Early Postnatal Life Research Articles

FRI281 Sexual Dimorphism In The LH Responses To Kisspeptin And Senktide Administration In Prepubertal Mice

Abstract Disclosure: L. Maione: Consulting Fee; Self; Pfizer, Inc., Ipsen. L. Naule: None. C. Li: None. M. Magnuson: None. J. Young: Consulting Fee; Self; Serono Laboratories, Ferring Pharmaceuticals. R.S. Carroll: None. U.B. Kaiser: None. Introduction: The hypothalamic-pituitary-gonadal (HPG) axis is regulated by pulsatile GnRH secretion and its action on the anterior pituitary, leading to the synthesis and secretion of LH and FSH. KNDy neurons, expressing kisspeptin, neurokinin B and dynorphin A, are the GnRH/LH pulse generator and are key regulators of puberty and fertility. The HPG axis is active during prenatal and early postnatal life in humans and rodents, but then remains quiescent until puberty in both species. The response of gonadotropes to exogenous upstream GnRH signals such as kisspeptin and neurokinin during prepubertal development in mice is unknown. Aim: To conduct a systematic assessment of LH responsiveness to exogenous kisspeptin and to the neurokinin-3 receptor agonist senktide at regular intervals postnatally and across pubertal maturation in mice. Materials and Methods: Male and female J129Sv mice were treated with intraperitoneal injections of kisspeptin-10 (0.0023 nmol/g), senktide (0.023 nmol/g) or vehicle every 3 days from postnatal day (PND) 10 until completion of puberty. Serum LH was measured by an ultra-sensitive ELISA at baseline and 15 minutes after injection. Results: Prepubertal mice responded in an age-dependent and sexually dimorphic manner to kisspeptin and senktide. LH levels increased following kisspeptin stimulation in both sexes, but responses were higher in females than in males from PND10 to PND16. The highest response was observed at PND10, with a pattern of decreasing response with advancing age. Senktide induced a robust increase in serum LH in females from PND10 to PND16, with a decrease in response with age, similar to that observed after kisspeptin treatment. In contrast, in males there was no increase in serum LH in response to senktide at any age. No difference in the onset of puberty or body weight was observed across treatment groups. Conclusions: The assessment of serum LH levels following IP administration of kisspeptin and senktide in prepubertal male and female mice demonstrated distinct age and sexually-dimorphic patterns of LH responses to GnRH upstream signals. LH responses are maximal at early ages with a decreasing pattern overtime, and are higher in females than in males, suggesting a different distribution of kisspeptin/neurokinin receptors or the presence of different and/or additional restraining factors on GnRH/LH in the two sexes. These findings provide new evidence for sexual dimorphism of the HPG axis in mice early in postnatal life, prior to the onset of puberty. Presentation: Friday, June 16, 2023

Metabolite profiling of peripheral blood plasma in pigs in early postnatal life fed whole bovine, caprine or ovine milk.

Ruminants' milk is commonly used for supplying nutrients to infants when breast milk is unavailable or limited. Previous studies have highlighted the differences between ruminants' milk composition, digestion, absorption, and fermentation. However, whether consuming different ruminants' milk impact the appearance of the circulatory blood metabolites in the early postnatal life is not well understood. The analysis conducted here aimed to determine the effect of feeding exclusively whole milk from bovine, caprine or ovine species to pigs, approximately 7 days-old for 15 days, on circulatory blood plasma metabolites. Relative intensities of plasma metabolites were detected using a liquid chromatography-mass spectrometry based metabolomic approach. Seven polar and 83 non-polar (lipids) metabolites in plasma were significantly different (false discovery rate < 0.05) between milk treatments. These included polar metabolites involved in amino acid metabolism and lipids belonging to phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, and triglycerides. Compared to the caprine or bovine milk group, the relative intensities of polar metabolites and unsaturated triglycerides were higher in the peripheral circulation of the ovine milk group. In contrast, relative intensities of saturated triglycerides and phosphatidylcholine were higher in the bovine milk group compared to the ovine or caprine milk group. In addition, correlations were identified between amino acid and lipid intake and their appearance in peripheral blood circulation. The results highlighted that consuming different ruminants' milk influences the plasma appearance of metabolites, especially lipids, that may contribute to early postnatal life development in pigs.

