Critical Neonatal Period Research Articles

Sleep-sensitive dopamine receptor expression in male mice underlies attention deficits after a critical period of early adversity.

Early life stress (ELS) yields cognitive impairments of unknown molecular and physiological origin. We found that fragmented maternal care of mice during a neonatal critical period from postnatal days P2-9 elevated dopamine receptor D2R and suppressed D4R expression, specifically within the anterior cingulate cortex (ACC) in only the male offspring. This was associated with poor performance on a two-choice visual attention task, which was acutely rescued in adulthood by local or systemic pharmacological rebalancing of D2R/D4R activity. Furthermore, ELS male mice demonstrated heightened hypothalamic orexin and persistently disrupted sleep. Given that acute sleep deprivation in normally reared male mice mimicked the ACC dopamine receptor subtype modulation and disrupted attention of ELS mice, sleep loss likely underlies cognitive deficits in ELS mice. Likewise, sleep impairment mediated the attention deficits associated with early adversity in human children, as demonstrated by path analysis on data collected with multiple questionnaires for a large child cohort. A deeper understanding of the sex-specific cognitive consequences of ELS thus has the potential to reveal therapeutic strategies for overcoming them.

Neonatal mortality rate and determinants among births of mothers at extreme ages of reproductive life in low and middle income countries

Neonatal mortality, which refers to the death of neonates during the first 28 completed days of life, is a critical global public health concern. The neonatal period is widely recognized as one of the most precarious phases in human life. Research has indicated that maternal extreme ages during reproductive years significantly impact neonatal survival, particularly in low- and middle-income countries. Consequently, this study aims to evaluate the neonatal mortality rate and determinants among neonates born to mothers at extreme reproductive ages within these countries. A secondary analysis of demographic and health surveys conducted between 2015 and 2022 in 43 low- and middle-income countries was performed. The study included a total sample of 151,685 live births. Researchers utilized a multilevel mixed-effects model to identify determinants of neonatal mortality. The measures of association were evaluated using the adjusted odds ratio within a 95% confidence interval. The neonatal mortality rate among neonates born to mothers at extreme ages of reproductive life in low- and middle-income countries was 28.96 neonatal deaths per 1000 live births (95% CI 28.13–29.82). Factors associated with higher rates of neonatal mortality include male gender, low and high birth weight, maternal education (no or low), home deliveries, multiple births, short preceding birth intervals, lack of postnatal checkups, and countries with high fertility and low literacy rates. This study sheds light on the neonatal mortality rates among neonates born to mothers at extreme ages of reproductive life in low- and middle-income countries. Notably, we found that neonatal mortality was significantly higher in this group compared to neonatal mortality rates reported regardless of maternal ages. Male babies, low and high birth-weighted babies, those born to mothers with no or low education, delivered at home, singletons, babies born with a small preceding birth interval, and those without postnatal checkups faced elevated risks of neonatal mortality. Additionally, neonates born in countries with high fertility and low literacy rates were also vulnerable. These findings underscore the urgent need for targeted interventions tailored to mothers at extreme ages. Policymakers and healthcare providers should prioritize strategies that address specific risk factors prevalent in these vulnerable populations. By doing so, we can improve neonatal outcomes and ensure the survival of these newborns during the critical neonatal period.

Neonatal GABAergic transmission primes vestibular gating of output for adult spatial navigation

