Developmental Neuroscience最新文献

Introduction: Prenatal alcohol exposure (PAE) can lead to a wide spectrum of deficits in growth and neurological function, and there is an established link between PAE and auditory dysfunction. However, the effects of PAE on auditory development are complex and vary depending on the age and pattern of alcohol exposure.

Methods: In this study, we developed a mouse model of PAE during the first half of the gestational period, mimicking alcohol consumption during the first trimester of pregnancy in humans.

Results: This exposure did not affect overall growth or induce anxiety-related symptoms in the offspring, as indicated by normal body weight change and largely unchanged behaviors in the open field and elevated zero maze tests. However, several aspects of auditory function were affected by PAE. Offspring born from prenatal alcohol-exposed dams displayed smaller auditory brainstem responses (ABRs) at 2-month-old as compared to those from control dams, suggesting weakened neuron synchronization within auditory brainstem circuits. Additionally, a reduction in the reproducibility of ABR peaks III/IV was observed in PAE offspring. In contrast, the overall hearing sensitivity and neuron transmission was not affected by PAE, as evaluated by ABR thresholds or peak latencies. In an acoustic startle test, PAE offspring failed to display prepulse inhibition to low levels of prepulses more frequently than control offspring at both 2 weeks old and 2 months old, suggesting an early-onset and lasting deficit in auditory gating or sound level differentiation.

Conclusion: These results demonstrate that mice exposed to alcohol during early gestation have largely preserved auditory responses but show significant alterations in specific features of auditory processing.

Background: It is well established that therapeutic hypothermia improves outcomes for infants with moderate-severe hypoxic-ischemic encephalopathy (HIE) in high-income counties. However, ∼29% of the infants treated with therapeutic hypothermia still have adverse outcome. Additionally, therapeutic hypothermia is not recommended as a treatment for infants with HIE in low- and middle-income countries. Therefore, there is an urgent need to develop alternative treatments for infants with HIE in low- and middle-income countries, as well as additive treatments to therapeutic hypothermia in high-income countries. Summary: Caffeine is widely used as an agent to prevent apnea in preterm infants, and more recently, it has been investigated as a potential neuroprotective treatment for perinatal hypoxic-ischemic (HI) brain injury, but the preclinical evidence so far has been mixed. Furthermore, there are concerns that caffeine, which is an adenosine receptor antagonist, could abolish the endogenous neuroprotective effects of adenosine, during and after HI. Key Messages: Further studies using caffeine particularly in large animal translational models of HI brain injury are required to establish the safety and efficacy of caffeine for HIE before conducting large randomized controlled trials.

Introduction: Lysophosphatidic acid (LPA) is a bioactive phospholipid that mediates a variety of biological actions through binding to G protein-coupled receptors known as LPA receptors (LPARs). In mammals, six LPAR subtypes (LPAR1-6) have been identified. This study aimed to determine the expression of LPAR4 in the developing mouse brain.

Methods: Brains samples were prepared from mice in various stages of development and biochemical and immunohistochemical analyses were conducted using anti-LPAR4.

Results: Western blot analysis detected two LPAR4-immunoreactive species at ∼50 kDa and ∼42 kDa from embryonic day 16.5 (E16.5). The ∼50 kDa molecule increased during development, reaching a peak at postnatal day 3 (P3), and then gradually decreased through P22. In contrast, the ∼42 kDa molecule continued to increase up to P22. Immunohistochemical analyses demonstrated strong LPAR4 expression in neural cells in the intermediate zone and cortical plate of the E15.5 cerebral cortex, whereas neural progenitors in the ventricular and subventricular zones exhibited weaker expression. At P15, fiber-like staining resembling the apical dendrites of cortical neurons and hippocampal pyramidal cells was also observed.

Conclusion: This study demonstrated dynamic, spatiotemporal changes of LPAR4 expression in the brain from embryonic to postnatal stages. These findings support a potential role for LPAR4 in neural development.

