A New Horizon for Understanding the Comparative Effectiveness for Cooling Prospectively Infants with Mild Encephalopathy.

The authors summarize the methodology for a new pragmatic comparative effectiveness research investigation, Cooling Prospectively Infants with Mild Encephalopathy (COOLPRIME), which uses sites' existing mild hypoxic-ischemic encephalopathy (HIE) treatment preference (hypothermia or normothermia) to assess hypothermia effectiveness and safety. COOLPRIME's primary aim is to determine the safety and effectiveness of hypothermia compared to normothermia in mild HIE. Engagement of Families and Community Affected by Hypoxic-Ischemic Encephalopathy strongly favored Effectiveness over Efficacy Trials leading to COOL PRIME design.

Persistence and activity levels of primitive reflexes in young high-level football players.

Introduction: Primitive reflexes (PR) induce involuntary automatic movements in response to specific stimuli. This study aimed to determine the prevalence of active PR in young high-level football players. Methodology: Sixty-nine national-level football players from a French academy were tested (17.0 ± 1.4 years; 69.6 ± 8.0 kg; 178.9 ± 6.9 cm) to evaluate the persistence of PR, following the methodology of the Institute for Neuro-Physiological Psychology (INPP) and the classification by a global score (GS). Based on the sum of seven tests, each was rated between 0 = null and 4 = max. The GS is classified into five categories from no activity to maximal (0-1 = no activity, 2-7 = low, 8-13 = medium, 14-21 = high, and 22-28 = maximal). Result: Around two-thirds (68.1%) of players presented active PR at different activity levels. Among them, a small proportion (7.2%) had medium GS, while 60.9% had a low GS. The GS was not dependent on field position or the age of the players (p > 0.05). However, playing football in an age category higher than their own was associated with significantly more active primitive reflexes (PR) compared to being in their age category (p < 0.01). The results showed that 72.7% of "upgraded" football players had low GS and 18.2% had medium GS, compared to 55.3% and 2.1% in the non-upgraded group. Discussion: The findings of the current study demonstrate that PR could still be active in a healthy population of high-level football players. Practicing a single sport for years and upgrading players could create a negative environment that can ultimately lead to the activation of otherwise integrated PR.

Disrupted neuregulin 1-ErbB4 signaling: Consequences of prenatal morphine exposure in rat pups and molecular gateway to neurological impairment.

Objective: Morphine exposure during pregnancy has detrimental effects on both the mother and her offspring, both during and after childbirth. This study aimed to investigate the impact of prenatal morphine exposure on rat pups and dams, specifically focusing on changes in Neuregulin-1 (Nrg-1)/ErbB4 gene expression, inflammation, and brain-derived neurotrophic factor (BDNF) levels. Materials and methods: Twenty female rats were randomized into two experimental groups:1-Morphine Group: Dams received morphine throughout pregnancy. 2-Control Group: Dams received no interventions.At the end of gestation, blood samples were collected from the dams. Subsequently, dams and their pups underwent tissue collection from the cortical area of the brain to evaluate the following parameters: Interleukin-6 (IL-6), Interleukin-10 (IL-10), total antioxidant capacity (TAC), Malondialdehyde (MDA), and Brain-derived neurotrophic factor (BDNF).Additionally, RNA was extracted from the pup's cortical brain tissue for the assessment of gene expression levels of Neuregulin-1 (NRG-1) and ErbB-4 using quantitative real-time polymerase chain reaction (qrt-PCR). Results: The molecular investigation revealed a decrease in NRG-1 and ErbB-4 expressions in the brain cortex of offspring exposed to morphine during prenatal development. Additionally, the levels of IL-6 and IL-10 in both the serum and brain of both the mothers and their offspring in the morphine group were significantly higher compared to the control group. The morphine-exposed group also exhibited significantly lower levels of TAC and higher levels of MDA, indicating increased oxidative stress. Furthermore, the levels of BDNF in the morphine group were significantly lower compared to the control group. Conclusion: Prenatal morphine exposure in rats has detrimental effects on both the dams and their offspring. This study demonstrates that prenatal morphine exposure disrupts critical molecular pathways involved in neurodevelopment, inflammation, oxidative stress, and neurotrophic signaling. These findings suggest that prenatal morphine exposure can have long-lasting consequences for the offspring, potentially contributing to neurodevelopmental disorders and other health issues later in life.

