Developmental Neuroscience最新文献

Introduction: Homeobox genes are highly conserved and play critical roles in brain development. Recently we have found that mammals have an additional fragment of approximately 20 amino acids in Emx1 and a poly-(Ala)6-7 in Emx2, compared to other amniotes. It has been shown that Emx1 and Emx2 have synergistic actions in the brain development. These reports raise an interesting issue whether the differences of Emx1 and Emx2 between mammals and non-mammals are concerned with the organization and evolution of amniote pallium.

Methods: Lentiviruses expressing mouse Emx1 and Emx2 (mEmx1/2) with additional fragments were injected into the ventricle of the chick telencephalon at embryonic day 3 to study the effects of mEmx1/2 on the development of chick pallium, whereas injections of lentiviruses containing chick Emx1 and Emx2 (cEmx1/2), no targeted gene insert or saline were as controls. The expressions of reelin, vimentin, GABA and MAP2, neurogenesis patterns for calbindin and parvalbumin neurons and the sizes of anterior commissure were then studied by immuohistochemical staining, and open-field tests were performed to assess locomotor activities and curious or exploratory behaviors of the chicks.

Results: Following the injections of lentiviruses expressing mEmx1/2, the expressions of reelin, vimentin, GABA and MAP2 increased in most parts of Wulst (W) and mesopallium (M), but not of nidopallium (N). Neurogenesis patterns for calbindin (CB) and parvalbumin (PV) neurons changed towards mammalian inside-out one, and the sizes of anterior commissure staining for neurofilament were significantly larger. In addition, posthatchling chicks showed higher rates of passive avoidance after training, but no significant differences in the total distance traveled and the percentage of time spent in the central rectangle, compared to those in the control group.

Conclusion: The present study indicated that mEmx1/2 had effects on the development of chick pallium, suggesting that they are probably involved in the organization and evolution of amniote pallium.

Introduction: This study 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 (SD) 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 (PND) 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 (CDYL) and Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) and histone methylation (H3K27me3) was elevated. Where as, the expression of p300, histone crotonylation (H3K18Cr) and neuropeptide VGF were suppressed. Notably, EE restore the normal expression pattern of MeCP2, REST, P300, SIRT1, CYDL, EZH2, H3K27me3, H3K18Cr and VGF.

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

Introduction: The underlying neural and/or perceptual mechanisms of different visual illusions are still unknown; thus, they continue to be the focus of many ongoing studies. Inconsistencies persist in the empirical findings for understanding how the perception of these illusions evolves over the course of development.

Methods: We assessed 513 participants between 6.5 and 18.9 years of age, with 103 pairs of illusory and control images spanning five illusion types (Ebbinghaus, Müller-Lyer, Contrast, Moving Snake, and Subjective Contour). Misleading and helpful contexts were added when possible.

Results: In general, we found that, except for the Ebbinghaus illusion susceptibility changes with age: while for the Müller-Lyer it decreases, for the Contrast, Moving Snake, and Kanizsa susceptibility increases. Across all illusory conditions participants' decision time decreased with age. Context also influenced the performance and choice latency. We also found a gender difference: boys were less susceptible than girls on contrast and moving snake illusions and were faster to answer on Müller-Lyer illusion trials.

Conclusion: The current study found that susceptibility to illusions change in a manner that is age and in some cases sex specific. The different developmental trajectories of the perception of visual illusions support the idea of the lack of a common neural and/or perceptual process behind them. We can suggest that at least some of the cognitive processes and neural pathways involved develop in heterochronically.

Introduction: Brain cholesterol relies on de novo biosynthesis and is crucial for brain development. Cholesterol synthesis is a complex series of reactions that involves more than twenty enzymes to reach the final product and generates a large number of intermediate sterols along two alternate pathways. This is a highly regulated and oxygen-dependent process and thus sensitive to hypoxia.

Methods: Using the modified Vannucci procedure, a clinically relevant animal model of neonatal hypoxia ischemia (HI), we characterized the profile of cholesterol and its sterol intermediates, along with the key enzymes on the cholesterol synthetic pathway over a time course of 5 days after HI in the postnatal day 10 mouse brain.

Results: Although the total cholesterol levels in the injured cortices appeared to be minimally attenuated at 5 days following HI, there was an overall repression of brain cholesterol biosynthesis. Lanosterol and the downstream sterols in both the Bloch and Kandutsch-Russell (K-R) pathways were consistently reduced for up to 3 days except for desmosterol, which was elevated. Correspondingly, protein expression of the controlling transcription factors sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1 was decreased at early time points (within 6 h), in parallel with the downregulation of several substrate enzymes for up to 5 days post-HI. HMG-CoA reductase (HMGCR), the first rate-limiting enzyme, was upregulated in the first 24 h after HI. The expression of 24-dehydrocholesterol reductase (DHCR24) that catalyzes the last step to produce cholesterol on the Bloch pathway and bridges the Bloch to K-R pathway was also augmented.

Conclusions: Our data suggest perturbed brain cholesterol biosynthesis following neonatal HI. As some sterol intermediates and enzymes have diverse functions in brain development and stress responses other than producing cholesterol, assessment of their dynamic changes after HI is important to understand the lipid responses in rodent HI models and to identify lipid-based targeted therapies in future studies.

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 Scutellariae radix.

Results: Scutellariae 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, Scutellariae radix maintained normal 11β-HSD1 expression in the placenta of prenatal stress mice, ensuring a normal level of glucocorticoid (GC) and glucocorticoid receptors (GR) in the fetus. Furthermore, Scutellariae 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 Scutellariae 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.

