Introduction: Upstream stimulating factor 2 (USF2) belongs to basic Helix-Loop-Helix-Leucine zipper transcription factor family, regulating expression of genes involved in immune response or energy metabolism network. Role of USF2 in neuropathic pain was evaluated.
Methods: Mice were intraspinally injected with adenovirus for knockdown of USF2 (Ad-shUSF2) and then subjected to spinal nerve ligation (SNL) to induce neuropathic pain. Distribution and expression of USF2 were detected by western blot and immunofluorescence. Mechanical and thermal pain sensitivity were examined by paw withdrawal thresholds (PWT) and paw withdrawal latency (PWL). Chromatin immunoprecipitation (ChIP) and luciferase activity assays were performed to detect binding ability between USF2 and SNHG5.
Results: The expression of USF2 was elevated and colocalized with astrocytes and microglia in L5 dorsal root ganglion (DRG) of SNL-induced mice. Injection of Ad-shUSF2 attenuated SNL-induced decrease of PWT and PWL in mice. Knockdown of USF2 increased the level of IL-10 but decreased TNF-α, IL-1β, and IL-6 in SNL-induced mice. Silence of USF2 enhanced protein expression of CD206 while reducing expression of CD16 and CD32 in SNL-induced mice. USF2 binds to promoter of SNHG5 and weakens SNL-induced up-regulation of SNHG5. SNHG5 binds to miR-181b-5p, and miR-181b-5p to interact with CXCL5.
Conclusion: Silence of USF2 ameliorated neuropathic pain, suppressed activation of M1 microglia, and inhibited inflammation in SNL-induced mice through regulation of SNHG5/miR-181b-5p/CXCL5 axis. Therefore, USF2/SNHG5/miR-181b-5p/CXCL5 might be a promising target for neuropathic pain. However, the effect of USF2/SNHG5/miR-181b-5p/CXCL5 on neuropathic pain should also be investigated in further research.
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: 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 to Contrast and Moving Snake illusions and were faster to answer in Müller-Lyer illusion trials.
Conclusion: The current study found that susceptibility to illusions changes in a manner that is age-specific 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 heterochronically.
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: GAPDH, β-actin, and β-tubulin are essential housekeeping proteins commonly used as reference controls for protein expression studies. GAPDH is a key glycolytic enzyme that facilitates the production of cellular energy, while β-actin and β-tubulin are major structural components of the cytoskeleton. Besides their well-established housekeeping functions, emerging studies have demonstrated critical roles for these proteins in brain developmental and pathological processes. However, few studies have examined how the expression patterns of these proteins change throughout mammalian brain development to adulthood. Considering the dynamic structural and functional changes that occur during brain development and the roles of GAPDH, β-actin, and β-tubulin in related biological processes, we investigated the developmental expression levels of these proteins in the mouse cortex at various embryonic and postnatal stages.
Methods: Cortical tissue was collected from mice at embryonic days 15 and 17, postnatal days 0, 5, 10, 15, 20, and during adulthood. Protein levels were analyzed using western blotting analysis with total protein normalization.
Results: We identified a substantial increase in GAPDH protein levels and a decrease in β-actin and β-tubulin protein levels in the mouse cortex between birth and early adulthood, which occurred during the second week of postnatal life. Analysis of RNA-seq data from the ENCODE Consortium revealed correlated changes at the RNA transcript level.
Conclusion: Overall, our study reveals robust age-dependent changes in cortical GAPDH, β-actin, and β-tubulin expression levels during mouse postnatal development and suggests precautions when using these proteins as reference controls in cortical development studies.
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: 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.
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