MicroRNAs: a symphony orchestrating evolution and disease dynamics.

The genesis of human disease lies in our evolutionary past. Evolution has featured a general trend towards increased morphological complexity, partly conferred by expansion in gene regulatory capacity via microRNA (miRNA) innovation. Many human diseases are directly related to the evolved roles of these miRNAs, and miRNA-based therapies are emerging as an appealing strategy for precision medicine. We focus on three categories of human disease - cancer, inflammation-linked pathologies, and neurological disorders - which are highly prevalent and are associated with substantial disease burden worldwide. In each category we discuss the pathogenic roles of miRNAs in the context of their evolved functions, as well as current and potential advances in targeting these miRNAs for disease therapy.

Maternal antenatal depression is associated with metabolic alterations that predict birth outcomes, neurodevelopment and mental health of the child.

BACKGROUND: Evidence regarding metabolic alterations associated with maternal antenatal depression (AD) is limited, and their role as potential biomarkers improving the prediction of AD and adverse child birth, neurodevelopmental, and mental health outcomes remains unexplored. METHODS: In a cohort of 331 mother-child dyads, we studied associations between AD (history of medical register diagnoses and/or Center of Epidemiological Studies Depression Scale score during pregnancy≥20) and 95 metabolic measures analyzed three times during pregnancy. We tested whether the AD-related metabolic measures increased variance explained in AD over its risk factors, and in child birth, neurodevelopmental, and mental health outcomes over AD. We replicated the findings in a cohort of 416 mother-child dyads. RESULTS: Elastic net regression identified 15 metabolic measures that collectively explained 25% (p<0.0001) of variance in AD, including amino and fatty acids, glucose, inflammation, and lipids. These metabolic measures increased the variance explained in AD over its risk factors (32.3%,p<0.0001 vs. 12.6%,p=0.004), and in child gestational age (9.0%,p<0.0001 vs. 0.7%, p=0.34), birth weight(9.0%,p=0.03 vs. 0.7%, p=0.33), developmental milestones at the age of 2.3-5.7 years(21.0%,p=0.002 vs. 11.6%,p<0.001) and any mental or behavioral disorder by the age of 13.1-16.8 years(25.2%,p=0.03 vs. 5.0%,p=0.11) over AD, child sex and age. These findings replicated in the independent cohort. CONCLUSIONS: AD is associated with alterations in 15 metabolic measures, which collectively improve the prediction of AD over its risk factors, and birth, neurodevelopmental and mental health outcomes of the child over AD. These metabolic measures may become biomarkers identifying at-risk mothers and children for personalized interventions.

Associations between body weight trajectories and neurodevelopment outcomes at 24 months corrected age in very-low-birth-weight preterm infants: a group-based trajectory modelling study.

Introduction: This study aimed to explore the relationship between the trajectories of body weight (BW) z-scores at birth, discharge, and 6 months corrected age (CA) and neurodevelopmental outcomes at 24 months CA. Methods: Conducted as a population-based retrospective cohort study across 21 hospitals in Taiwan, we recruited 3,334 very-low-birth-weight (VLBW) infants born between 2012 and 2017 at 23-32 weeks of gestation. Neurodevelopmental outcomes were assessed at 24 months CA. Instances of neurodevelopmental impairment (NDI) were defined by the presence of at least one of the following criteria: cerebral palsy, severe hearing loss, profound vision impairment, or cognitive impairment. Group-based trajectory modeling was employed to identify distinct BW z-score trajectory groups. Multivariable logistic regression was used to assess the associations between these trajectories, postnatal comorbidity, and neurodevelopmental impairments. Results: The analysis identified three distinct trajectory groups: high-climbing, mid-declining, and low-declining. Significant associations were found between neurodevelopmental impairments and both cystic periventricular leukomalacia (cPVL) [with an adjusted odds ratio (aOR) of 3.59; p < 0.001] and belonging to the low-declining group (aOR: 2.59; p < 0.001). Discussion: The study demonstrated that a low-declining pattern in body weight trajectory from birth to 6 months CA, along with cPVL, was associated with neurodevelopmental impairments at 24 months CA. These findings highlight the importance of early weight trajectory and specific health conditions in predicting later neurodevelopmental outcomes in VLBW infants.