Background: The fetal brain undergoes a dynamic process of development during gestation, marked by well-orchestrated events such as neuronal proliferation, migration, axonal outgrowth, and dendritic arborization, mainly elucidated through histological studies. Ex vivo magnetic resonance imaging (MRI) has emerged as a useful tool for 3D visualization of the developing fetal brain, serving as a complementary tool to traditional histology.

Summary: In this review, we summarized the commonly employed ex vivo MRI techniques and their advances in fetal brain imaging, and proposed a standard protocol for postmortem fetal brain specimen collection and fixation. We then provided an overview of ex vivo MRI-based studies on the fetal brain.

Key messages: According to our review, ex vivo T1- or T2-weighted structural MRI has contributed to the characterization of the anatomy of transient neuronal proliferative zones, the basal ganglia, and the cortex. Diffusion MRI-related techniques, such as diffusion tensor imaging and tractography, have helped investigate the microstructural patterns of fetal brain tissue, as well as the early emergence and development of neuronal migration pathways and white matter bundles. Ex vivo MRI findings have shown strong histological correlations, supporting the potential of MRI in evaluating the developmental events in the fetal brain. Postmortem MRI examinations have also demonstrated comparable, and in certain cases, superior performance to traditional autopsy in revealing fetal brain abnormalities. In conclusion, ex vivo fetal brain MRI is an invaluable tool that provides unique insights into the early stages of brain development.

Introduction: Pubertal maturation is marked by significant changes in stress-induced hormonal responses mediated by the hypothalamic-pituitary-adrenal (HPA) axis, with prepubertal male and female rats often exhibiting greater HPA reactivity compared to adult males and females. Though the implications of these changes are unclear, elevated stress responsiveness might contribute to the stress-related vulnerabilities often associated with puberty.

Methods: The current experiments sought to determine whether differences in cellular activation, as measured by FOS immunohistochemistry, or excitatory ionotropic glutamate receptor subunit expression, as measured by qRT-PCR, in the paraventricular nucleus (PVN) were associated with these noted pubertal shifts in stress reactivity in male and female rats. As the PVN is the key nucleus responsible for activating the hormonal stress response, we predicted greater cellular activation and higher expression levels of glutamate receptor subunits in the PVN of prepubertal males and females compared to their adult counterparts.

Results: Our FOS data revealed that while prepubertal males showed greater stress-induced activation in the PVN than adult males, prepubertal females showed less activation than adult females. Moreover, many of the NMDA, AMPA, and kainate receptor subunits measured, including Grin1, Grin2b, Gria1, Gria2, Grik1, and Grik2, had higher expression levels in adults, particularly in males.

Conclusions: Though not supporting our initial predictions, these data do indicate that age and stress influence the activation of the PVN and the expression of glutamate receptor subunits important in its function. These data also suggest that the effects of age and stress are different in males and females. Though still far from a clear understanding of what mechanism(s) mediate pubertal shift in stress reactivity, these data add to our growing understanding of how age, stress, and sex influence HPA function.

Introduction: Sevoflurane is an extensively used anesthetic for pediatric patients; however, numerous studies showed that sevoflurane (SEVO) may cause long-term neurodevelopmental toxicity. Dexmedetomidine (DEX) has been shown to be protective against SEVO-induced neurotoxicity, but the mechanism remains unclear. The effects and mechanisms of different DEX administration routes on SEVO-induced neurotoxicity and long-term cognitive defects were determined and further investigated the role of sex in these processes.

Methods: Male and female Sprague Dawley rats at postnatal day 7 (PND7) received an intraperitoneal injection of DEX (10 μg/kg) before or after exposure to 2.5% SEVO for 6 h, or before and after SEVO exposure. The respiratory and mortality rates of the pups were recorded during anesthesia. Neuroapoptosis was evaluated by TdT-mediated dUTP nick-end labeling staining. Immunohistochemistry and immunofluorescence were employed to detect the expression of caspase-3 in neuronal cells and neurons. The expression of GSK-3β and DISC1 was determined by Western blotting or RT-qPCR. Morris water maze (MWM) test was used to evaluate the learning and memory ability of rats until they were 3 weeks and 5 weeks old.

Results: Compared with the control group, exposure to 2.5% SEVO resulted in increased neuroapoptosis and decreased the expression of DISC1 at levels of mRNA and protein and phosphorylated GSK-3β in the developing brain. SEVO exposure during critical neurodevelopmental periods could cause persistent cognitive defects in adolescent male and female rats and inhibited DISC1 and phosphorylated GSK-3β protein expression. The neurotoxic impacts of SEVO were lessened by the administration of DEX (10 μg/kg) before or after exposure.

Conclusion: Our findings suggest that DEX (10 μg/kg) mitigates the neurotoxic effects of SEVO on the developing rat brain as well as postnatal cognitive defects by regulating the DISC1/GSK-3β signaling.

Background: In contemporary medical practice, general anesthesia plays an essential role in pediatric surgical procedures. While modern anesthetic protocols have demonstrated safety and efficacy across various pathological conditions, concerns persist regarding the potential neurotoxic effects associated with early exposure to general anesthesia.

Summary: Current research primarily examines the neurocognitive developmental impacts, with limited focus on neurobehavioral developmental disorders. This review presents a comprehensive analysis of clinical trial results related to five critical neurobehavioral developmental disorders: fine motor disability, attention-deficit hyperactivity disorder, impulse control disorders, autism spectrum disorder, and developmental coordination disorder. Furthermore, this review synthesizes insights from basic research on the potential toxicological mechanisms of general anesthetic agents that could influence clinical neurobehavioral changes. These findings provide valuable guidance for the prudent and safe utilization of anesthetic agents in pediatric patients.

Key messages: This review explores the potential connections between general anesthesia and five neurobehavioral disorders, highlighting the importance of cautious anesthetic use in children in light of current research findings.

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.