Developmental Neuroscience最新文献

Introduction: Mounting evidence indicates that the cerebral cortical folding pattern conveys information relevant to brain function, as well as the developmental trajectory, leading to the observed pattern at maturity. However, relatively little is known about the biomechanics of gyral and sulcal formation. Ferrets are a tractable animal model for studying folding, in which this process occurs over the first 40 days of postnatal life. Recently, high-resolution magnetic resonance brain imaging data have been made available for a template representing 10 ferrets (5 male, 5 female) at 6 equally spaced time points ranging from postnatal days (P)8 to P38.

Methods: For each hemisphere, cerebral cortex surface models representing the template brain at each of the six ages were registered to one another using the anatomical multimodal surface matching (aMSM) algorithm. Local cerebral cortical curvature was determined at each surface vertex at each developmental age, and the T2-weighted images were used to determine cortical thickness at each surface vertex. Relative surface area expansion between pairs of time points was also mapped onto each surface vertex. Systematic comparisons were performed between cortical growth and changes in curvature that accompany gyral and sulcal formation. The sequence of changes of these anatomical characteristics was delineated during folding.

Results: The cerebral cortex transitions between two patterns of regionally varying cortical thickness. In early stages of gyral and sulcal formation, the cortex is relatively thick in regions destined to exhibit high magnitudes of surface curvature (folding), regardless of whether the region will become part of a gyrus or a sulcus. In the mature brain, a different regional pattern of thickness is achieved in which gyral cortex is thicker than sulcal cortex. Surface area expansion is also observed to relate to folding, as reflected in the regional pattern of surface curvature changes. Over a given developmental interval, changes in surface curvature are positively correlated with subsequent surface area expansion but negatively correlated with previous surface area expansion.

Conclusions: These comparisons lay out a sequence of growth and folding events. First, relative thickening of the cortex occurs in regions that will be gyral and sulcal at maturity. These regions undergo increases in curvature, facilitating surface area increases in the folded cortex. During the final phases of fold formation, the rate of thickness increase in gyri outpaces that in sulci.

Introduction: Neuroinflammation plays a critical role in tissue injury and repair after neonatal hypoxic-ischemic (HI) brain injury and varies by sex. Growth differentiation factor-15 (GDF-15) is a cytokine released by macrophages during inflammation and is upregulated after brain ischemia. We examined the impact of GDF-15 knockout (KO) on volume loss and the combined microglia/macrophage response in the Rice-Vannucci model of neonatal HI injury.

Methods: Male and female wild-type (WT) Gdf15+/+, heterozygous Gdf15nuGFP-CE/+ (Het), and homozygous Gdf15nuGFP-CE/nuGFP-CE (KO) mice were bred at the University of Pittsburgh. Postnatal day 9-11 mice were randomized to sham procedure or unilateral common carotid artery ligation followed by exposure to 8% O₂ for 25 min. Pups were subsequently genotyped and survived for 14 days before sacrifice. Lesion volume and number of ionized calcium-binding adapter molecule 1 (Iba-1)-positive cells were quantified.

Results: Injured male KO pups had decreased hemispheric and hippocampal lesion volume versus injured male WT pups. Injured male Het pups demonstrated an intermediate phenotype. In males, the number of Iba-1-positive cells correlated with extent of tissue loss. In females, the extent of volume loss and Iba-1 cell counts post-injury did not vary by genotype.

Conclusion: GDF-15 exerts a sex-dependent deleterious effect on lesion volume in a neonatal HI model. Future work should identify how GDF-15 mediates different neuroinflammatory responses between sexes, establish if brain-secreted versus peripherally derived GDF-15 mediates the pro-injury phenotype that was inhibited in male KOs, and test if therapeutic inhibition of GDF-15 signaling is a novel treatment for neonatal HI brain injury.

Introduction: Neurosteroids have a variety of neurological functions, such as neurite growth, neuroprotection, myelination, and neurogenesis. P450scc, encoded by CYP11A1 gene, is the cholesterol side chain cleavage enzyme that catalyzes the first and rate-limiting step in steroidogenesis. In this study, we examine the dendritic morphology in developing hippocampal neurons of Cyp11a1 null mice at P15, a critical period for synapse formation and maturation.

Methods: Knockout mice were maintained until P15 with hormone administration. The Golgi-Cox method stained CA1 and CA3 pyramidal neurons in the hippocampus to reveal dendritic morphology.