Neurodevelopmental profiles of 14 individuals with phosphomannomutase deficiency (PMM2-CDG).

PMM2-CDG (formerly CDG-1a), the most common type of congenital disorders of glycosylation, is inherited in an autosomal recessive pattern. PMM2-CDG frequently presents in infancy with multisystemic clinical involvement, and it has been diagnosed in over 1000 people worldwide. There have been few natural history studies reporting neurodevelopmental characterization of PMM2-CDG. Thus, a prospective study was conducted that included neurodevelopmental assessments as part of deep phenotyping. This study, Clinical and Basic Investigations into Known and Suspected Congenital Disorders of Glycosylation (NCT02089789), included 14 participants (8 males and 6 females ages 2-33 years) with a confirmed molecular diagnosis of PMM2-CDG. Clinical features of PMM2-CDG in this cohort were neurodevelopmental disorders, faltering growth, hypotonia, cerebellar atrophy, peripheral neuropathy, movement disorders, ophthalmological abnormalities, and auditory function differences. All PMM2-CDG participants met criteria for intellectual disability (or global developmental delay if younger than age 5). The majority never attained certain gross motor and language milestones. Only two participants were ambulatory, and almost all were considered minimally verbal. Overall, individuals with PMM2-CDG present with a complex neurodevelopmental profile characterized by intellectual disability and multisystemic presentations. This systematic quantification of the neurodevelopmental profile of PMM2-CDG expands our understanding of the range in impairments associated with PMM2-CDG and will help guide management strategies.

The role of primary cilia in congenital heart defect-associated neurological impairments.

Congenital heart disease (CHD) has, despite significant improvements in patient survival, increasingly become associated with neurological deficits during infancy that persist into adulthood. These impairments afflict a wide range of behavioral domains including executive function, motor learning and coordination, social interaction, and language acquisition, reflecting alterations in multiple brain areas. In the past few decades, it has become clear that CHD is highly genetically heterogeneous, with large chromosomal aneuploidies and copy number variants (CNVs) as well as single nucleotide polymorphisms (SNPs) being implicated in CHD pathogenesis. Intriguingly, many of the identified loss-of-function genetic variants occur in genes important for primary cilia integrity and function, hinting at a key role for primary cilia in CHD. Here we review the current evidence for CHD primary cilia associated genetic variants, their independent functions during cardiac and brain development and their influence on behavior. We also highlight the role of environmental exposures in CHD, including stressors such as surgical factors and anesthesia, and how they might interact with ciliary genetic predispositions to determine the final neurodevelopmental outcome. The multifactorial nature of CHD and neurological impairments linked with it will, on one hand, likely necessitate therapeutic targeting of molecular pathways and neurobehavioral deficits shared by disparate forms of CHD. On the other hand, strategies for better CHD patient stratification based on genomic data, gestational and surgical history, and CHD complexity would allow for more precise therapeutic targeting of comorbid neurological deficits.

Neurological Disorders Induced by Drug Use: Effects of Adolescent and Embryonic Drug Exposure on Behavioral Neurodevelopment.

Clinical studies demonstrate that the risk of developing neurological disorders is increased by overconsumption of the commonly used drugs, alcohol, nicotine and cannabis. These drug-induced neurological disorders, which include substance use disorder (SUD) and its co-occurring emotional conditions such as anxiety and depression, are observed not only in adults but also with drug use during adolescence and after prenatal exposure to these drugs, and they are accompanied by long-lasting disturbances in brain development. This report provides overviews of clinical and preclinical studies, which confirm these adverse effects in adolescents and the offspring prenatally exposed to the drugs and include a more in-depth description of specific neuronal systems, their neurocircuitry and molecular mechanisms, affected by drug exposure and of specific techniques used to determine if these effects in the brain are causally related to the behavioral disturbances. With analysis of further studies, this review then addresses four specific questions that are important for fully understanding the impact that drug use in young individuals can have on future pregnancies and their offspring. Evidence demonstrates that the adverse effects on their brain and behavior can occur: (1) at low doses with short periods of drug exposure during pregnancy; (2) after pre-conception drug use by both females and males; (3) in subsequent generations following the initial drug exposure; and (4) in a sex-dependent manner, with drug use producing a greater risk in females than males of developing SUDs with emotional conditions and female offspring after prenatal drug exposure responding more adversely than male offspring. With the recent rise in drug use by adolescents and pregnant women that has occurred in association with the legalization of cannabis and increased availability of vaping tools, these conclusions from the clinical and preclinical literature are particularly alarming and underscore the urgent need to educate young women and men about the possible harmful effects of early drug use and to seek novel therapeutic strategies that might help to limit drug use in young individuals.