Introduction: The combination of prenatal alcohol exposure (PAE) and placental insufficiency (PI) places infants at an increased risk for preterm birth and may worsen brain injury and neurobehavioral outcomes. In this preclinical study, the effect of PAE + PI on lateral, medial, and ventral prefrontal cortex (PFC), striatum and corpus callosum microstructure were investigated using diffusion tensor imaging (DTI). These brain regions are important for executive and higher cognitive functions, like cognitive flexibility.

Methods: Pregnant Long-Evans rat dams voluntarily drank 5% ethanol in saccharin water or plain saccharin water until embryonic day 18 (E18) to mimic moderate PAE. On E19, an open laparotomy was completed, and the uterine arteries were transiently occluded for 1 h. The dams in the sham group underwent the same procedure, but without uterine artery occlusion. Offspring are delivered normally on E22 and matured with their dams. On postnatal day 35 (P35), tissue was collected from male and female rat offspring from all four prenatal treatment groups (Sham, PAE, PI, and PAE+PI). Fixed brain tissue was then scanned ex vivo on a Bruker 11.7 T magnetic resonance imaging. Fractional anisotropy (FA) and directional diffusion were measured in regions of interest. Two-way analysis of variance with Tukey's correction was used, with p < 0.05 significant.

Results: DTI analyses of the medial PFC (n = 14-30/group) revealed a significant impact of the prenatal exposure/insult on the FA (p < 0.05), with sham having the lowest FA (0.24 ± 0.01) and PI having the highest FA (0.28 ± 0.02) as well as a lower mean diffusivity (MD; 3.32 × 10-4 ± 2.35 × 10-5 mm2/s; p < 0.01) compared to PAE (4.35 × 10-4 ± 1.47 × 10-5 mm2/s). The lateral PFC was significantly impacted by prenatal exposure/insult with sham having the highest radial diffusivity (RD; 4.97 × 10-4 ± 2.20 × 10-5 mm2/s; p < 0.05) and MD (4.41 × 10-4 ± 2.10 × 10-5 mm2/s; p < 0.05) compared to the other groups. The striatum was sensitive to the prenatal exposure/insult, with the axial diffusivity (AD), RD, and MD all significantly increased in the PAE group and decreased in the PI group (p < 0.05). In the corpus callosum, the prenatal exposure/insult significantly decreased the AD (p < 0.05; PAE+PI AD: 5.00 × 10-4 ± 4.60 × 10-5 mm2/s).

Conclusion: While all areas analyzed were impacted by the prenatal insults, the striatum, which consists primarily of efferent pathways, appears more vulnerable to injury compared to the PFC. Additional studies are needed to characterize the impact this may have on function related to these critical brain regions.

Introduction: Innervation of the paraventricular nucleus of the hypothalamus (PVN) by the orexigenic agouti-related protein (AgRP) and anorexigenic α-melanocyte-stimulating hormone (α-MSH) neurons of the arcuate nucleus (ARC) is a key element in the appetite-regulating neuronal circuitry whose development is influenced by circulating metabolic signals. In the present work, we studied if PVN innervation by the AgRP and α-MSH fibers is influenced by gut microbiota.

Methods: To this aim, we compared, using immunohistochemistry, the innervation of PVN by AgRP and α-MSH fibers between germ-free and specific pathogen-free 7-week-old female mice.

Results: We found that germ-free mice display an increased innervation of the PVN by both AgRP and α-MSH fibers, but also that the increase in AgRP fiber density was about twice as pronounced as that of α-MSH.

Conclusion: These data reveal that gut microbiota plays a modulatory role in the development of the ARC/PVN axonal projections. An imbalance between AgRP and α-MSH innervation in germ-free mice may contribute to their metabolic and behavioral alterations.

Background: Small for gestational age (SGA) infants face a heightened risk of motor delays that can persist into childhood, affecting cognitive and language development. Early identification and intervention are critical for better long-term outcomes.