GABAergic interneurons are poised with the capacity to shape circuit output via inhibitory gating. How early in the development of medial vestibular nucleus (MVN) are GABAergic neurons recruited for feedforward shaping of outputs to higher centers for spatial navigation? The role of early GABAergic transmission in assembling vestibular circuits for spatial navigation was explored by neonatal perturbation. Immunohistochemistry and confocal imaging were utilized to reveal the expression of parvalbumin (PV)-expressing MVN neurons and their perineuronal nets. Whole-cell patch-clamp recording, coupled with optogenetics, was conducted in vitro to examine the synaptic function of MVN circuitry. Chemogenetic targeting strategy was also employed in vivo to manipulate neuronal activity during navigational tests. We found in rats a neonatal critical period before postnatal day (P) 8 in which competitive antagonization of GABAergic transmission in the MVN retarded maturation of inhibitory neurotransmission, as evidenced by deranged developmental trajectory for excitation/inhibition ratio and an extended period of critical period-like plasticity in GABAergic transmission. Despite increased number of PV-expressing GABAergic interneurons in the MVN, optogenetic-coupled patch-clamp recording indicated null-recruitment of these neurons in tuning outputs along the ascending vestibular pathway. Such perturbation not only offset output dynamics of ascending MVN output neurons, but was further accompanied by impaired vestibular-dependent navigation in adulthood. The same perturbations were however non-consequential when applied after P8. Results highlight neonatal GABAergic transmission as key to establishing feedforward output dynamics to higher brain centers for spatial cognition and navigation.

Short-term Dendritic Dynamics of Neonatal Cortical Neurons Revealed by in vivo Imaging with Improved Spatiotemporal Resolution.

Individual neurons in sensory cortices exhibit specific receptive fields based on their dendritic patterns. These dendritic morphologies are established and refined during the neonatal period through activity-dependent plasticity. This process can be visualized using two-photon in vivo time-lapse imaging, but sufficient spatiotemporal resolution is essential. We previously examined dendritic patterning from spiny stellate (SS) neurons, the major type of layer 4 (L4) neurons, in the mouse primary somatosensory cortex (barrel cortex), where mature dendrites display a strong orientation bias toward the barrel center. Longitudinal imaging at 8-h intervals revealed the long-term dynamics by which SS neurons acquire this unique dendritic pattern. However, the spatiotemporal resolution was insufficient to detect the more rapid changes in SS neuron dendrite morphology during the critical neonatal period. In the current study, we imaged neonatal L4 neurons hourly for 8 h and improved the spatial resolution by uniform cell-surface labeling. The improved spatiotemporal resolution allowed detection of precise changes in dendrite morphology and revealed aspects of short-term dendritic dynamics unique to the neonatal period. Basal dendrites of barrel cortex L4 neurons were highly dynamic. In particular, both barrel-inner and barrel-outer dendrites (trees and branches) emerged/elongated and disappeared/retracted at similarly high frequencies, suggesting that SS neurons acquire biased dendrite patterns through rapid trial-and-error emergence, elongation, elimination, and retraction of dendritic trees and branches. We also found correlations between morphology and behavior (elongation/retraction) of dendritic tips. Thus, the current study revealed short-term dynamics and related features of cortical neuron dendrites during refinement.Significance StatementThe formation of proper dendritic patterns during early postnatal development is essential for normal neuronal circuit function in adulthood. To elucidate the mechanisms responsible for this refinement, in vivo imaging with high spatiotemporal resolution is useful. Our previous long-term in vivo imaging studies have clarified aspects of dendritic refinement mechanism; however, due to the long intervals (8-h) between image acquisitions, rapid changes in dendritic morphology were missed. Here hourly in vivo time-lapse imaging of neonatal mouse barrel cortex over 8 h revealed the rapid changes in the dendrite morphology of layer 4 neurons, thereby providing a more comprehensive record of dendritic refinement during postnatal development for mechanistic analysis.

Anatomical changes in descending serotonergic projections from the rostral ventromedial medulla to the spinal dorsal horn following repetitive neonatal painful procedures

