Converging evidence indicates that schizophrenia reshapes the embodied structure of subjectivity, profoundly altering how individuals experience their bodies and surrounding space. This Perspective proposes a neurodevelopmental framework linking measurable distortions of personal space (PS) and peripersonal space (PPS) to deeper phenomenological disruptions of lived spatiality. Experimental findings consistently show an enlarged PS and a contracted PPS, maybe reflecting an excessive feeling of overexposure as well as a diminished sense of possible spatial enactment of bodily capacities. These anomalies likely stem from early neurodevelopmental disturbances in multisensory integration and sensorimotor learning. Phenomenological psychopathology further reveals how such spatial disorganization manifests as instability in self-world boundaries and a pervasive sense of altered atmosphere. Integrating neurodevelopmental, cognitive, and experiential dimensions provides a unified account of how schizotaxic vulnerability unfolds into spatial and Self-disturbances. This approach reframes embodiment and spatiality as developmental interfaces between neural processes and subjective transformation in schizophrenia.
Serotonin 2A receptors (5-HT2ARs) play a complex role in focal and generalized seizures due to their diverse cellular and regional distribution. Although systemic activation of 5-HT2ARs suppresses absence seizures (ASs) in Genetic Absence Epilepsy Rats From Strasbourg (GAERS) rats, the contribution of thalamic receptors and their cell-type specificity remains unclear. Here, we performed a developmental immunohistochemical analysis in the nucleus reticularis thalami (NRT) and the ventrobasal thalamic nucleus (VB) of GAERS rats to assess developmental alterations in 5-HT2AR expression and used genetic manipulation to determine whether the antiabsence effect of systemic 5-HT2AR activation depends on thalamocortical (TC) neurons or astrocytes. Double-immunofluorescence labeling of 5-HT2ARs with either γ-aminobutyric acid (GABA) or glial fibrillary acidic protein in adult GAERS rats was used to investigate the neuronal and astrocytic distribution of these receptors in the NRT and VB. In addition, [3H]GABA uptake and its modulation by 5-HT2AR activation were assessed in thalamic slices. Electroencephalographic and video recordings in freely moving GAERS were used to evaluate the effects of VB microinjection of TCB-2, a 5-HT2AR agonist, on ASs. Finally, the cellular mechanisms underlying these effects were investigated using selective shRNA-mediated knockdown of 5-HT2ARs in either TC neurons or astrocytes in the VB. In the VB, at postnatal day (P) 25, 5-HT2ARs were mainly expressed in TC neurons and in the majority of the few GABAergic interneurons, whereas by P90 they were exclusively localized to TC neurons. In the NRT, neuronal expression increased from ~60% to nearly 100% over development. Astrocytic 5-HT2AR expression increased developmentally in the NRT but remained unchanged in the VB. GABA uptake was decreased in GAERS compared to Wistar rats and was not modified by 5-HT2AR activation. In vivo, intra-VB injection of TCB-2 reduced ASs; this effect was abolished by shRNA knockdown of 5-HT2ARs in TC neurons, but not in astrocytes. The developmental reorganization of thalamic 5-HT2AR signaling coincides with the expression of ASs, suggesting a contributory role. Our findings indicate that neuronal, but not astrocytic, thalamic 5-HT2ARs drive seizure modulation, identifying a potential therapeutic target.
Spatial transcriptomics extends traditional transcriptomic methods by quantifying gene expression within intact tissues while preserving each cell's precise spatial context. This technology also captures gene expression under physiological conditions, including interactions with the surrounding microenvironment, thereby enhancing our understanding of cellular states in both health and disease. Rapid recent advances have improved throughput, transcript capture, accuracy, and overall data quality. In this review, we summarize the major spatial transcriptomics platforms and outline their strengths and limitations. We also highlight key applications in neuroscience, including brain cell-type identification, structure-function relationships, and developmental processes. Additionally, we examine spatial gene-expression patterns in psychiatric and neurodegenerative disorders such as Alzheimer's disease and depression. Finally, we discuss emerging directions, including spatial multi-omics integration and the potential for artificial intelligence to advance brain research. Collectively, this work provides a foundation for future studies in neuroscience and brain disorders.