Results: We demonstrated that Cyp11a1 null mice usually die within 7 days after birth and thus collected brain samples at postnatal day 5 (P5) for examination. There was significant shrinkage of dendrite size and diminishment of dendritic branching in CA1 and CA3 pyramidal neurons in the hippocampus of Cyp11a1 null mice, suggesting a developmental delay. We wonder if this delay may catch up later in life. Since the age of P15 is a critical period for synapse formation and maturation, the Cyp11a1 null mice were rescued by receiving hormone administration until P15 that the dendritic morphology in the developing hippocampal neurons could be examined. The results indicated that the total dendritic length, the number of dendritic branches, as well as dendritic arborization in the CA1 and CA3 pyramidal neurons are significantly decreased in P15 knockout mice when compared to the wild type. The spine densities were also significantly decreased. In addition, the Western blot analysis revealed decreased PSD-95 expression levels in the knockout mice compared to the wild type at P15.

Conclusion: These results suggested that Cyp11a1 deficiency impairs the dendritic structures in the developing hippocampal pyramidal neurons.

Introduction: Caffeine and theophylline are methylxanthines and nonselective adenosine antagonists commonly used to treat apnea of prematurity. Both human and animal data suggest that xanthines also have clinically important long-term neuroprotective effects in the presence of inflammation in the perinatal period as seen following hypoxic-ischemic brain insults. Moreover, these protective effects appear to be more robust when administered shortly (<48 h) after preterm birth.

Method: To evaluate the importance of the postdelivery therapeutic window, we collected and analyzed medical data from preterm infants meeting criteria (23-30 weeks' gestational age [GA]), born at the University of Connecticut Health Center (UCHC), and cared for at the UCHC/Connecticut Children's Medical Center (CCMC) NICU from 1991 to 2017 (n = 858). Eighteen-month follow-up data included cognitive and language scores from the Neonatal Neurodevelopmental Follow-Up Clinic records, with a retention of 81% of subjects (n = 696). Differences were analyzed via multivariate ANOVA and ANCOVA.

Results: Analyses showed that infants who received xanthine treatment within the first 48 h after preterm birth showed significantly better 18-month behavioral outcomes than those treated later than 48 h, despite a lack of a priori differences in GA, birth, or length of stay. The positive effect of early xanthine therapy was particularly robust for infants exposed prenatally to the inflammatory conditions of chorioamnionitis and/or preeclampsia.

Conclusions: Current findings are consistent with human and animal data, showing that caffeine exerts protective effects, at least in part via attenuation of inflammation. Results add to the evidence supporting routine immediate prophylactic neuroprotective xanthine therapy (i.e., caffeine) in preterm infants. Findings also add important new evidence of the augmented value of caffeine for infants with inflammatory exposure due to mothers with preeclampsia or chorioamnionitis.

Introduction: This study was designed to examine whether social/environmental experiences can induce the epigenetic modification, and influence the associated physiology and behaviour. To test this, we have used social stress (prenatal stress [PNS]) model and then housed at environmental enrichment (EE) condition to evaluate the interaction between specific epigenetic modification and its influence on behaviour.

Methods: Pregnant rats were randomly divided into a control group, PNS group, and PNS+EE group. PNS and PNS+EE animals were subjected to social defeat stress during their gestational day (GD) 16-18. PNS animals and their offspring were always housed in standard laboratory condition, PNS+EE animal was housed in EE cage during GD-10 to the pup's age of postnatal day 30. Animals were tested for anxiety-like behaviour using open-field test (OFT) and memory was examined by passive avoidance test. Western blotting was used to detect the expression pattern of molecules associated with histone crotonylation.

Result: We observed anxiety-like behaviour, memory deficit in the animals experienced PNS. Further, level of methyl-CpG binding protein-2 (MeCP2), repressor element-1 silencing transcription factor (REST), sirtuin 1(SIRT1), chromodomain Y-like and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and histone methylation (H3K27me3) was elevated. Whereas, the expression of p300, histone crotonylation (H3K18Cr), and neuropeptide VGF were suppressed. Notably, EE restores the normal expression pattern of MeCP2, REST, P300, SIRT1, CYDL, EZH2, H3K27me3, H3K18Cr, and VGF.

Conclusion: EE reverses the PNS induced alterations, including suppression of histone crotonylation (H3K18Cr), which possibly involved in the regulation of expression of VGF and behaviour.

Introduction: This study aimed to explore the impact and mechanism of Scutellariae radix (SR), dried root of Scutellaria baicalensis Georgi of Labiatae, on prenatal stress (PS)-induced anxiety-like and depression-like behavior in the offspring in a mouse prenatal stress model.

Methods: The open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were utilized to assess the behavior of the offspring. Histological changes were evaluated using HE staining and Nissl staining. ELISA was employed to detect the levels of related factors in the serum and fetal brains of offspring mice. Immunohistochemistry was used to determine the expressions of doublecortin and neurotrophic factors in the hippocampus, and RT-PCR reflected the expression of factors in the hippocampus and placenta of offspring mice. These various techniques collectively provided insight into the neurodevelopmental status by detecting indicators related to neurodevelopmental status. LC-MS/MS and molecular docking were used to clarify the chemical constituents and the pharmacodynamic components in S. radix.

