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.

Plain Language SummaryThis study aimed to explore the role of the cold shock protein RNA-binding motif 3 (RBM3) in therapeutic hypothermia (TH)-induced neuroprotection following hypoxia-ischemia (HI) using Hyperpolarized 13C MRI. The findings demonstrated that RBM3 may be one of the key factors associated with TH-induced neuroprotection by reducing the anaerobic glycolysis process in HI mice, suggesting that RBM3 upregulation may enhance the efficacy of TH for hypoxic-ischemic encephalopathy.

Introduction: Staphylococcus epidermidis (SE) is a predominant hospital-acquired bacterium leading to late-onset sepsis in preterm infants. Recent findings have suggested that postnatal SE infection is associated with short-term neurodevelopmental consequences. However, the potential effects of postnatal SE infection on long-term neuronal plasticity and cognitive functions, which are sensitive to early life brain insults, remain unclear. In light of these findings, we investigated the effects of postnatal SE infection on recognition memory function using a neonatal mouse model. Methods: On postnatal day 4, male and female C57Bl/6 mice were injected intraperitoneally with either 3.5 × 107 colony-forming units of SE or sterile saline. On postnatal day 45 (±5 days), the mice were subjected to the novel object recognition test (NORT) to assess recognition memory function. Following NORT, the brains of the mice were collected for neuronal plasticity analyses by considering maturation of neurons and 3-D analysis of synaptic plasticity and hippocampal, measuring the nerve growth factor (NGF) expression. Results: Postnatal SE infection induced long-term, sex-specific effects on recognition memory and hippocampal neuroplasticity. Female SE-infected mice showed enhanced recognition memory, whereas males showed no significant difference in the recognition memory after neonatal SE infection. At the cellular level, both sexes displayed a significant decrease in doublecortin-positive neurons in the dentate gyrus after SE infection, indicating impaired neuroplasticity. However, male mice showed increased spine density, particularly of immature thin spines and disrupted spatial organization of spines, while females demonstrated no change in spines. Notably, SE infection elevated hippocampal NGF expression in males, but not in females, suggesting sex-specific molecular responses that may contribute to the observed differences in neuroplasticity and cognitive outcomes. Conclusion: This study demonstrates that postnatal SE infection induces long-lasting, sex-specific changes in recognition memory. Early life immune activation disrupted hippocampal neuroplasticity, with males showing greater vulnerability. These findings indicate distinct neurodevelopmental trajectories shaped by neonatal immune challenges in preterm infants, with implications for understanding sex-specific cognitive outcomes.

Background: Folding of the neocortex is a fundamental feature of brain development in many mammalian species, notably in most non-human primates and in particular in human. Cortical folding is thought to allow a larger cortical surface area, with a greater number of neurons, to fit into the limited size of the cranial cavity. Summary: Here, we review the following key topics related to cortical folding. We first discuss the principles of cortical folding and dissect the factors contributing to the mechanical asymmetry that is thought to have a key role in driving fold formation. We then address the evolution of cortical folding and discuss the two principal types of folding, conserved and evolved, and the roles of neuron production vs. neuron migration in these. We also review the different model systems used, such as human tissue/cell-based, animal, and computational models of cortical folding. Key Messages: This includes a discussion of human malformations of cortical folding, the potential of cerebral organoids to study folding, the power of the ferret model to dissect mechanisms of cortical folding, and the use of computational models to make predictions about cortical folding. Finally, we address future perspectives of folding research and outline directions that research may take.