Caregiver-infant interaction represents the space where development happens through time. According to the mutual regulation model (MRM) by Tronick, meaning-making, emotion regulation, and stress resilience all emerge from the complex fabric of caregiver-infant interaction. Within this model, the dyadic expansion of consciousness (DEC) identifies how adult caregivers and infants co-create an expanded state of consciousness characterized by greater complexity through reciprocal interactions of their individual states of consciousness and alternating phases of matching, mismatching, and reparation. The well-validated Face-to-Face Still-Face paradigm (FFSF), by introducing experimental manipulations of caregiver's interactive availability, represents a reliable procedure to investigate these early forms of socio-emotional and socio-cognitive exchanges. Nonetheless, there is a general lack of studies investigating and providing measures of DEC. Recent advancements in the developmental neuroscience field (i.e., hyperscanning protocols) hold promises to provide renewed interest in studying DEC by exploring the dyadic co-regulation of inter-brain coupling and uncoupling from a caregiver-infant perspective. By employing diverse emerging metrics of neural coupling, researchers can investigate, using unprecedented neuroscientific approaches, how the behavioral and neural activity of each interactive partner may lead to the emergence of a "two-brained system" capable of producing dyadic meanings through dynamically synchronized and resonating individual brain networks. In the present contribution, we highlight how developmental hyperscanning research can be beneficial to our comprehension of the early mutual regulation processes occurring in caregiver-infant dyads.
Misophonia is a decreased sound tolerance (DST) condition characterized by disproportionate emotional, autonomic, and behavioral responses to specific, typically low-intensity sounds. Despite increasing recognition, its neurobiological basis remains incompletely understood, particularly with respect to its typical onset during late childhood and adolescence. Existing models emphasize auditory-limbic conditioning but may not fully account for developmental vulnerability or stimulus specificity. This theory-building review proposes a developmental neurobiological framework in which misophonia is conceptualized as a disorder of perception-emotion coupling, potentially shaped by maladaptive plasticity across interacting auditory, salience, limbic, and prefrontal networks during sensitive periods of maturation. A theory-driven narrative review was conducted, integrating evidence from neuroimaging, electrophysiological, autonomic, and clinical studies. Relevant literature was identified through PubMed, Scopus, and Web of Science databases, covering the period up to early 2026. Search terms included "misophonia," "auditory processing," "salience network," and "development." Jastreboff's conditioned reflex model was considered alongside contemporary frameworks from network neuroscience. This review is selective and hypothesis-generating rather than systematic. Available evidence suggests that exaggerated, stimulus-specific salience attribution to auditory stimuli-potentially mediated by anterior insula-centered networks-may interact with relatively immature prefrontal regulatory mechanisms during development. This interaction may contribute to the strengthening of auditory-limbic associations and the emergence of persistent, context-dependent misophonic responses. Reframing misophonia within a developmental network framework may help situate the condition within disorders involving altered sensory appraisal and emotional regulation, while preserving its stimulus-specific profile. This perspective generates testable hypotheses and may provide a basis for future empirical research and the development of mechanism-informed intervention strategies.
