Introduction: Hypoxia-inducible factor-1α (HIF-1α) has a wide-ranging role in the cellular responses to hypoxia. We previously found that neuron-specific HIF-1α-deficient mice (HIF-KO) that underwent neonatal hypoxia-ischemia (HI) had increased brain injury suggesting its neuroprotective function. To investigate whether HIF-1α is also involved in the mechanisms of protection by hypothermia (HT), the standard of care for hypoxic-ischemic encephalopathy, we tested the effect of HT on HIF-KO and wild-type (WT) littermates after HI in postnatal day 9 mice.
Methods: Cooling at 32°C began 1 h following HI and lasted for 3.5 h. Mice were perfused 5-7 days later for histological determination of injury severity. For Western blots, mice were killed 4 h or 24 h after HI with HT or HI with normothermia (NT) and ipsilateral cortices and hippocampi were evaluated for expression of HIF-1α, spectrin, ERK1/2, phosphorylated-ERK1/2 (p-ERK), and RNA-binding motif protein 3 (RBM3), one of the main cold-inducible mRNA-binding proteins.
Results: Histological evaluation showed WT mice with HT had less injury than WT with NT, but HIF-KO mice showed no reduction of injury with HT. Regionally, the reduction of injury in WT with HT is greater in the hippocampus than in the cortex. Protein expression of HIF-1α was lower in HIF-KO cortex at 4 h with NT or HT and at 24 h with NT, but HIF-1α was higher in WT with NT at 24 h. Expression of spectrin 145/150 in WT cortex with HT was not different than sham at 4 h, indicating limitation of necrosis with HT. In the HIF-KO cortex at 4 h spectrin 145/150 was higher in both NT and HT, indicating no protection with HT. In the hippocampus at 4 h and 24 h, spectrin 145/150 was elevated in all groups compared to sham. ERK activity, as represented by the ratio of p-ERK/ERK, was upregulated at 24 h in the cortex in WT with NT or HT compared to sham and in HIF-KO mice with NT or HT treatment compared to sham. RBM3 was elevated at 4 h in both WT and HIF-KO cortex with HT, but there was no change in the hippocampus.
Conclusion: These results support a critical role for HIF-1α in the mechanisms of protection with HT.
Background: Homeostasis of water content in the brain during fetal development is of crucial physiological importance. Aquaporins (AQPs) play a critical role in maintaining brain water balance, supporting normal brain development, and are increasingly recognized for their relevance in understanding neurodevelopmental disorders.
Summary: This review provides a comprehensive overview of AQPs and their essential roles in the central nervous system (CNS), specifically AQP4, AQP11, and AQP9, which play a crucial role in water transport in the brain, maintaining water homeostasis and facilitating water movement across cell membranes. The review also highlights how disruptions in AQP expression and function may contribute to the pathology of neurodevelopmental disorders such as autism and Fragile X syndrome.
Key messages: AQPs are vital for brain water regulation and normal neural development. Altered expression or function of AQPs can impact blood-brain barrier integrity, neuroinflammation, and synaptic activity. AQP dysfunctions are linked to neurodevelopmental disorders and may represent promising therapeutic targets.
Introduction: Unilateral brain injury in neonates results in largely contralateral hand function impairment in children. Most research investigating neurorehabilitation targets for movement recovery has focused on the effects of brain injury on descending motor systems, especially the corticospinal tract. However, a recent human study demonstrated that sensory tract injury may have larger effects on dexterity than motor tract injury. To test this, we first developed a model of sensory tract injury in neonatal rats by targeting the thalamocortical tract (TCT), and then we used this model to assess the effects of sensory lesions on paw use.
Methods: In the postnatal day 7 rats, we used three types of lesions to the TCT: periventricular blood injection, photothrombotic lesion, and electrolytic lesion. To test the sensitivity and specificity of these techniques, viral tracers were injected into the primary sensory or motor cortex immediately after injury. To test the forelimb use, the cylinder exploration and pasta handling tests were used.
Results: Electrolytic lesions were the most specific and reproducible for inducing a lesion compared to the other two methods. Electrolytic lesions disrupted 63% of the TCT while sparing the adjacent corticospinal tract in the internal capsule. Given that electrolytic lesions were the most specific and sensitive for targeting the TCT, this model was used for behavioral experiments to measure the impact of sensory tract lesion on dexterity. Lesions to the TCT were associated with a significant decrease in the use of the contralateral forelimb in the cylinder task, and the degree of impairment positively correlated with the degree of injury.
Conclusion: Overall, specific sensory system lesions of the TCT impair forelimb use, suggesting a key role for skilled movement.
Introduction: Children with specific language impairment (SLI) have difficulties in different speech and language domains. Electrophysiological studies have documented that auditory processing in children with SLI is atypical and probably caused by delayed and abnormal auditory maturation. During the resting state, or different auditory tasks, children with SLI show low or high beta spectral power, which could be a clinical correlate for investigating brain rhythms.
Methods: The aim of this study was to examine the electrophysiological cortical activity of the beta rhythm while listening to words and nonwords in children with SLI in comparison to typical development (TD) children. The participants were 50 children with SLI, aged 4 and 5 years, and 50 age matched TD children. The children were divided into two subgroups according to age: (1) children 4 years of age; (2) children 5 years of age.
Results: The older group differed from the younger group in beta auditory processing, with increased values of beta spectral power in the right frontal, temporal, and parietal regions. In addition, children with SLI have higher beta spectral power than TD children in the bilateral temporal regions.
Conclusion: Complex beta auditory activation in TD and SLI children indicates the presence of early changes in functional brain connectivity.
Introduction: Children with specific language impairment (SLI) have difficulties in different speech and language domains. Electrophysiological studies have documented that auditory processing in children with SLI is atypical and probably caused by delayed and abnormal auditory maturation. During the resting state, or different auditory tasks, children with SLI show low or high beta spectral power, which could be a clinical correlate for investigating brain rhythms.
Methods: The aim of this study was to examine the electrophysiological cortical activity of the beta rhythm while listening to words and nonwords in children with SLI in comparison to typical development (TD) children. The participants were 50 children with SLI, aged 4 and 5 years, and 50 age matched TD children. The children were divided into two subgroups according to age: (1) children 4 years of age; (2) children 5 years of age.
Results: The older group differed from the younger group in beta auditory processing, with increased values of beta spectral power in the right frontal, temporal, and parietal regions. In addition, children with SLI have higher beta spectral power than TD children in the bilateral temporal regions.
Conclusion: Complex beta auditory activation in TD and SLI children indicates the presence of early changes in functional brain connectivity.
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.
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