Early weaning and biological sex shape long-term immune and metabolic responses in pigs

During the early pre and postnatal life, host and environmental factors can impart a major influence on immune development, thus shaping lifelong disease resistance. Two major factors known to influence immune function and mortality in animals and people are early life stress and biological sex. How these two factors interact to shape long-term immune development and later life disease risk is poorly understood. Here we investigated how early weaning, a common early life stressor in pigs, and biological sex impacts long-term systemic inflammatory responses and hypothalamic–pituitary–adrenal axis (HPA axis) activation later in life. Ten-week-old female (F), intact-male (IM) and castrated-male (CM) pigs that were randomly assigned to early weaning (EW) and later weaning (LW) (at 15 or 28 days of age, respectively) were intramuscularly injected with either saline vehicle or lipopolysaccharide (LPS) to induce a systemic inflammatory response. Complete blood counts (CBC), proinflammatory cytokines, cortisol, testosterone, estradiol, and rectal temp were measured at 0 h, 2 h, and 4 h post-LPS challenge. At 4 h post-LPS, peritoneal fluid (PF) and white blood cells (WBC) were collected for differential analysis. LPS challenge significantly increased rectal temp and plasma cortisol level in all treatment groups. Together, the CBC results and immune cell counts in peritoneal cavity indicated that EW-F exhibited greater systemic immune response characterized by increased neutrophils to lymphocytes ratio (NLR) and enhanced neutrophil trafficking to the peritoneal cavity. Early weaning had an opposite effect on IM and CM pigs, which exhibited a suppressed LPS-induced neutrophil migration. Early weaning induced significantly greater cortisol responses only in IM pigs indicating a heightened HPA axis responses in EW-IM. how early weaning and biological sex affect immune and stress responses in pigs. Together, these results demonstrate that early weaning and biological sex and castration shape later life immune responses in pigs and provides insight into potential mechanisms driving sex differences in later life inflammatory disease risk and mortality.

Intermittent Hypoxia in Preterm Neonates and Its Effect on Neonatal Morbidity and Mortality: A Systematic Review.

The goal of the present systematic review was to investigate the occurrence patterns of intermittent hypoxemia in newborns throughout the early postnatal period as well as the link between neonatal intermittent hypoxemia exposure and harmful consequences such as neonatal morbidity and death. We collected data from 2014 to 2023 using several abstracting, referencing, and indexing database libraries in the field of medical sciences. A total of 715 papers were evaluated by both authors, and only seven articles met the specified review criteria after a thorough analysis. In preterm neonates with intermittent hypoxia (IH), severe morbidities such as bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), motor impairment, and cognitive delay were found. Only one study that extended to 18 months noted mortality. The length and occurrence of intermittent hypoxemia and the stage of premature neonates at the time of delivery are all closely associated with these morbidities. Therefore, it becomes important to continuously measure the patterns of occurrence of intermittent hypoxemia during early postnatal life to avoid its long-term morbidity and mortality impact.

Characterisation of the neonatal brain using myelin-sensitive magnetisation transfer imaging

Abstract A cardinal feature of the encephalopathy of prematurity is dysmaturation of developing white matter and subsequent hypomyelination. Magnetisation transfer imaging (MTI) offers surrogate markers for myelination, including magnetisation transfer ratio (MTR) and magnetisation transfer saturation (MTsat). Using data from 105 neonates, we characterise MTR and MTsat in the developing brain and investigate how these markers are affected by gestational age at scan and preterm birth. We explore correlations of the two measures with fractional anisotropy (FA), radial diffusivity (RD) and T1w/T2w ratio which are commonly used markers of white matter integrity in early life. We used two complementary analysis methods: voxel-wise analysis across the white matter skeleton, and tract-of-interest analysis across 16 major white matter tracts. We found that MTR and MTsat positively correlate with gestational age at scan. Preterm infants at term-equivalent age had lower values of MTsat in the genu and splenium of the corpus callosum, while MTR was higher in central white matter regions, the corticospinal tract and the uncinate fasciculus. Correlations of MTI metrics with other MRI parameters revealed that there were moderate positive correlations between T1w/T2w and MTsat and MTR at voxel level, but at tract level FA had stronger positive correlations with these metrics. RD had the strongest correlations with MTI metrics, particularly with MTsat in major white matter tracts. The observed changes in MTI metrics are consistent with an increase in myelin density during early postnatal life, and lower myelination and cellular/axonal density in preterm infants at term-equivalent age compared to term controls. Furthermore, correlations between MTI-derived features and conventional measures from diffusion MRI provide new understanding about the contribution of myelination to non-specific imaging metrics that are often used to characterise early brain development.

Lifelong restructuring of 3D genome architecture in cerebellar granule cells.

The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell three-dimensional (3D) genome assay-diploid chromosome conformation capture, or Dip-C-into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we resolved the first 3D genome structures of single cerebellar cells, created life-spanning 3D genome atlases for both humans and mice, and jointly measured transcriptome and chromatin accessibility during development. We found that although the transcriptome and chromatin accessibility of cerebellar granule neurons mature in early postnatal life, 3D genome architecture gradually remodels throughout life, establishing ultra-long-range intrachromosomal contacts and specific interchromosomal contacts that are rarely seen in neurons. These results reveal unexpected evolutionarily conserved molecular processes that underlie distinctive features of neural development and aging across the mammalian life span.