Background/Objectives: Autophagy is an evolutionarily conserved degradation and recycling pathway through which cells deliver cytoplasmic components, including toxic or damaged proteins and organelles, to lysosomes for clearance. In neurons, which are largely post-mitotic, degradative pathways are essential to prevent the accumulation of cellular waste and to maintain nutrient and energy homeostasis. Increasing evidence suggests that autophagy plays a critical role during early brain development, when neuronal circuits are established, synaptic connections are refined, and activity-dependent mechanisms shape network architecture. However, the developmental regulation of autophagy-related genes and the composition of the autophagic machinery at synapses remain poorly understood. This study aimed to characterize the maturation-dependent dynamics of autophagy-lysosomal genes and to investigate the synaptic autophagy-associated proteome during cortical development. Methods: Genome-wide transcriptomic analyses were performed in the cortical brain region across developmental stages to assess changes in the expression of autophagy-lysosomal genes. In parallel, synaptosomes were isolated and subjected to proteomic analysis to identify autophagy-related proteins associated with synaptic compartments. Results: Transcriptomic profiling revealed stage-dependent regulation of autophagy-lysosomal genes during cortical maturation. Proteomic analysis of synaptosomes identified multiple autophagy-associated proteins enriched at synaptic sites, suggesting that components of the autophagic machinery are present at synapses and may participate in synaptic remodeling and function during key phases of neuronal network formation. Conclusions: These findings provide new insights into the developmental regulation of autophagy in the brain and highlight the potential contribution of synaptic autophagy to neuronal circuit maturation. Understanding these mechanisms may help identify novel therapeutic targets for neurological disorders associated with impaired synaptic and cellular homeostasis.
Dominant conceptions of habit in addiction science remain theoretically limited. Dual-process and stimulus-response accounts explain behavioural repetition, but they insufficiently specify why particular cues become compelling, how salience narrows in patterned ways and how lived history enters the architecture of compulsion. This review synthesises cognitive neuroscience, attentional science, developmental psychopathology and clinical research to propose an alternative formulation: habit as history-guided attention. On this account, habitual action is not mindless repetition but the enactment of salience structures sedimented through reinforcement history, affective learning and relational experience. The article first critiques prevailing models of addiction then develops a tripartite framework distinguishing goal-directed, stimulus-driven and history-guided attention. It next examines how affective biography and developmental experience shape attentional bias, reconceptualises compulsion as a narrowing of attentional possibility considering implications for assessment and intervention. Integrating work on reward learning, salience attribution, trauma, stress sensitisation, and mindfulness-based relapse prevention, the review argues that addiction is more adequately understood as a historically organised attentional ecology than as the endpoint of automatic stimulus-response habit.
Monogenic developmental and epileptic encephalopathies (DEE) frequently feature co-occurring movement disorders. Gene discovery has expanded epilepsy-dyskinesia syndromes (EDS) from classic associations such as stereotypies in Rett syndrome to PRRT2-related infantile seizures with paroxysmal dyskinesia and crouched gait in SCN1A-associated Dravet syndrome. To outline the movement disorders spectrum in EDS, propose a pragmatic syndrome-based clinical framework, group implicated genes into mechanistic categories, highlight selected genotype-phenotype correlations, and summarize symptomatic and precision therapeutic options. A non-systematic, structured literature review identified monogenic disorders reported with EDS, grouping publications into four tiers: multi-etiology cohorts; small series and narrative/systematic reviews; single-gene or pathway-focused reports; and mechanistic/therapeutic studies. Eight cohort studies and multiple tier 2-3 series and reviews yielded 245 single-gene associations, most mapping to ion channel and synaptic signaling pathways. Across DEE cohorts, movement disorders occurred in roughly one-quarter to over one-half of patients, were often hyperkinetic (notably dystonia and stereotypies), and frequently combined multiple phenomenologies. We grouped clinical presentations into early and late infantile-onset EDS, Rett and Rett-like syndromes, paroxysmal/episodic and relapsing-remitting disorders, disorders with severe acute motor exacerbations, and hypokinetic/progressive phenotypes. Treatments are guided by gene- and mechanism-informed strategies including sodium-channel blockers, glutamatergic modulators, ketogenic diet, agents for paroxysmal dyskinesias, and deep brain stimulation in life-threatening crises. Movement disorders are common, often severe, and genetically heterogeneous across EDS. A syndrome-based approach integrating clinical features, neuroimaging, and broad genetic testing (including copy number variants and repeat expansions) can guide symptomatic management and emerging precision therapies.