AbstractExcessive noxious stimulation during the critical neonatal period impacts the nociceptive network lasting into adulthood. As descending serotonergic projections from the rostral ventromedial medulla (RVM) to the spinal dorsal horn develop postnatally, this study aims to investigate the long‐term effect of repetitive neonatal procedural pain on the descending serotonergic RVM–spinal dorsal horn network. A well‐established rat model of repetitive noxious procedures is used in which neonatal rats received four noxious needle pricks or tactile stimulation with a cotton swab per day in the left hind paw from day of birth to postnatal Day 7. Control animals were left undisturbed. When animals reached adulthood, tissue was collected for quantitative immunohistochemical analysis of serotonin (5‐hydroxytryptamine, 5‐HT) in the RVM and spinal dorsal horn. Both repetitive noxious and tactile procedures in the neonate decreased the 5‐HT staining intensity in the adult ipsilateral but not contralateral spinal dorsal horn. Repetitive neonatal noxious procedures resulted in an increased area covered with 5‐HT staining in the adult RVM ipsilateral to the side of injury, whereas repetitive neonatal tactile stimulation resulted in increased 5‐HT staining intensity in both the ipsi‐ and contralateral RVM. The number of 5‐HT cells in adult RVM is unaffected by neonatal conditions. This detailed anatomical study shows that not only neonatal noxious procedures but also repetitive tactile procedures result in long‐lasting anatomical changes of the descending serotonergic system within the RVM and spinal dorsal horn. Future studies should investigate whether these anatomical changes translate to functional differences in descending serotonergic modulation after neonatal adverse experiences.

The olfactory critical period is determined by activity-dependent Sema7A/PlxnC1 signaling within glomeruli

In mice, early exposure to environmental odors affects social behaviors later in life. A signaling molecule, Semaphorin 7A (Sema7A), is induced in the odor-responding olfactory sensory neurons. Plexin C1 (PlxnC1), a receptor for Sema7A, is expressed in mitral/tufted cells, whose dendrite-localization is restricted to the first week after birth. Sema7A/PlxnC1 signaling promotes post-synaptic events and dendrite selection in mitral/tufted cells, resulting in glomerular enlargement that causes an increase in sensitivity to the experienced odor. Neonatal odor experience also induces positive responses to the imprinted odor. Knockout and rescue experiments indicate that oxytocin in neonates is responsible for imposing positive quality on imprinted memory. In the oxytocin knockout mice, the sensitivity to the imprinted odor increases, but positive responses cannot be promoted, indicating that Sema7A/PlxnC1 signaling and oxytocin separately function. These results give new insights into our understanding of olfactory imprinting during the neonatal critical period.

Increased Excitability and Heightened Magnitude of Long-Term Potentiation at Hippocampal CA3-CA1 Synapses in a Mouse Model of Neonatal Hyperoxia Exposure.

Preterm infants exposed to supraphysiological oxygen (hyperoxia) during the neonatal period have hippocampal atrophy and cognitive dysfunction later in childhood and as adolescents. Previously, we reported that 14-week-old adult mice exposed to hyperoxia as newborns had spatial memory deficits and hippocampal shrinkage, findings that mirror those of human adolescents who were born preterm. The area CA1 region of the hippocampus that is crucial for spatial learning and memory is highly vulnerable to oxidative stress. In this study, we investigated the long-term impact of neonatal hyperoxia exposure on hippocampal CA3–CA1 synaptic function. Male and female C57BL/6J mouse pups were continuously exposed to either 85% normobaric oxygen or air between postnatal days 2–14. Hippocampal slice electrophysiology at CA3–CA1 synapses was then performed at 14 weeks of age. We observed that hyperoxia exposed mice have heightened strength of basal synaptic transmission measured in input-output curves, increased fiber volley amplitude indicating increased axonal excitability, and heightened LTP magnitude at CA3–CA1 synapses, likely a consequence of increased postsynaptic depolarization during tetanus. These data demonstrate that supraphysiological oxygen exposure during the critical neonatal developmental period leads to pathologically heightened CA3–CA1 synaptic function during early adulthood which may contribute to hippocampal shrinkage and learning and memory deficits we previously reported. Furthermore, these results will help shed light on the consequences of hyperoxia exposure on the development of hippocampal synaptic circuit abnormalities that could be contributing to cognitive deficits in children born preterm.

Metabolomics and adductomics of newborn bloodspots to retrospectively assess the early-life exposome.