Examining cognition and brain networks using magnetoencephalography in paediatric autoimmune encephalitis and acute disseminated encephalomyelitis: a preliminary study.

Paediatric autoimmune encephalitis, including acute disseminated encephalomyelitis, are inflammatory brain diseases presenting with cognitive deficits, psychiatric symptoms, seizures, MRI and EEG abnormalities. Despite improvements in disease recognition and early immunotherapy, long-term outcomes in paediatric autoimmune encephalitis remain poor. Our aim was to understand functional connectivity changes that could be associated with negative developmental outcomes across different types of paediatric autoimmune encephalitis using magnetoencephalography. Participants were children diagnosed with paediatric autoimmune encephalitis at least 18 months before testing and typically developing children. All completed magnetoencephalography recording at rest, T1 MRI scans and neuropsychology testing. Brain connectivity (specifically in delta and theta) was estimated with amplitude envelope correlation, and network efficiency was measured using graph measures (global efficiency, local efficiency and modularity). Twelve children with paediatric autoimmune encephalitis (11.2 ± 3.5 years, interquartile range 9 years; 5M:7F) and 12 typically developing controls (10.6 ± 3.2 years, interquartile range 7 years; 8M:4F) participated. Children with paediatric autoimmune encephalitis did not differ from controls in working memory (t(21) = 1.449; P = 0.162; d = 0.605) but had significantly lower processing speed (t(21) = 2.463; P = 0.023; Cohen's d = 1.028). Groups did not differ in theta network topology measures. The paediatric autoimmune encephalitis group had a significantly lower delta local efficiency across all thresholds tested (d = -1.60 at network threshold 14%). Theta modularity was associated with lower working memory (ß = -0.781; t(8) = -2.588, P = 0.032); this effect did not survive correction for multiple comparisons (P(corr) = 0.224). Magnetoencephalography was able to capture specific network alterations in paediatric autoimmune encephalitis patients. This preliminary study demonstrates that magnetoencephalography is an appropriate tool for assessing children with paediatric autoimmune encephalitis and could be associated with cognitive outcomes.

Early life stress and iron metabolism in developmental psychoneuroimmunology.

An estimated 250 million children face adverse health outcomes from early life exposure to severe or chronic social, economic, and nutritional adversity, highlighting/emphasizing the pressing concern about the link between ELS and long-term implications on mental and physical health. There is significant overlap between populations experiencing high levels of chronic stress and those experiencing iron deficiency, spotlighting the potential role of iron as a key mediator in this association. Iron, an essential micronutrient for brain development and immune function, is often depleted in stress conditions. Iron deficiency among the most common nutrient deficiencies in the world. Fetal and infant iron status may thus serve as a crucial intermediary between early chronic psychological stress and subsequent immune system changes to impact neurodevelopment. The review presents a hypothesized pathway between early life stress (ELS), iron deficiency, and neurodevelopment through the hypothalamic-pituitary-adrenocortical (HPA) axis and the IL-6-hepcidin axis. This hypothesis is derived from (1) evidence that stress impacts iron status (2) long-term neurodevelopmental outcomes that are shared by ELS and iron deficiency exposure, and (3) possible mechanisms for how iron may mediate the relation between ELS and iron deficiency through alterations in the developing immune system. The article concludes by proposing future research directions, emphasizing the need for rigorous studies to elucidate how stress and iron metabolism interact to modify the developing immune system. Understanding these mechanisms could open new avenues for improving human health and neurodevelopment for women and children globally, making it a timely and vital area of study in psychoneuroimmunology research.

Comparing Neurodevelopmental Outcomes in Infants With Patent Ductus Arteriosus Stenting Versus Blalock-Taussig-Thomas Shunt: A Pilot Study.