Germline pathogenic variants that activate the Ras/mitogen-activated protein kinase (MAPK) pathway cause neurodevelopmental disorders called 'Rasopathies'. Because many affected proteins directly regulate Ras, causative mutations may alter other Ras-dependent pathways in addition to MAPK signaling. To better understand which Rasopathy sequelae result from hyperactivation of downstream MAP kinases, we engineered mice with a gain-of-function mutation in the terminal MAP kinase gene Mapk1, which encodes ERK2 and is associated with the recently described genetic syndrome MAPK1-related Rasopathy (MRR). Mapk1 mutant mice successfully modeled key aspects of the human MRR phenotype, including small stature, facial dysmorphism, and impaired cognitive function. Importantly, they recapitulated phenotypes identified in Rasopathy models with upstream Ras activation, such as neurofibromatosis type 1 (NF1): oligodendrocyte lineage defects, reactive astrogliosis, memory deficits, and hypersensitivity to sensory stimuli. These findings emphasize the importance of downstream MAPK signaling in the pathophysiology of neurocognitive symptoms observed in Rasopathy syndromes.
暂无摘要（点击查看详情）
To determine whether prompt genetic diagnosis in children with KCNQ2 neonatal epilepsy enabling targeted therapy is associated with improved outcomes, and identify early predictors of developmental outcomes. Thirty-seven children with KCNQ2 neonatal epilepsy were recruited from five pediatric centers. We reviewed demographic, clinical, EEG, and genetic data. We determined differences in outcomes between individuals with prompt (greater than 30 days from seizure onset) and later genetic diagnosis, and we identified neonatal factors associated with developmental outcome. Baseline characteristics were similar between children with prompt (n = 6, median age at genetic diagnosis 15 days) and later (n = 31, median age 309 days, p < .05) diagnosis. All with prompt diagnosis received sodium channel blocking (SCB) anti-seizure medication (ASM) in the neonatal period compared with 15/31 (48%) in the later diagnosis group. Children with prompt diagnosis had higher rates of seizure freedom at age 12 months than those with later diagnosis (6/6 [100%] vs. 17/31 [54%]; p .049], and lower number of emergency department representations (median 0 vs. 2), and hospital readmissions (median 0 vs. 1). Factors in the neonatal period associated with abnormal developmental outcome included neurological abnormalities (e.g., abnormal tone) and markedly abnormal neonatal EEG background (11/11 [100%] with markedly abnormal EEG vs. 11/24 [46%] with normal to moderately abnormal EEG). Prompt genetic diagnosis was associated with targeted therapy, resulting in improved seizure control and reduced hospital representation. Clinical features present in the neonate assist in predicting outcome severity, which is critically important in counselling families receiving a KCNQ2 diagnosis soon after seizure onset. In KCNQ2 neonatal epilepsy, sodium channel blocking antiseizure medicines are recommended, but the benefits of starting treatment early have been uncertain. Our findings show that prompt genetic diagnosis enabled early targeted treatment, with potential to improve outcomes. Specifically, prompt genetic diagnosis was associated with improved seizure control and reduced hospital visits compared with delayed diagnosis. However, a prospective, long-term study is needed to determine whether early treatment also improves developmental outcomes. Predicting outcome severity in newborns remains challenging, although abnormal neurological examination and markedly abnormal EEG in the newborn period were linked to abnormal developmental outcomes.
Alcohol use disorder (AUD) represents a critical public health challenge, with early-life adversity conferring heightened risk for compulsive drinking patterns. Alcohol has long been known to exert direct effects on developing neurotransmitter systems, targeting among others GABAergic, glutamatergic, and dopaminergic signaling. Recent evidence however indicates that early adversity also primes microglial activation and establishes chronic low-grade neuroinflammation, disrupting maturation of prefrontal-limbic-striatal circuits governing executive control and affect regulation. Hence, alcohol use may emerge in adolescents as a maladaptive coping mechanism, transiently alleviating stress-related dysphoria while exacerbating neuroimmune and neurocircuit dysfunction. While traditional neurocentric models convincingly depict how repeated withdrawal episodes may unmask this underlying vulnerability, precipitating relapse cycles that consolidate compulsive use, they inadequately explain the persistence and treatment resistance characteristic of adolescent-onset alcohol misuse because they fail to account for the peripheral biological systems that amplify central vulnerability. The gut-microbiota-brain axis represents one such amplifier: stress- and alcohol-related perturbations in barrier integrity and immunometabolic signaling increase peripheral inflammatory load reaching the brain, intensifying neuroimmune tuning of still-maturing control circuits. Integrating these central and peripheral processes reframes adolescent alcohol vulnerability as a systems-level phenomenon embedded within developmental and inflammatory biology, rather than a disorder of reward circuitry alone. This developmental framework suggests that adjunctive therapeutic strategies combining targeted neuroimmune modulation, behavioral intervention, and ecological stabilization during critical developmental windows may offer superior outcomes over conventional reward-focused pharmacotherapies. Realizing this potential will require biomarker-driven risk stratification, precision medicine approaches, and careful developmental consideration of intervention timing.