Introduction: Combined therapeutic hypothermia (TH) and 24-h hydrogen (H2) gas inhalation reduces seizure burden in piglets in the latent phase of hypoxic-ischemic (HI) injury versus TH alone. Nevertheless, the effects of H2 gas in the earliest phase following resuscitation were unclear. Methods: After HI insult, 17 piglets ≤24 h old were divided into a HI insult group (HI, n = 8) and a HI and H2 gas group (HI-H2, 2.1%–2.7% H2 gas, 6 h, n = 9). Time to recovery to a normal amplitude-integrated electroencephalogram background (RT-aEEG) was examined for 6 h after HI insult and undamaged neurons were counted. Results: The duration of low-amplitude (<5 μV) EEG after insult was not different between the two groups. Undamaged neuron numbers were significantly higher in the HI-H2 group than in the HI group (p < 0.01), although RT-aEEG was not different. Conclusion: Six hours of H2 gas inhalation initiated from resuscitation significantly increased the number of undamaged neurons compared to the untreated group, although there was no difference in RT-aEEG. Six hours of hydrogen gas inhalation exerts a neuroprotective effect even in piglets with delayed functional recovery.

Introduction: Inflammatory oxidative microenvironments can alter heme oxygenase-1 (HO-1) homeostasis. Dysregulation of HO-1 favors proinflammatory signals, while transferrin receptor 1 (TfR1) regulates anti-inflammatory signal transduction. Previously, we have shown that chorioamnionitis (CHORIO) induces sustained elevations in HO-1/TfR1 at postnatal day (P)2 and mononuclear cell-driven inflammation at term age equivalent P7. Here, we hypothesized that an altered HO-1/TfR1 developmental time course would coincide with inflammatory/immune signal changes in the brain. Methods: To induce CHORIO in rats, we performed a laparotomy followed by bilateral transient uterine artery occlusion and intra-amniotic injection of lipopolysaccharide (LPS) at E18. The control group received laparotomy only with equivalent duration of anesthesia. We used real-time polymerase chain reaction (RT-PCR), multiplex electrochemiluminescent immunoassay (MECI), and flow cytometry (FC) to study changes in pro- and anti-inflammatory gene expression, immune cell secretome, and immune cells at critical and clinically relevant timepoints following CHORIO. Results: We found an acute reduction in anti-inflammatory signals in the cortex on embryonic day (E)19. This was followed by an increased proinflammatory signature on postnatal day (P)2. There were also significant alterations in the phenotypic distribution of splenic T cells on P7, a key organ in immune function. Furthermore, we showed that the microenvironment of the cortex at P21 was skewed toward a proinflammatory state by significant increases in IL-6. The prominence of T-helper cells (Th) in brain concomitant with a proinflammatory state at P21 suggests emerging inflammation and potential for neural injury. Conclusions: Defining how these and other inflammatory/immune signatures contribute to perinatal brain injury and investigating distinct immune signatures at more developmental time courses will be beneficial for targeting emerging therapies.

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.

Background: Fetal growth restriction (FGR) corresponds to the fetus’s inability to achieve an adequate weight gain based on genetic potential and gestational age. It is an important cause of morbidity and mortality. Summary: In this review, we address the challenges of diagnosis and classification of FGR. We review how chronic fetal hypoxia impacts brain development. We describe recent advances on placental and fetal brain imaging using magnetic resonance imaging and how they offer new noninvasive means to study growth restriction in humans. We go on to review the impact of FGR on brain integrity in the neonatal period, later childhood, and adulthood and review available therapies. Key Messages: FGR consequences are not limited to the perinatal period. We hypothesize that impaired brain reserve, as defined by structure and size, may predict some concerning epidemiological data of impaired cognitive outcomes and dementia with aging in this group of patients. Background: Fetal growth restriction (FGR) corresponds to the fetus’s inability to achieve an adequate weight gain based on genetic potential and gestational age. It is an important cause of morbidity and mortality. Summary: In this review, we address the challenges of diagnosis and classification of FGR. We review how chronic fetal hypoxia impacts brain development. We describe recent advances on placental and fetal brain imaging using magnetic resonance imaging and how they offer new noninvasive means to study growth restriction in humans. We go on to review the impact of FGR on brain integrity in the neonatal period, later childhood, and adulthood and review available therapies. Key Messages: FGR consequences are not limited to the perinatal period. We hypothesize that impaired brain reserve, as defined by structure and size, may predict some concerning epidemiological data of impaired cognitive outcomes and dementia with aging in this group of patients.