Background: Patent ductus arteriosus stenting (PDAS) is a nonsurgical alternative to Blalock-Taussig-Thomas shunt (BTTS) for infants with ductal-dependent congenital heart disease. In this single-center study, we aimed to compare neurodevelopmental outcomes in children who underwent BTTS as initial palliation versus PDAS. Methods: Bayley Scales of Infant and Toddler Development Screening Test (Bayley-III) reports and mode of feeding data were collected for any patient who underwent PDAS or BTTS at Rady Children's Hospital from 2013 to 2021. We also prospectively administered the Parents' Evaluation of Development Status questionnaire (PEDS) to parents of children aged 2-8 years in this patient population. Results: Of the 99 patients, 64 received a Bayley-III assessment and/or PEDS screen. Of the 35 who had a Bayley-III, there was a higher proportion of patients with PDAS who scored as developmentally appropriate compared with BTTS. PEDS screen showed that a higher proportion of patients with PDAS had no parental concern for delay than that of patients with BTTS (63% vs 30%). Patients with BTTS were more likely to undergo gastrostomy tube placement than patients with PDAS. Conclusions: Our study suggests that neurodevelopmental measures are feasible, clinically relevant, and should be included in comparative effectiveness studies of infant congenital interventions. Whether PDAS offers neurodevelopmental benefit over BTTS should be confirmed in a prospective powered randomized controlled clinical trial.

Prenatal broad-spectrum cannabidiol administration prevents an autism-like phenotype in male offspring from a maternal stress/terbutaline rat model.

Recently, the diagnosis of autism spectrum disorder (ASD) has increased from 1 in 150 to every 1 in 36 children in the United States, warranting a need for novel prevention and therapeutic strategies. Broad-spectrum cannabidiol oil, free from delta-9-tetrahydrocannabinol, the psychoactive component of cannabis, may be one such therapeutic. It has a high safety profile and is frequently used as a complementary and integrative intervention by persons experiencing symptoms of anxiety, stress, and inflammation. Using a neurodevelopmental rat model of ASD (based on neuroinflammation induced by stress and terbutaline exposure during pre- and postnatal development), we sought to prevent the development of ASD-like behaviors in male offspring by administering broad-spectrum cannabidiol oil to dams throughout pregnancy (10 mg/kg, i.p., daily, embryonic days 3-16). To assess an ASD-like phenotype in the offspring, we used three behavioral measures relevant to three core ASD symptoms: 1) social communication (time spent vocalizing when alone); 2) repetitive behavior (marbles buried during a marble burying test); and 3) social interaction (time spent interacting with a novel conspecific during the three-chamber social interaction test). Broad-spectrum cannabidiol oil given during pregnancy decreased scores for all three ASD-related behavioral responses, resulting in an overall significant prevention of the ASD-like phenotype. These findings highlight the potential of broad-spectrum cannabidiol oil as a complementary and integrative approach for prevention of stressor-induced sequelae relevant to development of an ASD-like phenotype.

Is an Exclusive Human Milk Diet at the Time of Neonatal Intensive Care Unit Discharge Adequate to Maintain Growth and Neurodevelopment among Very Preterm Infants?

Background: An exclusive human milk (EHM) diet has numerous benefits. Formula supplementation may be recommended for former preterm infants at the time of neonatal intensive care unit (NICU) discharge to meet perceived metabolic demands and caloric goals. Recommendations addressing postdischarge nutrition for very preterm infants (VPTIs) are controversial, as the benefits of human milk supplementation regarding long-term growth, neurodevelopment, and chronic conditions are mixed. Objective: To compare growth and neurodevelopment of former VPTI fed an EHM diet to a supplemented/formula diet at NICU discharge. Materials and Methods: A retrospective cohort study of VPTI was followed at the Regional Neonatal Follow-up Program. Patients were categorized by diet at NICU discharge: EHM diet; mixed diet (EHM and formula); and exclusive formula diet. Growth percentile ranks at the first neonatal follow-up visit and 3 years of age were compared by diet type at NICU discharge. Neurodevelopmental outcomes as measured by the Bayley Scales of Infant Development 3rd Edition at 3 years of age were also compared. Results: Among 835 VPTIs, weight percentiles at the first neonatal follow-up visit were similar between the three NICU discharge diet types. One hundred fifty-eight subjects received neurodevelopmental evaluations at 3 years of age; anthropometrics and neurodevelopment were similar irrespective of diet at NICU discharge. Conclusion: An EHM diet at NICU discharge is appropriate to support growth in infancy as well as growth and neurodevelopment through 3 years of age. Thus, this raises the question of whether routine nutritional supplementation is necessary for VPTIs at NICU discharge.