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by loss-of-function variants in SCN1A, with seizures typically emerging during the first year of life. Although DS pathophysiology has largely been attributed to inhibitory network dysfunction underlying seizures, early developmental alterations in inhibitory interneurons remain poorly understood. We generated inhibitory interneuron-enriched subpallial organoids from patient-derived induced pluripotent stem cells carrying an SCN1A loss-of-function variant and the corresponding isogenic control. Using complementary molecular and functional approaches, including quantitative polymerase chain reaction, bulk RNA sequencing, whole-cell patch-clamp electrophysiology, and two-photon calcium imaging, we investigated early inhibitory interneuron development and functional maturation in a human cellular context. Transcriptomic profiling revealed early dysregulation of ventral forebrain interneuron developmental programs, including altered expression of medial ganglionic eminence-associated transcriptional regulators, preceding inhibitory network dysfunction. Patient-derived organoids exhibited marked reductions in intrinsic neuronal excitability and synaptic activity. Acute application of fenfluramine, a clinically approved antiseizure medication for DS, partially restored neuronal activity, demonstrating the translational relevance of this model. These findings demonstrate that SCN1A loss of function disrupts early inhibitory interneuron development and functional maturation, defining a developmental vulnerability that likely precedes the emergence of epilepsy in DS. This work establishes patient-derived inhibitory organoids as a human-relevant platform for dissecting disease mechanisms and evaluating therapeutic responses in SCN1A-related epileptic encephalopathies.
Huntington's disease (HD) patients with anterior cingulate cortex atrophy typically exhibit mood symptomatology. However, the midcingulate cortex's (MCC) role in HD is poorly understood. mRNA sequencing was utilized to examine the MCC transcriptome in HD, and differentially expressed transcripts were validated by NanoString analysis. Transcriptomic analysis of 14 HD patients exhibiting mood, motor, or mixed symptoms revealed differential expression of 223 genes, including several homeo-domain, developmental, and noncoding genes in the MCC. Protein-protein interaction, gene ontology, and cell-type enrichment analyses identified dysregulated pathways in the adult MCC involved in processes linked to embryonic development and organogenesis, epigenetic modification, transcription regulation, neuronal differentiation, and motor system development. Key findings include misexpressed genes associated with limb, muscle and motor neuron development in the motor cohort. These alterations suggest that mutant huntingtin may influence developmental processes via aberrant WNT (Wingless), REST (RE1-silencing transcription factor), and transcription factor signaling, potentially affecting MCC motor function circuitry and neuronal maturation. This study indicates a developmentally associated transcriptional signature in the adult HD MCC that may contribute to altered neuronal function.
Background: Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition for which non-pharmacological interventions remain the primary therapeutic approach. Although research output in this field has increased substantially, a comprehensive synthesis of its developmental trajectory and emerging directions is still lacking. Methods: We conducted a bibliometric analysis of publications on non-pharmacological interventions for ASD indexed in the Web of Science Core Collection between 2001 and 2025. Knowledge structures, research hotspots, and temporal trends were visualized and analyzed using CiteSpace. Results: The field has transitioned from an early focus on behavioral interventions in children to a diversified and interdisciplinary research ecosystem spanning the lifespan. Recent growth has been driven by the integration of neuroscience-based approaches, particularly neuromodulation techniques, alongside continued refinement of behavioral, sensorimotor, and complementary therapies. Increasing attention has been paid to individual heterogeneity, methodological rigor, and mechanism-oriented research. Current frontiers emphasize multimodal intervention strategies, neural plasticity-based mechanisms, and the development of personalized precision intervention frameworks. Conclusions: This bibliometric analysis delineates the intellectual evolution of non-pharmacological intervention research for ASD and identifies key research gaps, particularly the need for longitudinal and pragmatic studies targeting individualized treatment response. The findings provide an evidence-informed overview of current concepts and emerging research directions in non-pharmacological care for ASD, with important implications for future clinical research, intervention design, and strategic research planning.