Summary: This narrative review highlights evidence on motor development in SGA children, focusing on risk factors, neurobiological mechanisms, and early interventions. Motor delays in SGA infants correlate with lower birth weight, shorter gestation, adverse intrauterine conditions, and perinatal complications. Structural brain changes, especially in white matter and cerebellum, along with prenatal and postnatal inflammation, contribute to these deficits. Nutritional support, physical therapy, and family-based stimulation initiated in the first 2 years show promise for improving motor outcomes.

Key messages: SGA children are at high risk for motor developmental disorders. A comprehensive early intervention approach targeting nutrition, neurodevelopment, and family support is essential. Future research should aim to clarify mechanisms and optimize intervention timing and strategies to enhance long-term outcomes.

Introduction: Neurodevelopmental disorders (NDDs) are chronic conditions marked by abnormal brain development, presenting with significant clinical heterogeneity. Early diagnosis is crucial but challenging due to the complex symptoms. Genetic factors play a dominant role in NDD etiology. This study was to evaluate the diagnostic utility of dual-dimension whole-exome sequencing (WES) analysis in Chinese patients with NDDs and to deepen the understanding of genotype-phenotype correlations.

Methods: This study retrospectively analyzed WES data of 128 Chinese NDD patients from Hubei Maternal and Child Health Hospital (July 2020-March 2024) for single-nucleotide variants (SNVs)/small insertions-deletions (Indels) and copy number variants (CNVs). Pathway enrichment, tissue-expression analyses, and functional experiments were conducted to interpret pathogenic genes and variants of uncertain significance.

Results: The overall diagnostic rate for NDDs was 35.9% (46/128), with 28 cases confirmed by SNV/Indel analysis (30 variants in 29 genes) and 18 by CNV analysis (22 variants). Dual-dimension analysis markedly improved the diagnostic rate compared to conventional SNV/Indel analysis (35.9% vs. 21.9%). Patients with multisystem abnormalities had a higher diagnostic rate (63.2% vs. 31.2%). Among the 30 SNV/Indel variants, 86.7% (26) were de novo, and 70.0% (21) were novel. Recurrent pathogenic variants in ASXL3, SHANK3, and EHMT1 genes were identified. Most pathogenic genes were enriched in transcription-regulation pathways and highly expressed in the cerebellum and cerebral cortex. Functional experiments showed that the NLGN3 c.562G>A (p.G188R) hemizygous variant affects protein stability and is deleterious, aiding prenatal diagnosis and the birth of a healthy offspring.

Conclusion: Integrating CNV analysis into routine WES workflows effectively clarifies the genetic heterogeneity of NDDs, expands the gene variant spectrum, and provides a basis for NDD prognosis assessment and precision diagnosis and treatment.

Introduction: The developing brain exhibits rostro-caudal gradients that align with the maturation of functionally organized circuits. The barrel cortex, a spatially precise sensory structure, serves as an ideal model to examine such gradients within a confined functional domain. GABAergic interneurons, characterized by subtype-specific developmental trajectories and pivotal roles in early cortical dynamics, provide a strategic cellular entry point for this investigation.

Methods: To explore cellular and functional gradients in the developing barrel cortex, we combined transgenic mouse lines, immunohistochemical analyses with in vivo electrophysiological recordings of whisker-evoked activity during early postnatal stages. We also employed a model of ethanol exposure to assess potential differences in apoptotic vulnerability along the rostro-caudal axis.

Results: Immunohistochemistry revealed distinct layer- and subtype-specific gradients of GABAergic neurons. Notably, we observed a widespread rostro-caudal gradient in 5-HT3AR-expressing cells and a localized gradient of somatostatin-positive (SST+) interneurons in the deep layers. These gradients diminished in a subtype-specific manner from postnatal day (P)5 to P10, indicating transient developmental features. In vivo recordings showed that caudal whisker stimulation elicited stronger responses, while rostral stimulation produced a broader spatial spread of activity, suggesting region-specific functional properties. Furthermore, rostral regions exhibited higher expression of the maturation marker KCC2, supporting the notion of more advanced maturation in the rostral barrel cortex. Ethanol exposure induced greater apoptosis in caudal layer 5 compared to its rostral counterpart, revealing layer- and region-specific vulnerabilities.