Exposomics studies can measure health-relevant chemical exposures during a lifetime and estimate the 'internal' environment. However, sampling limitations make these features difficult to capture directly during the critical neonatal time period. We review the use of newborn dried bloodspots (DBS) archived from newborn screening programs for exposomic analysis in epidemiological children's health studies. Emerging 'omics technologies such as adductomics and metabolomics have been adapted for DBS analysis, and these technologies can now provide valuable etiological information on the complex interplay between exposures, biological response, and population phenotypes. Adductomics and metabolomics of DBS can provide robust measurements for retrospective epidemiological investigations. With extensive bioarchiving programs in the United States and other countries, DBS are poised to substantially aid epidemiological studies, particularly for rare and low-frequency childhood diseases and disorders.

Female rats are more vulnerable to lasting cognitive impairment after isoflurane exposure on postnatal day 4 than 7

BackgroundThe factors determining peak susceptibility of the developing brain to anaesthetics are unclear. It is unknown why postnatal day 7 (P7) male rats are more vulnerable to anaesthesia-induced memory deficits than littermate females. Given the precocious development of certain regions in the female brain during the neonatal critical period, we hypothesised that females are susceptible to anaesthetic brain injury at an earlier time point than previously tested. MethodsFemale rats were exposed to isoflurane (Iso) 1 minimum alveolar concentration or sham anaesthesia at P4 or P7. Starting at P35, rats underwent a series of behavioural tasks to test their spatial and recognition memory. Cell death immediately after anaesthesia was quantified by Fluoro-Jade C staining in select brain regions, and developmental expression of the chloride transporters KCC2 and NKCC1 was analysed by immunoblotting in male and female rats at P4 and P7. ResultsFemale rats exposed to Iso at P4 displayed impaired spatial, object-place, -context, and social recognition memory, and increased cell death in the hippocampus and laterodorsal thalamus. Female rats exposed at P7 exhibited only decreased performance in object-context compared with control. The ratio of NKCC1/KCC2 expression in cerebral cortex was higher in P4 females than in P7 females, and similar to that in P7 males. ConclusionsFemale rats exposed to Iso at P4 are sensitive to anaesthetic injury historically observed in P7 males. This is consistent with a comparably immature developmental state in P4 females and P7 males. The window of anaesthetic vulnerability correlates with sex-specific cortical expression of chloride transporters NKCC1 and KCC2. These findings suggest that both sex and developmental age play important roles in determining the outcome after early anaesthesia exposure.

Sex Differences in Medium Spiny Neuron Excitability and Glutamatergic Synaptic Input: Heterogeneity Across Striatal Regions and Evidence for Estradiol-Dependent Sexual Differentiation.

Steroid sex hormones and biological sex influence how the brain regulates motivated behavior, reward, and sensorimotor function in both normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the caudate–putamen, nucleus accumbens core (AcbC), and shell. These brain regions are of particular interest to neuroendocrinologists given that they express membrane-associated but not nuclear estrogen receptors, and also the well-established role of the sex steroid hormone 17β-estradiol (estradiol) in modulating striatal dopamine systems. Indeed, output neurons of the striatum, the medium spiny neurons (MSNs), exhibit estradiol sensitivity and sex differences in electrophysiological properties. Here, we review sex differences in rat MSN glutamatergic synaptic input and intrinsic excitability across striatal regions, including evidence for estradiol-mediated sexual differentiation in the nucleus AcbC. In prepubertal animals, female MSNs in the caudate–putamen exhibit a greater intrinsic excitability relative to male MSNs, but no sex differences are detected in excitatory synaptic input. Alternatively, female MSNs in the nucleus AcbC exhibit increased excitatory synaptic input relative to male MSNs, but no sex differences in intrinsic excitability were detected. Increased excitatory synaptic input onto female MSNs in the nucleus AcbC is abolished after masculinizing estradiol or testosterone exposure during the neonatal critical period. No sex differences are detected in MSNs in prepubertal nucleus accumbens shell. Thus, despite possessing the same neuron type, striatal regions exhibit heterogeneity in sex differences in MSN electrophysiological properties, which likely contribute to the sex differences observed in striatal function.

Long-Term Neonatal Estrogen Exposure Causes Irreversible Inhibition of LH Pulses by Suppressing Arcuate Kisspeptin Expression via Estrogen Receptors α and β in Female Rodents.