Theories of emotion development propose that negative affect decreases over time as attention control and emotion regulation improve. Yet, research on infancy suggests that the first year of life can be characterised by a different developmental pattern: increased negative affect as infants age. Implementing an emotion-eliciting task, we measured infants' observed emotion reactivity and regulation, and physiological arousal (heart rate) during the challenge (toy retraction) and recovery (toy play) conditions at age 6 months (n = 82, 43 boys) and age 12 months (n = 68, 36 boys) continuously on a second-by-second basis. We first measured mean intensity of reactivity, regulation, and arousal by calculating within-person averages. Then, we measured three temporal dynamics: estimates of variability by calculating variance, lability by calculating root mean square of successive differences, and persistence of changes by calculating autocorrelation. Intensity, variability, and lability in negative reactivity increased from 6 to 12 months with no change in persistence, indicating a larger and quicker negative reaction to toy retraction with age. Regulatory strategy use increased from 6 to 12 months during challenge, whereas during recovery, it reduced and became more stable. Heart rate decreased from challenge to recovery at 12 months but not at 6 months. We then examined how the temporal associations between reactivity, regulation and arousal change over time. Cross-correlation analyses revealed stronger temporal associations between reactivity, regulation, and heart rate at 12 months, suggesting increased coherence between behavioural and physiological responses with age. We discuss these developmental changes in emotion dynamics and behaviour-physiology associations in the context of functionalist perspectives on emotion. SUMMARY: This study employs momentary recordings of emotional expressions, regulatory behaviours, and physiological arousal, focusing on two key aspects: within-task context and temporal dynamics. As they grow, infants show stronger negative reactions and greater regulatory efforts during stress but calmer reactions and reduced use of regulation once stressor ends. Temporal associations between emotional behaviours and physiology (heart rate) increased from 6 to 12 months, suggesting stronger emotional coherence with age in infancy. Together, these patterns may reflect improved emotional flexibility, with older infants showing more context-appropriate emotion responses.
Progress in defining the proteome of the developing human brain has lagged behind our understanding of the adult human brain, primarily due to challenges in tissue acquisition and in preservation of anatomical structure during experimental processing. Single-cell transcriptomics alone is an excellent resource for defining cellular identity, but has limited capacity to trace neuronal connectivity because proteins, the active molecules in interactions, may be transported significant distances from cell bodies and their site of synthesis. There are numerous protein-mediated transient interactions between cellular elements in the developing brain, such as between migrating cortical neurons and subplate, and thalamic projections and cortical progenitors. Anatomical approaches have identified specific cell populations that interact, allowing us to characterize the transient and dynamically changing early circuits. Proteomic data generation is now essential for ligand-receptor pair prediction and validation. Upon receipt of a single, exceptionally well-preserved 20 postconception week human brain hemisphere, we conducted fine dissections of 18 anatomically distinct brain regions, including the pia mater. These samples underwent in-depth analysis of both the total and posttranslationally modified proteomes, with the aim of creating a reference resource for investigators studying this critical stage of neurodevelopment. Here, we have presented an overview of the resulting dataset, compared the proteomic profiles across regions, and highlighted examples of variable posttranslational modifications within individual proteins. As expected, non-modified protein profiles revealed substantial differences across brain regions and structures. For instance, pia mater and thalamus were enriched for proteins involved in transcription and chromatin organization, which may suggest a higher proportion of dividing cells and/or significant epigenetic regulation in these areas at this developmental stage. In contrast, the cortical and hippocampal proteome reflected active synaptogenesis and cytoskeletal remodeling. While interregional differences in phosphorylated and acetylated peptides largely mirrored those observed in the non-modified proteome with respect to gene ontology categories, the glycosylated peptidome of the pia mater was markedly distinct. This divergence is driven by the secretion of extracellular matrix proteins and the region's intimate association with the basement membrane of the pia. Finally, by integrating our proteomic data with publicly available single-cell RNA sequencing datasets from the same developmental stage, we identified high-confidence ligand-receptor pairs (e.g., L1CAM:CD9, CNTN4:PTPRG, LGALS1:ITGB1) likely involved in thalamocortical interactions.