Lifelong effects of prenatal and early postnatal stress on the hippocampus, amygdala, and psychological states of Holocaust survivors

This study focuses on hippocampal and amygdala volume, seed-based connectivity, and psychological traits of Holocaust survivors who experienced stress during prenatal and early postnatal development. We investigated people who lived in Central Europe during the Holocaust and who, as Jews, were in imminent danger. The group who experienced stress during their prenatal development and early postnatal (PreP) period (n = 11) were compared with a group who experienced Holocaust-related stress later in their lives: in late childhood, adolescence, and early adulthood (ChA) (n = 21). The results of volumetry analysis showed significantly lower volumes of both hippocampi and the right amygdala in the PreP group. Seed-based connectivity analysis revealed increased connectivity from the seed in the right amygdala to the middle and posterior cingulate cortex, caudate, and inferior left frontal operculum in the PreP group. Psychological testing found higher levels of traumatic stress symptoms (TCS-40) and lower levels of well-being (SOS-10) in the PreP group than in the ChA group. The results of our study demonstrate that extreme stress experienced during prenatal and early postnatal life has a profound lifelong impact on the hippocampus and amygdala and on several psychological characteristics.

Perinatal serotonergic manipulation shapes anhedonic and cognitive behaviors in a sex- and age-dependent manner: Identification of related biological functions at central and peripheral level

Poor knowledge about psychiatric disorders often results in similar diagnoses for patients with different symptoms, thus limiting the effectiveness of the available medications. As suggested by several lines of evidence, to improve these shortcomings, it is essential to identify biomarkers associated with specific symptoms and to stratify patients into more homogeneous populations taking a further step toward personalized medicine.Here, we aimed to associate specific behavioral phenotypes with specific molecular alterations by employing an animal model based on the pharmacological manipulation of the serotonergic system, which mimics a condition of vulnerability to develop psychiatric disorders. In particular, we treated female and male rats with fluoxetine (FLX 15 mg/kg dissolved in drinking water) during prenatal or early postnatal life, and we evaluated different pathological-like phenotypes (cognitive deficit, anhedonia, and anxiety) by exposing the rats to a battery of behavioral tests during adolescence and adulthood. In addition, we carried out molecular analyses on specific brain areas and in the blood.Our results showed that perinatal FLX administration determined age- and sex-dependent effects, with males being more sensitive to prenatal manipulation and manifesting anhedonic-like behavior and females to early postnatal exposure, exhibiting cognitive deficits and a less anxious phenotype. Furthermore, we identified, peripherally and centrally, biological functions altered by perinatal serotonin modulation regardless of the timing of exposure and sex, and other pathways specific for the pathological-like phenotypes.The results presented here provide new insights into potential biomarkers associated with specific behavioral phenotypes that may be useful for broadening knowledge about psychiatric conditions.

Developmental changes in cerebral NAD and neuroenergetics of an antioxidant compromised mouse model of schizophrenia

Defects in essential metabolic regulation for energy supply, increased oxidative stress promoting excitatory/inhibitory imbalance and phospholipid membrane dysfunction have been implicated in the pathophysiology of schizophrenia (SZ). The knowledge about the developmental trajectory of these key pathophysiological components and their interplay is important to develop new preventive and treatment strategies. However, this assertion is so far limited. To investigate the developmental regulations of these key components in the brain, we assessed, for the first time, in vivo redox state from the oxidized (NAD+) and reduced (NADH) form of Nicotinamide Adenine Dinucleotide (NAD), energy and membrane metabolites, inhibitory and excitatory neurotransmitters by 31P and 1H MRS during the neurodevelopment of an SZ animal model with genetically compromised glutathione synthesis (gclm-KO mice). When compared to age-matched wild type (WT), an increase in NAD+/NADH redox ratio was found in gclm-KO mice until early adulthood, followed by a decrease in full adults as observed in patients. Especially, in early postnatal life (P20, corresponding to childhood), levels of several metabolites were altered in gclm-KO mice, including NAD+, NAD+/NADH, ATP, and glutamine + glutamate, suggesting an interactive compensation for redox dysregulation between NAD, energy metabolism, and neurotransmission. The identified temporal neurometabolic regulations under deficits in redox regulation provide insights into preventive treatment targets for at-risk individuals, and other neurodevelopmental disorders involving oxidative stress and energetic dysfunction.

