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Significance Newborns can hear their mother’s voice and heartbeat sounds before birth. However, it is unknown whether, how early, and to what extent the newborn's brain is shaped by exposure to such maternal sounds. This study provides evidence for experience-dependent plasticity in the auditory cortex in preterm newborns exposed to authentic recordings of maternal sounds before full-term brain maturation. We demonstrate that the auditory cortex is more adaptive to womb-like maternal sounds than to environmental noise. Results are supported by the biological fact that maternal sounds would otherwise be present in utero had the baby not been born prematurely. We theorize that exposure to maternal sounds may provide newborns with the auditory fitness necessary to shape the brain for hearing and language development. Brain development is largely shaped by early sensory experience. However, it is currently unknown whether, how early, and to what extent the newborn’s brain is shaped by exposure to maternal sounds when the brain is most sensitive to early life programming. The present study examined this question in 40 infants born extremely prematurely (between 25- and 32-wk gestation) in the first month of life. Newborns were randomized to receive auditory enrichment in the form of audio recordings of maternal sounds (including their mother’s voice and heartbeat) or routine exposure to hospital environmental noise. The groups were otherwise medically and demographically comparable. Cranial ultrasonography measurements were obtained at 30 ± 3 d of life. Results show that newborns exposed to maternal sounds had a significantly larger auditory cortex (AC) bilaterally compared with control newborns receiving standard care. The magnitude of the right and left AC thickness was significantly correlated with gestational age but not with the duration of sound exposure. Measurements of head circumference and the widths of the frontal horn (FH) and the corpus callosum (CC) were not significantly different between the two groups. This study provides evidence for experience-dependent plasticity in the primary AC before the brain has reached full-term maturation. Our results demonstrate that despite the immaturity of the auditory pathways, the AC is more adaptive to maternal sounds than environmental noise. Further studies are needed to better understand the neural processes underlying this early brain plasticity and its functional implications for future hearing and language development.

\"By the time a baby is born, its brain has nearly 100 billion intricately shaped neurons wired together to comprise a small, soft-matter supercomputer. How is this incredibly complicated organ built in just nine months? This book is a step-by-step guide to what we know about the development of the human brain, from its earliest embryonic origin to birth and a little beyond. Written from an experimental neuroscientist's perspective, this book provides readers with a conceptual understanding of the field of developmental neurobiology, outlining both the biological mechanisms (genetic, environmental, and stochastic) that play significant and interrelated roles in neural development, and how we have come to understand the human brain's construction and function. Highlighting the major questions that have propelled the field forward - including those pushing at the frontiers of the field today - and the stories of major discoveries made by pioneering scientists around the world, the book describes how the structures and mechanisms of the developing brain were discovered. Chapters progress chronologically, tracking the actual growth and development of the human brain from conception to just after birth, as well as the history of how these mechanisms were revealed. Throughout, findings from studies of model organisms, such as nematodes, flies, frogs, fish, birds, mice, and sometimes non-human primates, are woven into the narrative and put into the context of a human embryo or fetus, as there are clear indications that the same processes involving the same genes are found across species. The book concludes with a discussion of what makes individual brains unique and how research on early neural development is helping us better understand the genetic and embryonic origins of many neurological and cognitive traits that only reveal themselves later in life\"-- Provided by publisher.

The blood-brain barrier (BBB) has a key role in maintaining brain homeostasis and, thus, brain function. This Review outlines recent advances in understanding the development and maintenance of the BBB and the contribution of BBB disruption to various neurological diseases. It also discusses how such insights might be used to design new therapeutic strategies for BBB repair. The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair.

Microglia are cells that defend the central nervous system. However, because they migrate into the brain during development, the changes that they undergo, including those that affect gene expression, have been difficult to document. Matcovitch-Natan et al. transcriptionally profiled gene expression and analyzed epigenetic signatures of microglia at the single-cell level in the early postnatal life of mice. They identified three stages of microglia development, which are characterized by gene expression and linked with chromatin changes, occurring in sync with the developing brain. Furthermore, they showed that the proper development of microglia is affected by the microbiome. Science , this issue p. 789 The microbiota help regulate the development of active immune defense in the central nervous system of mice. Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain—early, pre-, and adult microglia—which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.

Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that plays an essential role during brain development. Using genetically engineered mouse model and primary neuronal cells, we identify the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U 34 ). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensures proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlight a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

DHA is an important component of neural lipids accumulating in neural tissue during development. Inadequate DHA in gestation may compromise infant development, but it is unknown whether there are lasting effects. We sought to determine whether the observed effects of fetal DHA inadequacy on infant development persist into early childhood. This follow-up study assessed children (5–6 years) whose mothers received 400 mg/d DHA or a placebo during pregnancy. Child neurodevelopment was assessed with several age-appropriate tests including the Kaufman Assessment Battery for Children. A risk-reduction model was used whereby the odds that a child from the maternal placebo group would fail to achieve a test score in the top quartile was calculated. The association of maternal DHA intake and status in gestation with child test scores, as well as with child DHA intake and status, was also determined. No differences were detected in children (n 98) from the maternal placebo and DHA groups achieving a high neurodevelopment test score (P>0·05). However, maternal DHA status was positively related to child performance on some tests including language and short-term memory. Furthermore, child DHA intake and status were related to the mother’s intake and status in gestation. The neurodevelopment effects of fetal DHA inadequacy may have been lost or masked by other variables in the children. Although we provide evidence that maternal DHA status is related to child cognitive performance, the association of maternal and child DHA intake and status limits the interpretation of whether DHA before or after birth is important.

Insults to the developing brain often result in irreparable damage resulting in long-term deficits in motor and cognitive functions. The only treatment today for hypoxic-ischemic encephalopathy (HIE) in newborns is hypothermia, which has limited clinical benefit. We have studied changes to the blood–brain barriers (BBB) as well as regional cerebral blood flow (rCBF) in a neonatal model of HIE to further understand the underlying pathologic mechanisms. Nine-day old mice pups, brain roughly equivalent to the near-term human fetus, were subjected to hypoxia-ischemia. Hypoxia-ischemia increased BBB permeability to small and large molecules within hours after the insult, which normalized in the following days. The opening of the BBB was associated with changes to BBB protein expression whereas gene transcript levels were increased showing direct molecular damage to the BBB but also suggesting compensatory mechanisms. Brain pathology was closely related to reductions in rCBF during the hypoxia as well as the areas with compromised BBB showing that these are intimately linked. The transient opening of the BBB after the insult is likely to contribute to the pathology but at the same time provides an opportunity for therapeutics to better reach the infarcted areas in the brain.

Understanding the timing of fetal brain vulnerability to inflammatory changes in pregnancy complications is crucial for predicting neurodevelopmental risks. Beyond the placenta, the developing brain’s vascular system is believed to form a secondary defense, the blood–brain barrier (BBB), which restricts harmful substances that could disrupt neurodevelopment. However, the precise timing and mechanisms underlying BBB development are poorly understood. In this study, we examined the spatiotemporal expression of key BBB components and fetal brain vascularization in mice from gestational days (GD) 10 to 18. Fetal brain sections were immunostained to identify BBB components, including CD31, Factor VIII, NG2, and claudin-5. Our results showed that endothelial precursor cells form the primitive vascular network in a caudal-to-rostral gradient by GD10, with pericyte recruitment stabilizing vessels by GD12 in a lateral-to-medial gradient that aligns with neurogenesis, despite some regional exceptions. However, Factor VIII was not detected until GD15, and claudin-5 until GD18, suggesting a significant delay in endothelial maturation and tight junction formation. These findings highlight the critical timing of structural developments in the fetal brain vasculature and its vulnerability to placental diseases, laying the groundwork for future research on the impact of placental disorders on fetal brain development and potential therapeutic interventions.

‘Dysbiosis’ of the maternal gut microbiome, in response to challenges such as infection 1 , altered diet 2 and stress 3 during pregnancy, has been increasingly associated with abnormalities in brain function and behaviour of the offspring 4 . However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain. Small molecules that arise from the maternal gut microbiome in pregnant dams promote fetal thalamocortical axonogenesis in their offspring.