Conclusions: These findings highlight spatially regulated trajectories of cortical maturation and underscore how regional differences in development may influence sensory processing and contribute to the heterogeneity of symptoms observed in neurodevelopmental disorders.

Introduction: Single-cell transcriptomic analyses in adult mice show that cortical projection neuron subclasses exhibit heterogenous gene expression profiles that reflect their projection targets and laminar and areal positions. Further analyses revealed that projection neurons within the same subclass also exhibit transcriptomic heterogeneity. Recent evidence suggests that differences in maturation state reflect one source of this heterogeneity. The MET receptor tyrosine kinase, a regulator of synapse maturation, is expressed in a subpopulation within cortical projection neuron subclasses, providing an experimental model to address transcriptomic heterogeneity within developing projection neuron subclasses.

Methods: Single-cell RNA sequencing and smFISH were used to identify transcriptomic differences between Met+ and Met- projection neuron populations in the mouse visual and frontal cortices during the early phase of synapse formation and dendritic growth.

Results: Analyses confirmed enrichment of Met in select projection neuron subclasses and further identified astrocytes as the major source of its ligand, Hgf. No genes were expressed uniquely in Met+ or Met- projection neurons within a subclass; rather, there were graded differences in gene expression between the populations. While the identity of differentially expressed genes varied between subclass and cortical area, there was a consistent overrepresentation of genes associated with axon growth, as well as synapse structure, development, and function, with a subset associated with the MET interactome. Further, compared to Met- projection neurons, expression differences in genes associated with maturation indicate less mature excitatory synapses and spines in the Met+ population at this age.

Conclusion: The current findings provide support for the hypothesis that Met+ projection neurons are in a less mature state than Met- projection neurons within the same subclass. Further, the data are consistent with converging lines of biochemical and electrophysiological evidence that MET contributes to asynchronous maturation of developing cortical circuits.

Introduction: KCTD7-related epilepsy is a rare neurogenetic disorder characterized by marked genetic and phenotypic heterogeneity, typically presenting with early onset and often exhibiting poor response to conventional antiseizure medications.

Methods: We performed exome sequencing in 134 Iranian pediatric patients with drug-resistant epilepsy and selected mutations in the KCTD7 gene. The pathogenicity of the identified variants was assessed using multiple in silico prediction tools and classified according to the ACMG guidelines. Additionally, we reviewed the genotype-phenotype correlations and treatment histories of all reported cases with KCTD7 mutations.

Results: Three novel homozygous variants - c.14C>T (p.Thr5Met), c.840delC (p.Ile281Serfs*11), and c.746T>G (p.Val249Gly) - were identified in 4 patients. Significant phenotypic heterogeneity was observed among patients, with disease severity ranging from mild to profound. Independent in silico analyses of each variant yielded concordant results, consistently predicting their potential to impact the structure and function of the KCTD7 protein. To date, 72 patients from 55 families have been reported, including 26.66% of homozygous cases born to non-consanguineous parents and 37% of reported variants localized within BTB domain. Although 88.9% of patients experienced seizure onset before age two, clinical trajectories were highly variable. Among 45 patients with treatment data, valproate, levetiracetam, and clonazepam were the most frequently prescribed antiseizure medications; however, seizure control remained inconsistent. Notably, we observed subfertility in two heterozygous fathers, an unexpected finding that may suggest a potential role for KCTD7 beyond the central nervous system.

Conclusion: These findings expand the mutational and phenotypic landscape of KCTD7-related epilepsy and underscore its clinical heterogeneity and therapeutic challenges.