Exposure to estrogen during the developmental period causes reproductive dysfunction in mammals, because the developing brain is highly sensitive to estrogens. In the present study, we report that long-term exposure to supraphysiological doses of estrogen during the neonatal critical period causes irreversible suppression of Kiss1/kisspeptin expression in the arcuate nucleus (ARC) via estrogen receptor-alpha (ERα) and ERβ, resulting in reproductive dysfunction in female rats. Daily estradiol-benzoate (EB) administration from days 0 to 10 postpartum caused persistent vaginal diestrus in female rats. The female rats showed profound suppression of pulsatile luteinizing hormone (LH) release and ARC Kiss1/kisspeptin expression even after ovariectomy at adulthood. In contrast, female rats treated with a single EB injection at day 5 postpartum exhibited persistent vaginal estrus and showed comparable LH pulses and numbers of ARC Kiss1-expressing cells to vehicle-treated controls after ovariectomy at adulthood. Because the LH secretory response to exogenous kisspeptin was spared in female rats with neonatal long-term estrogen exposure, the LH pulse suppression was most probably due to ARC kisspeptin deficiency. Furthermore, neonatal estrogen might act through both ERα and ERβ, because EB exposure significantly reduced the number of ARC Kiss1-expressing cells in wild-type mice but not in ERα or ERβ knockout mice. Taken together, long-term exposure to supraphysiological doses of estrogen in the developing brain might cause defects in ARC kisspeptin neurons via ERα and ERβ, resulting in inhibition of pulsatile LH release and lack of estrous cyclicity.

The Effects of Acoustic White Noise on the Rat Central Auditory System During the Fetal and Critical Neonatal Periods: A Stereological Study.

Aim:To evaluate the effects of long-term, moderate level noise exposure during crucial periods of rat infants on stereological parameters of medial geniculate body (MGB) and auditory cortex.Materials and Methods:Twenty-four male offspring of 12 pregnant rats were divided into four groups: fetal-to-critical period group, which were exposed to noise from the last 10 days of fetal life till postnatal day (PND) 29; fetal period group that exposed to noise during the last 10 days of fetal life; critical period group, exposed to noise from PND 15 till PND 29, and control group. White noise at 90 dB for 2 h per day was used.Statistical Analysis Used:Variance for variables was performed using Proc GLM followed by mean comparison by Duncan’s multiple range test.Results:Numerical density of neurons in MGB of fetal-to-critical period group was lower than control group. Similar results were seen in numerical density of neurons in layers IV and VI of auditory cortex. Furthermore, no significant difference was observed in the volume of auditory cortex among groups, and only MGB volume in fetal-to-critical period group was higher than other groups. Estimated total number of neurons in MGB was not significantly different among groups.Conclusion:It seems necessary to prevent long-term moderate level noise exposure during fetal-to-critical neonatal period.

Transcriptome analysis reveals regional and temporal differences in mucosal immune system development in the small intestine of neonatal calves.

BackgroundPostnatal development of the mammalian mucosal immune system is crucial for responding to the rapid colonization by commensal bacteria and possible exposure to pathogens. This study analyzed expression patterns for mRNAs and their relationship with microRNAs (miRNAs) in the bovine small intestine during the critical neonatal period (0 to 42 days). This analysis revealed molecular mechanisms regulating the postnatal development of the intestinal mucosal immune system.ResultsSmall intestine samples (jejunum and ileum) were collected from newborn male, Holstein calves immediately post-partum (n = 3) and at 7 (n = 5), 21 (n = 5), and 42 (n = 5) days of age and the transcriptomes were profiled using RNA-Seq. When analyzing all time points collectively, greater expression of genes encoding the complement functional pathway, as well as lower expression of genes encoding Toll-like receptors and NOD-like receptors were observed in the jejunum when compared to the ileum. In addition, significant changes in the expression of immune-related genes were detected within the first week post-partum in both jejunum and ileum. For example, increased expression of genes encoding tight junction proteins (claudin 1, claudin 4 and occludin), an antimicrobial peptide (Regenerating Islet-Derived 3-γ), NOD-like receptors (NACHT, LRR and PYD domain-containing protein 3), regulatory T cell marker (forkhead box P3), and both anti-inflammatory (interleukin 10) and pro-inflammatory (interleukin 8) cytokines was observed throughout the small intestine of 7-day-old calves when compared to newborn calves. Moreover, the expression of mucosal immune-related genes were either positively or negatively correlated with total bacterial population depending on both intestinal region and age. The integrated analysis of miRNAs and mRNAs supported the conclusion that miRNAs may regulate temporal changes in the expression of genes encoding tight junction proteins (miR-335), cytokines (miR-335) and bacterial recognition (miR-100) during the first week of small intestine development.ConclusionThe rapid development of transcriptional differences between jejunum and ileum reveal that these two intestinal regions make distinct contributions to the intestinal mucosal immune system during the early neonatal period. In addition, transcriptome analysis indicates that the first week after birth is a very dynamic developmental period for the intestinal mucosal immune system and these changes may be regulated by both miRNAs and microbial colonization. Findings from this study indicate that a detailed analysis of both the abundance and diversity of the colonizing microbiome may be necessary to understand factors regulating the rapid development of the mucosal immune system during the first week of life.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2957-y) contains supplementary material, which is available to authorized users.