Results: S. radix ameliorated prenatal stress-induced anxiety-like and depression-like behavior in the offspring. It also alleviated hippocampal neurogenesis impairment caused by prenatal stress and restored abnormal expression of hippocampal glutamate (Glu) and brain-derived neurotrophic factor in the offspring. Additionally, S. radix maintained normal 11β-HSD1 expression in the placenta of prenatal stress mice, ensuring a normal level of glucocorticoids (GCs) and glucocorticoid receptors (GRs) in the fetus. Furthermore, S. radix increased the mRNA expression of GR and 11β-HSD2 while decreasing the mRNA expression of 11β-HSD1, thereby normalizing levels of serum CRH, ACTH, and GC in the offspring. Finally, docking results indicated that baicalein, wogonin, wogonoside, and baicalin exhibited stronger binding ability with the target.

Conclusion: The results of our study indicate that S. radix may have the potential to alleviate prenatal stress-induced anxiety-like and depression-like behaviors in offspring, at least partially through protecting placental barrier function, reversing HPA axis hyperfunction, and ameliorating neurodevelopmental dysfunction.

Introduction: Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing children can also be affected. Infections or other stressors are likely triggers. The underlying causes are unclear, but a current hypothesis suggests the convergence of genes that influence neuronal and immunological function. We previously identified 11 genes in pediatric acute-onset neuropsychiatric syndrome (PANS), in which two classes of genes related to either synaptic function or the immune system were found. Among the latter, three affect the DNA damage response (DDR): PPM1D, CHK2, and RAG1. We now report an additional 17 cases with mutations in PPM1D and other DDR genes in patients with acute onset of psychiatric symptoms and/or regression that their clinicians classified as PANS or another inflammatory brain condition.

Methods: We analyzed genetic findings obtained from parents and carried out whole-exome sequencing on a total of 17 cases, which included 3 sibling pairs and a family with 4 affected children.

Results: The DDR genes include clusters affecting p53 DNA repair (PPM1D, ATM, ATR, 53BP1, and RMRP), and the Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI, and FANCC). We hypothesize that defects in DNA repair genes, in the context of infection or other stressors, could contribute to decompensated states through an increase in genomic instability with a concomitant accumulation of cytosolic DNA in immune cells triggering DNA sensors, such as cGAS-STING and AIM2 inflammasomes, as well as central deficits on neuroplasticity. In addition, increased senescence and defective apoptosis affecting immunological responses could be playing a role.

Conclusion: These compelling preliminary findings motivate further genetic and functional characterization as the downstream impact of DDR deficits may point to novel treatment strategies.

Introduction: Birth asphyxia-induced encephalopathy is a major cause of long-term neurological morbidity, including cognitive and motor deficits. A proposed treatment is maternal creatine supplementation for prophylactic neuroprotection. This study examined how maternal creatine supplementation with or without birth asphyxia affected the behaviour of spiny mice offspring.

Methods: On day 20 of gestation (mid-gestation; term = 39 days), dams were randomly allocated to either a daily diet containing 5% w/w creatine monohydrate or remained on standard rodent chow. On gestational day 38, dams underwent either control caesarean section where offspring were delivered and recovered immediately, or birth asphyxia whereby the pregnant uterus was excised and placed in a saline bath for 7.5 min, inducing global hypoxia. All offspring were then cross-fostered to a lactating dam. Behavioural assessments were then completed on recovered offspring from neonatal to adolescent/adult ages (postnatal day [PND] 3-41) using the open-field, elevated plus maze, and novel object recognition test.

Results: Offspring that underwent birth asphyxia displayed locomotor deficits and increased anxiety-like behaviour at PND 3-7 in the open-field test (p < 0.05) and impaired novel object discrimination at PND 18 (p < 0.05). Antenatal creatine exposure reduced anxiety-like behaviour irrespective of asphyxia in pups at PND 3, indicating an amelioration of the asphyxia-induced anxiety-like behaviour. In adolescence/adulthood, creatine and asphyxia-exposed offspring showed reduced object exploration (p < 0.0001). Antenatal creatine led to sustained reductions in anxiety-like behaviour in the elevated plus maze at adolescence and increased body weight, regardless of birth asphyxia exposure (p < 0.05).

Conclusion: Antenatal creatine exposure following maternal dietary creatine supplementation decreased anxiety-like behaviour in spiny mice offspring. This change negated behavioural abnormalities caused by birth asphyxia in the neonatal period, though it may have broader influences on long-term emotional and information processing in offspring which warrants further investigation.