Impaired motor and social skill development in infancy predict high autistic traits in toddlerhood.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder. Early diagnosis in the critical period is important for ASD children. Recent studies of neurodevelopmental behavioral features and joint attention in high-risk infants showed there are some special cues which can distinguish ASD from typical development infant. But the findings of high-risk population may not be applicable to the general population. It is necessary to "analogically" study the potential warning traits of ASD in infancy in the general population. We did a nested case-control study from June 2019 to November 2022 in Tianjin, China, including 76 general infants whom completed the neurodevelopmental evaluation, the Checklist for Autism in Toddlers-23 (CHAT-23) screening, and eye tracking task. Social behavior quotient in infancy was negatively correlated to CHAT-23 total scores in toddlerhood. Social behavior quotient in infancy was positively correlated to initiating joint attention in toddlerhood. Regression model showed that high fine motor scale and social behaviour scale quotient in infancy were associated with an decreased risk of the total score of CHAT-23 ≥ 2 in toddlerhood. The Receiver operating characteristic curve showed the social behaviour in infancy alone and the combination of fine motor and social behaviour in infancy contributed to auxiliary diagnosis of higher level of autistic traits in toddlerhood. These findings suggest that Impaired development of fine motor and social behavior in infancy are potential warning features of high autistic traits in general population.

Head circumference growth in children with Autism Spectrum Disorder: trend and clinical correlates in the first five years of life.

Background: Macrocephaly is described in almost 15% of children with Autism Spectrum Disorder (ASD). Relationships between head growth trajectories and clinical findings in ASD children show a high degree of variability, highlighting the complex heterogeneity of the disorder. Objectives: The aim of this study was to measure differences of the early growth trajectory of head circumference (HC) in children with ASD and macrocephaly compared to ASD normocephalic children, examining clinical correlates in the two groups of patients. Methods: HC data were collected from birth to 5 years of age in a sample of children with a confirmed diagnosis of ASD. Participants were classified into two groups: ASD macrocephaly (ASD-M, Z-scores ≥1.88 in at least two consecutive HC measurements), and ASD non-macrocephaly (ASD-N). Based on the distribution of HC measurements (Z-scores), five age groups were identified for the longitudinal study. Developmental and behavioral characteristics of the ASD-M children compared to the ASD-N group were compared by using standardized scores. Results: 20,8% of the children sample met criteria for macrocephaly. HC values became indicative of macrocephaly in the ASD-M group at the age range from 1 to 6 months, and persisted thereafter throughout the first five years of age. ASD-M children showed significantly higher developmental quotients of Griffiths III B and D subscales compared to ASD-N group. No significant differences in the severity of ASD symptoms assessed by ADOS-2 were observed between ASD-M and ASD-N groups. Conclusion: In this study HC size from birth to 5 years links to accelerated HC growth rate as early as the first 6 months of age in children with ASD and macrocephaly, preceding the onset and diagnosis of ASD. We found that in early childhood, children with ASD-M may exhibit some advantages in language and social communication and emotional skills without differences in autism severity, when compared with age-matched normocephalic ASD children. Longitudinal analyses are required to catch-up prospectively possible relationships between head size as proxy measure of brain development and neuro-developmental and behavioral features in children with ASD.

Neurogenesis in Caenorhabditis elegans.