Epigenetic-Imprinting Changes Caused by Neonatal Fasting Stress Protect From Future Fasting Stress.

Unfavourable nutritional conditions during the neonatal critical period can cause both acute metabolic disorders and severe metabolic syndromes in later life. These phenomena have been tightly related to the epigenetic modification controlling the balance between satiety and hunger in the hypothalamus. In the present study, we investigated epigenetic modification associated with both the fasting stress effects and the short-term resilience to fasting stress in the hypothalamic paraventricular nucleus (PVN) of chicks. Fasting for 24 h at 3 days of age (D) (i.e. D3) significantly increased global methylation at lysine 27 of histone 3 (H3K27) and its specific histone methyltransferase (HMT) expression level in the PVN. Because global methylation could not fully reveal the changes at specific genes, the regulation of the gene for brain-derived neurotrophic factor (Bdnf), which was recently also found to have an anorexigenic effect, was evaluated as a potential target. Chromatin immunoprecipitation assay analysis revealed that tri- (me3) and di-methylated (me2) H3K27 exhibited an instant (on D4 only) and latent increase (on both D11 and D41), respectively, at the putative promoter of Bdnf after 24 h of fasting on D3. This indicated that fasting could regulate energy-expenditure-related genes via modifying methylation at H3K27, which we suspected might be a protective mechanism for keeping the inner environment homeostatic. To test this hypothesis, a short-term repetitive fasting stress was applied to chickens, which were fasted for 24 h either on D10 only or on both D3 and D10. It was found that pre-existing fasting on D3 could induce a short-term fasting resilience, which rescued the reduction of Bdnf expression from future fasting on D10. We call this phenomenon the ‘molecular memory’, which was mainly conducted by HMTs and H3K27me2/me3 in the PVN. In conclusion, chicks respond to fasting with dynamic methylation at H3K27 in the PVN during the neonatal critical period. This allows the PVN to form a ‘molecular memory’, which keeps the individual inner environment homeostatic and resilient to future fasting over the short term.

Intestinal proteomics in pig models of necrotising enterocolitis, short bowel syndrome and intrauterine growth restriction

Necrotising enterocolitis (NEC), short bowel syndrome (SBS) and intrauterine growth restriction (IUGR) are three conditions associated with intestinal dysfunction in newborn infants, particularly those born preterm. Piglet (Sus scrofa) models have recently been developed for NEC, SBS and IUGR, and tissue proteomic analyses have identified unknown pathways and new prognostic disease markers. Intestinal HSPs, iron metabolism proteins and proteins related to amino acid (e.g. arginine) and glucose metabolism are consistently affected by NEC progression and some of these proteins are also affected by SBS and IUGR. Parallel changes in some plasma and urinary proteins (e.g. haptoglobin, globulins, complement proteins, fatty acid binding proteins) may mirror the intestinal responses and pave the way to biomarker discovery. Explorative non-targeted proteomics provides ideas about the cellular pathways involved in intestinal adaptation during the critical neonatal period. Proteomics, combined with other -omic techniques, helps to get a more holistic picture of intestinal adaptation during NEC, SBS and IUGR. Explorative -omic research methods also have limitations and cannot replace, but only supplement, classical hypothesis-driven research that investigate disease mechanisms using a single or few endpoints.

