Developmental Neuroscience最新文献

Lipopolysaccharide (LPS) plays a role in innate immunity and is used in animal models of maternal immune activation. The current study attempted to clarify the effect of LPS exposure on the dentate gyrus progenitors in ferret neonates.

Methods: LPS was administered subcutaneously at 500 μg/g of body weight to ferrets on postnatal days 6 and 7. Animals were injected intraperitonially with BrdU simultaneously with a second LPS injection to label the proliferating cells following LPS exposure.

Results: Two hours after BrdU injection, a significantly greater density of BrdU-labeled cells was observed in the hilus of the hippocampal dentate gyrus in LPS-exposed ferrets than in that of the controls. The majority of BrdU-labeled cells were Sox2 immunopositive in either the granular/subgranular layers or hilus in both groups. The percentages of BLBP (a marker of adult-type dentate gyrus progenitors), S100 (a marker of glial cells), and cleaved caspase 3 (a marker of apoptosis) were significantly lower in the granular/subgranular layers and/or hilus of LPS-exposed ferrets than in those of the controls.

Conclusions: These findings suggest that LPS promotes the proliferation of dentate gyrus progenitors. LPS may further act on the post-proliferative dentate gyrus progenitors to sustain their embryonic-type characteristics by preventing their transitions into the BLBP-expressing adult-type and/or S100-expressing glial cell lineages and by inhibiting programmed cell death.

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.

Introduction: Repeated use of methamphetamine (METH) is known to dysregulate the dopaminergic system and induce long-lasting changes in behavior, which may be influenced by sex and age of exposure. Catechol-o-methyltransferase (COMT) is an enzyme that is involved in the breakdown of catecholamines, and its role in dopamine clearance is thought to be especially important in the prefrontal cortex (PFC) where dopamine transporter expression is relatively scarce.

Methods: The first study in this report utilized a rat model to characterize the ontogeny of COMT protein expression in the PFC and nucleus accumbens (NAc) across adolescence, which is a developmental stage that has been shown to involve significant reorganization of dopaminergic innervation. Drug-naïve male and female Sprague-Dawley rats were sacrificed on postnatal day (P) 29, 39, 49, or 69, and expression levels of COMT protein within the PFC and NAc were analyzed via Western blot. A separate group of rats were injected daily from P40 to P48 (adolescence) or P70 to P78 (adulthood) with saline or 3.0 mg/kg METH and sacrificed on P49 or P79.

Results: We found that COMT expression in the PFC increases across adolescence in a sex-dependent manner but does not significantly change in the NAc during this timeframe. While METH decreased COMT in adult rats of both sexes, METH increased COMT expression in the PFC of rats exposed in adolescence.

Conclusion: The results of this work suggest that exposure to METH during adolescence uniquely effects dopamine clearance within the PFC, potentially contributing to differences in neurobiological outcomes from METH use.

Background: Intraventricular haemorrhage (IVH) is the primary neuropathology in infants born very preterm. IVH describes bleeding into the ventricular space of the newborn brain, originating from the germinal matrix, termed germinal matrix haemorrhage. IVH is diagnosed at a rate of 1 in 5 infants born very preterm (less than 32 weeks' gestation), but the incidence increases with earlier gestation at birth. IVH is graded in severity (I to IV), and the neurological sequelae of IVH in infants born very preterm are significant, with more than 1 in 4 infants with any grade of IVH subsequently diagnosed with a moderate to severe neurodevelopmental deficit, increasing to more than half of infants diagnosed with severe IVH (grade III/IV).

Summary: The high susceptibility to IVH in infants born at less than 32 weeks' arises in part to the presence of the germinal matrix. The germinal matrix is a transient brain region that produces neural stem and progenitor cells. The germinal matrix region is rich in angiogenic blood vessels that have a low density of pericyte and astrocyte coverage to provide structural stability, and it is a border zone for vascular endpoints that are highly fragile to haemodynamic instability. In addition to immaturity, antenatal complications may also adversely impact cerebrovascular development, pericyte and astrocyte coverage, and subsequently the structural integrity of the blood-brain barrier that might increase the risk for IVH.

Key messages: Here, we will report the maturational profile of cerebrovascular development in the extremely preterm neonate, and implications for susceptibility to IVH, the complications that may contribute to the risk of haemorrhage, and neurodevelopmental deficits that primarily arise from IVH. We aimed to elucidate the cellular foundations of IVH to provide insight into neuroprotective targets.

Background: Healthcare costs are rising at an exponential rate. Given the constraints of limited resources, it is essential to make informed decisions about priorities to ensure the best possible health outcomes globally. The history of medicine illustrates how these priorities have shifted over time - from early focus on infectious diseases to later emphasis on noncommunicable conditions such as metabolic disorders. Today, neurodegenerative diseases and aging brain are the forefront of medical research, as these conditions profoundly affect individuals, families, and society.

Summary: One in three people will experience a mental health disorder in their lifetime, yet it is not widely recognized that many of these conditions may have origins in pre-birth experiences and early life influences. Disruptions in progenitor proliferation, neuronal and glial migration, and differentiation during prenatal development can contribute to lifelong neurodevelopmental abnormalities. Despite the fundamental importance of brain development, most of the neuroscience funding is allocated to studying neurodegeneration, such as dementia and Parkinson's disease, while early life influences remain underexplored. Crucially, the impact of developmental factors begins even before conception. Environmental risks extend beyond direct maternal exposures during pregnancy; they include cumulative parental exposure to teratogenic agents affecting both male and female gametes, as well as early life environmental exposures affecting newborns, infants, and children. These influences are complex yet highly relevant to long-term health outcomes.

Key messages: We urge greater recognition of the developmental origins of disease and advocate for increased investment in preventive strategies. These include lifestyle modifications, dietary improvements, targeted supplementation, regular exercise, and minimizing exposure to environmental pollutants. Addressing these factors proactively could yield profound benefits for both individual and public health.

Introduction: Gyrification is a shared phenotype of brain development across many species. The identification of human- and primate-specific genes is a topic of great research interest to uncover the genetic mechanisms that drive human gyrification. Here we investigated a human transcript variant of FOXM1 with a unique ninth exon proposed to have a crucial role in primate gyrification.

Method: We performed comprehensive bioinformatic analyses, including several BLASTs and multiple sequence alignment, utilising available deposited sequencing data. We aimed to determine the degree of conservation of human FOXM1 exon 9 across a wide range of species, with a particular focus on gyrencephalic primates. Furthermore, we aimed to determine the degree of conservation of the remaining regions of FOXM1 across a subset of gyrencephalic and lissencephalic species.

Results: Our results revealed that the exon is only partially detected in four other primates, challenging its presumed conservation in humans, apes, and other primates. The remaining regions of FOXM1 had a remarkably high level of conservation, and, given its role in regulating proliferation and differentiation, the results suggested that FOXM1 may be required for early brain development across all species. However, the sporadic presence of the exon 9 sequence even in other gyrencephalic primates raises questions about its indispensability in the process of gyrification.

Conclusion: Therefore, we conclude that the FOXM1 transcript variant comprising the exon 9 sequence in its entirety could be more appropriately reclassified as a human-specific cortical folding variant not found in other species. This research lays the foundation for further investigating the role of FOXM1 exon 9 in human gyrification and brain development.