Animals rely on their nervous systems to process sensory inputs, integrate these with internal signals, and produce behavioral outputs. This is enabled by the highly specialized morphologies and functions of neurons. Neuronal cells share multiple structural and physiological features, but they also come in a large diversity of types or classes that give the nervous system its broad range of functions and plasticity. This diversity, first recognized over a century ago, spurred classification efforts based on morphology, function, and molecular criteria. Caenorhabditis elegans, with its precisely mapped nervous system at the anatomical level, an extensive molecular description of most of its neurons, and its genetic amenability, has been a prime model for understanding how neurons develop and diversify at a mechanistic level. Here, we review the gene regulatory mechanisms driving neurogenesis and the diversification of neuron classes and subclasses in C. elegans. We discuss our current understanding of the specification of neuronal progenitors and their differentiation in terms of the transcription factors involved and ensuing changes in gene expression and chromatin landscape. The central theme that has emerged is that the identity of a neuron is defined by modules of gene batteries that are under control of parallel yet interconnected regulatory mechanisms. We focus on how, to achieve these terminal identities, cells integrate information along their developmental lineages. Moreover, we discuss how neurons are diversified postembryonically in a time-, genetic sex-, and activity-dependent manner. Finally, we discuss how the understanding of neuronal development can provide insights into the evolution of neuronal diversity.

Direct breastfeeding: Predictive factors and possible effects on neurodevelopment in very preterm infants.

BACKGROUND: the importance of sucking milk directly at the mother's breast is often underestimated and many aspects of direct breastfeeding of very preterm infants are not investigated. AIM: The primary endpoint of the study was to identify maternal and infant clinical predictors of direct breastfeeding in a cohort of infants born at <32 weeks of gestation or weighing <1500 g. The secondary endpoint was to evaluate the possible effects of direct breastfeeding on infant neurodevelopment. STUDY DESIGN: Seventy-two infants born between July 2018 and December 2019 were divided into the subgroup that were directly breastfed (n = 42) and not directly breastfed (n = 30) at discharge. Maternal and infant characteristics were compared, and differences were analysed. RESULTS: Logistic regression analysis demonstrated that the percentage of maternal milk taken during hospitalization, maternal age, and weight (z-score) at discharge were positively correlated with the likelihood of direct breastfeeding at discharge. Direct breastfeeding was not correlated with the cognitive score at 24 months corrected age. CONCLUSIONS: Direct breastfeeding at discharge is more probable in infants of older mothers who receive more breastmilk and who experience greater weight gain. Direct breastfeeding is not correlated with the cognitive score at 24 months corrected age.

Emerging X-linked genes associated with neurodevelopmental disorders in females.

A significant source of risk for neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorder (ASD), lies in genes located on the X chromosome. Males can be particularly vulnerable to X-linked variation because of hemizygosity, and male-specific segregation in pedigrees has guided earlier gene discovery for X-linked recessive conditions. More recently, X-linked disorders disproportionally affecting females, with complex inheritance patterns and/or presenting with sex differences, have surfaced. Here, we discuss the genetics and neurobiology of X-linked genes that are paradigmatic to understand NDDs in females. Integrating genetic, clinical, and functional data will be key to understand how X-linked variation contributes to the risk architecture of NDDs.

Molecular Characterization and Expression of Lactoferrin Receptor (LfR) in Different Regions of the Brain Responding to Lactoferrin Intervention.

Lactoferrin (LF), an iron-binding glycoprotein rich in human milk, promotes neurodevelopment and cognition, but whether it acts through the LF receptor (LfR) and its expression profile in the brain remains unknown. We characterized 972 bp of piglet brain LfR cDNA and found LfR mRNA was expressed all brain regions being highest in the frontal lobe, followed by parietal lobe, brainstem, occipital lobe, cingulate gyrus, subventricular zone, olfactory bulb, hippocampus, amygdala, cerebellum, and thalamus. LfR mRNA and protein in different regions of the brain responded to low (155 mg/kg/day) and high (285 mg/kg/day) LF supplementation of piglets from postnatal days 3 to 38. By postnatal day 39, the low LF diet significantly increased LfR protein expression in the occipital lobe compared to controls, but not the high LF diet. LfR protein in the subventricular zone of the high LF group was 42% and 38% higher than that of the low LF group and controls, respectively. There was a trend for a dose-response relationship between LF intervention and LfR protein expression only in the prefrontal and parietal lobes. LF supplementation significantly improved piglet working memory for a difficult task, which was positively correlated with LfR protein in the prefrontal, parietal, and occipital lobes, but no dose response. Brain LfR responds to dietary LF supplementation, a mechanism by which LF can promote learning and working memory through its receptor. LfR is expressed in the whole brain, and its expression level is anatomic region specific.