The cerebellum undergoes substantial maturation with regionally distinct developmental trajectories. This study examined cerebellar gray matter volume (GMV) in healthy children, adolescents, and adults, using voxel-based morphometry, the ACAPULCO algorithm, and the SUIT toolbox for cerebellum-optimized analyses. A total of 104 typically developing children (n = 31, 6-9 years), adolescents (n = 35, 13-17 years), and adults (n = 38, 30-40 years) were included. We hypothesized age-group differences in cerebellar GMV, with adolescents showing the greatest volume, specifically in posterolateral regions. RESULTS: revealed significant group differences in GMV. We observed region-specific volumetric patterns, with some areas (e.g., Crus II, lobule X) showing higher GMV in adolescents that in children, while other areas (e.g., lobules I-IV and VI, Crus I, vermis VI and VIIb) showed higher GMV in the adolescent group compared with both children and adults. These patterns were partly consistent with our hypothesis. Notably, no regions showed greater GMV in adults than adolescents, suggesting that the adolescent cerebellum shows a pattern consistent with transient highest GMV relative to both children and adults. Our findings indicate differential developmental patterns both between and within lobules of the cerebellum, and highlight adolescence as a period when GMV is higher relative to both childhood and adulthood, with potential implications for the development of cerebellar-supported cognitive and emotional functions that undergo significant changes during this period.
Hypothalamic arginine vasopressin (AVP) and oxytocin (OXT) magnocellular neurons (MCNs), share a developmental lineage. The transcription factors driving specification are yet unknown. Using gene regulatory network analysis on published single-cell RNA-sequencing data of the developing mouse hypothalamus, we identified RORA, EBF3, FOXP1, FOXP2, and BCL11B as candidate transcription factors for differential MCN specification. We modeled developmental gene expression dynamics using computational cell fate mapping, revealing enrichment of EBF3 and BCL11B in the Avp lineage, and FOXP1 and FOXP2 in the Oxt lineage. In silico analysis of Avp and Oxt promoters predicted a binding site for FOXP1 and FOXP2, and an in vitro reporter assay identified regulation on both Avp and Oxt genomic promoters. Finally, heterozygous FOXP1 knockout mice exhibited a significant reduction in AVP and OXT neuron abundance, with OXT neurons disproportionally affected. We conclude that FOXP1 participates in MCN development, while being differentially active in OXT MCNs relative to AVP MCNs.
Across the globe, rates of mood and anxiety disorders have been increasing steadily, a trend accelerated by the COVID-19 pandemic. Stress triggers these disorders, precipitating initial episodes and provoking relapses. In this perspective, we argue that the stress system is not merely a threat mechanism but also an ongoing and active monitor of the environment and that resilience is not simply the lack of sensitivity to stress but an active function with an intrinsic neurobiology. Through the interplay of genetic, developmental, and experiential mechanisms, individuals evolve their own "stress-resilience algorithm" that determines their stress reactivity and the resulting adaptive or maladaptive consequences. This algorithm represents a dynamic, lifelong process that is often self-reinforcing. We underscore the importance of focusing on prevention by assessing and enhancing an individual's "stress fitness." This perspective offers a new conceptualization of the neurobiology of stress and resilience as a framework for basic and translational neuroscience research aimed at confronting the challenges of stress disorders.