventral nerve cord (VNC) at synaptic resolution. Here, we present a first look at the organization of the networks connecting DNs to MNs. We first proofread and curated all DNs and MNs, then systematically matched their morphology to light microscopy data. We report both broad organizational patterns of the entire network and fine-scale analysis of selected circuits of interest. We discover that direct DN-MN connections are infrequent and identify neuron communities putatively linked to control of different motor systems, including walking, flight steering and power generation, and coordinated action of wings and legs. Our analyses generate hypotheses for future functional experiments and empowers others to investigate these and other circuits of the VNC in richer mechanistic detail.

The purpose of this study was to examine the association between adiposity and depressive symptoms in ethnically and racially diverse early adolescents, age 11-14 years old. The design was a cross-sectional observational study, with 78 participants from two middle schools in the southeast. Height, weight, and waist circumference were measured, and body fat percentage (BF%) was obtained using a bioelectrical impedance analysis (BIA) scale. Body mass index (BMI) and waist-to-height ratio (WHtR) were calculated. Participants completed the Children's Depression Inventory II (CDI-2) measure. Estimates of effect size based on general multiple linear regression was used to assess the association between adiposity and depressive symptoms, controlling for gender, puberty, and physical activity. Increased adiposity was associated with decreased depressive symptoms in the context of racially and ethnically diverse early adolescents, with a large effect size (ω2 = 0.14, 95% CI = 0.03, 1.00) between depressive symptoms and BMI category, and small effect sizes for the associations for WHtR (ω2 = 0.02, 95% CI = 0.00, 1.00) and BF% (ω2 = 0.01, 95% CI = 0.00, 1.00) with depressive symptoms. Our findings indicate an inverse association between adiposity and depressive symptoms among early adolescents, which contrasts with many prior studies and underscores the complexity of the relationship between adiposity and mental health during this developmental period. Given the pilot nature of the study and the small sample size, these findings should be interpreted cautiously and warrant confirmation in fully powered studies that include diverse populations across racial and ethnic groups. Greater attention should be paid to overweight and obesity status, and improved screening for depression should be implemented.