Invited Review: The preterm pig as a model in pediatric gastroenterology

At birth, the newborn mammal undergoes a transition from a sterile uterine environment with a constant nutrient supply, to a microbe-rich environment with intermittent oral intake of complex milk nutrients via the gastrointestinal tract (GIT). These functional challenges partly explain the relatively high morbidity and mortality of neonates. Preterm birth interrupts prenatal organ maturation, including that of the GIT, and increases disease risk. Exemplary is necrotizing enterocolitis (NEC), which is associated closely with GIT immaturity, enteral feeding, and bacterial colonization. Infants with NEC may require resection of the necrotic parts of the intestine, leading to short bowel syndrome (SBS), characterized by reduced digestive capacity, fluid loss, and dependency on parenteral nutrition. This review presents the preterm pig as a translational model in pediatric gastroenterology that has provided new insights into important pediatric diseases such as NEC and SBS. We describe protocols for delivery, care, and handling of preterm pigs, and show how the immature GIT responds to delivery method and different nutritional and therapeutic interventions. The preterm pig may also provide a sensitive model for postnatal adaptation of weak term piglets showing high mortality. Attributes of the preterm pig model include close similarities with preterm infants in body size, organ development, and many clinical features, thereby providing a translational advantage relative to rodent models of GIT immaturity. On the other hand, the need for a sow surgical facility, a piglet intensive care unit, and clinically trained personnel may limit widespread use of preterm pigs. Studies on organ adaptation in preterm pigs help to identify the physiological basis of neonatal survival for hypersensitive newborns and aid in defining the optimal diet and rearing conditions during the critical neonatal period.

Amorium Asağı Sehir Kilisesi bebek ve çocuk iskeletleri

Amorium is a Byzantine city situated within the Emirdag district of the province of Afyonkarahisar. Excavations in the 2007, 2008, and 2009 seasons yielded many tombs containing infant and child skeletons forming part of a cemetery datable to the 10th and 11th centuries. Many are multiple burials and were located principally to the north of the main church in an area called A20 situated to the east of the baptistery. Skeletal remains of 128 individuals from 36 tombs were analysed to reveal the demography and health status of the population. Among them 42,9% of the individuals died prenatally, at birth, or soon after birth. The results of this study indicate that the unfavourable geographic conditions of Amorium’s location might have produced inadequate hygienic conditions and the malnourishment of the mothers which in turn caused infections and complications during birth, leading to premature and stillbirths. Those infants that did survive the critical neonatal and postnatal periods were generally able carry on their lives into puberty and adulthood.

Normal neonatal microbiome variation in relation to environmental factors, infection and allergy

Bacterial colonization of the infant intestinal tract begins at birth. We are at the forefront of understanding complex relationships between bacteria and multiple parameters of health of the developing infant. Moreover, the establishment of the microbiome in the critical neonatal period is potentially foundational for lifelong health and disease susceptibility. Recent studies utilizing state-of-the-art culture-independent technologies have begun to increase our knowledge about the gut microbiome in infancy, the impact of multiple exposures, and its effects on immune response and clinical outcomes such as allergy and infection. Postnatal exposures play a central role in the complex interactions between the nearly blank canvas of the neonatal intestine, whereas genetic factors do not appear to be a major factor. Infant microbial colonization is affected by delivery mode, dietary exposures, antibiotic exposure, and environmental toxicants. Successive microbiome acquisition in infancy is likely a determinant of early immune programming, subsequent infection, and allergy risk. The novel investigation of the neonatal microbiome is beginning to unearth substantial information, with a focus on immune programming that coevolves with the developing microbiome early in life. Several exposures common to neonatal and infant populations could exert pressure on the development of the microbiome and major diseases including allergy and infection in large populations.

Musculoskeletal manifestations of neonatal nonketotic hyperglycinemia

Neonatal nonketotic hyperglycinemia is an autosomal recessive inborn disorder of glycine metabolism in which large quantities of glycine accumulate in all body tissues. It is characterized by a progressive lethargy, hypotonia, myoclonic jerks, and early death secondary to respiratory problems. As a result of early diagnosis and treatment protocols, more patients survive the critical neonatal period with profound mental retardation, delayed developmental milestones, seizures, and spasticity. There are no reports about the orthopaedic manifestations of neonatal nonketotic hyperglycinemia. The purpose of this study is to evaluate the musculoskeletal findings of neonatal nonketotic hyperglycinemia. This is a retrospective IRB-approved study of all patients in our Orthopaedic and Genetics Clinics with the diagnosis of neonatal nonketotic hyperglycinemia during a 10-year period. Demographic, clinical, and imaging data were analyzed. Twelve patients with neonatal nonketotic hyperglycinemia were evaluated, with a mean age of 7years and 2months (range: 5months to 21years). Seven were male and five were female. Eleven patients (92%) have evidence of progressive early-onset neuromuscular scoliosis with a mean Cobb angle of 55° (range: 30-95°). Five children (42%) presented evidence of progressive hip dislocation secondary to spasticity. All the patients have severe multiple joint contractures. Neonatal nonketotic hyperglycinemia is a rare metabolic disorder presented in the past as a lethal condition. Recent advances in early diagnosis and neonatal care improve overall outcome. As pediatric orthopaedic surgeons, we need to establish treatment based on update information of the disease and probability to improve quality of life.

Transient Inactivation of the Neonatal Ventral Hippocampus Permanently Disrupts the Mesolimbic Regulation of Prefrontal Cholinergic Transmission: Implications for Schizophrenia

These experiments determined the mesolimbic modulation of cortical cholinergic transmission in a neurodevelopmental model of schizophrenia. Mesolimbic-cholinergic abnormalities are hypothesized to contribute to the cognitive deficits seen in schizophrenia. Stimulation of NMDA receptors in nucleus accumbens (NAC) increases acetylcholine (ACh) release in the prefrontal cortex (PFC), a mechanism recently demonstrated to contribute to the control of attentional performance. We determined the ability of intra-NAC administration of NMDA to increase prefrontal ACh levels in adult rats that had received bilateral infusions of tetrodotoxin (TTX) to transiently interrupt impulse flow in the ventral hippocampus (VH) during development. Rats received infusions of TTX or saline on postnatal day 7 (PD7) or day 32 (PD32), and the effects of NAC NMDA receptor stimulation on prefrontal cholinergic neurotransmission were assessed in adulthood. In animals treated as controls on PD7, NMDA increased prefrontal ACh levels by 121% above baseline. In contrast, PD7 infusions of TTX into the VH abolished the ability of NAC NMDA to activate prefrontal cholinergic neurotransmission (7% increase). In animals that received TTX infusions on PD32, NMDA-evoked cholinergic activity did not differ from controls, indicating a restricted, neonatal critical period during which VH TTX impacts the organization of mesolimbic-basal forebrain-cortical circuitry. Importantly, the failure of NAC NMDA to evoke cholinergic activity in rats treated with TTX on PD7 did not reflect a reduced excitability of corticopetal cholinergic neurons because administration of amphetamine produced similar elevations of prefrontal ACh levels in PD7 TTX and PD7 control animals. A third series of experiments demonstrated that the effects of PD7 TTX are a specific consequence of transient disruption of impulse flow in the VH. Intra-NAC NMDA evoked prefrontal ACh release in rats receiving TTX, on PD7, into the dorsal hippocampus (DH), basolateral amygdala, or NAC. Thus, impulse flow specifically within the VH, during a sensitive period of development, is necessary for the functional organization of a mesolimbic-cortical circuit known to mediate attentional control processes. Therefore, neonatal inactivation of VH represents an effective animal model for studying the basis of certain cognitive symptoms of schizophrenia.