Abstract P3093: Early Myocarditis In The Desmoglein 2 Mutant Mouse Model Of Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is an inherited disease caused by mutations in desmosome proteins. Patients with ACM are born with normal hearts but develop arrhythmias, fibrofatty infiltration, and sudden death. The desmoglein 2 (DSG2) mutant mouse is a well-established model of ACM that recapitulates the human phenotype of the disease. This mouse develops severe ventricular arrhythmias, systolic dysfunction, myocardial fibrosis and exercise induced sudden death. Here, we present evidence of early myocardial immune cell infiltration as well as an inverse relationship between cardiac function and adult myocardial cytokine expression in DSG2 mutant mice. We examined 20 week old adult DSG2 homozygote mice and wildtype littermate controls for systolic function using echocardiography, cytokine expression using rtPCR and fibrosis using masons trichrome staining. Consistent with previous studies we found ventricular fibrosis is significantly increased in mutant hearts (p=0.003). We demonstrate that osteopontin, an inflammatory cytokine released by macrophages, is highly expressed in these hearts (p=2.0x10 -4 ). We detected an inverse correlation between systolic function and the osteopontin expression levels in these mutant mice (p=0.0015, r=-0.8315, R 2 =0.6914). These results lead us to suspect that immune cell infiltration may contribute to the disease progression. Subsequently, we examined immune cell populations in 3 week old DSG2 hearts, a period of time before the development of fibrosis, systolic dysfunction or arrhythmias. We measured &gt;40-fold higher number of CD45 + leukocytes (with increased Ly6G + neutrophils and Ly6C + monocytes) within the heart muscle of DSG2 homozygotes via flow cytometry (p=7.4x10 -5 ), consistent with myocarditis. These results suggest myocarditis precedes fibrosis in the DSG2 mutant mouse model. Our ongoing work is focused on further characterizing the immune response in early post-natal life in the DSG2 mouse heart and determining whether early myocarditis contributes to the phenotype in ACM. Our results highlight potentially novel therapeutic targets to prevent disease progression in ACM.

Exposure to manganese during sertoli cell formation and proliferation disturbs early testicular development in rats

Manganese (Mn) is a metal and important micronutrient. However, exposure to supraphysiological levels of Mn, which occur through fungicides, atmospheric emissions, drainages, and spills, has been related to health risks, including morphometric changes in the male reproductive organs and impairment on gametogenesis and sperm quality, impacting the fertile ability of adult animals. Despite the relevance of the fetal/perinatal period for toxicological studies on Mn, previous data only deal with the physical and neurological development of the offspring, without mentioning their reproductive development. The present study investigated whether exposure to Mn during fetal/perinatal phase, specifically during the period of formation and proliferation of Sertoli cells, impairs the reproductive development of male offspring in early postnatal life. Therefore, pregnant Wistar rats were randomly distributed into 3 experimental groups: Ctl (received saline solution), Mn-9 (received 9 mg/kg of MnCl2), and Mn-90 (received 90 mg/kg of MnCl2). The female rats received the experimental treatment by gavage from gestational day 13 to lactational day 15, i.e., postnatal day (PND) 15 of the pups. Oxidative damage to the genetic material of germ and Sertoli cells, together with a decrease in connexin 43 immunolabeling were observed in the testis of male pups evaluated at PND 15. In addition, an increase in the seminiferous tubules presenting slight epithelium vacuolization and cells with eosinophilic cytoplasm were observed, without apparent epididymal changes. In conclusion, it was demonstrated that Mn perturbed the initial testicular development by altering Sertoli cell integrity through oxidative insult, which may compromise the spermatogenesis in the long-term.

Effects of postnatal exposure to cadmium on male sexual incentive motivation and copulatory behavior: Estrogen and androgen receptors expression in adult brain rat

There are numerous evidence showing that cadmium (Cd) is an endocrine disruptor that exerts multiple toxic effects at different reproductive levels, including male sexual behavior (MSB). The effect of early exposure to Cd on sexual incentive motivation (SIM) and MSB in adult stage, and the immunoreactivity of receptors for hormones such as estrogens and androgens in brain regions that are relevant for the SIM and MSB display, have not been studied until now. The present study evaluated the effects of 0.5 and 1 mg/kg CdCl2 from day 1–56 of postnatal life on SIM and MSB in adults rats, as well as serum testosterone concentrations, Cd concentration in blood, testis, and brain areas, and the immunoreactivity in estrogen receptors (ER-α and -β), and androgen receptor (AR) in the olfactory bulbs (OB), medial preoptic area (mPOA), and medial amygdala (MeA). Our results showed that both doses of Cd decreased SIM and MSB, accompanied by low serum concentrations of testosterone. Also, there was a significant reduction in immunoreactivity of ER-α and AR in mPOA, and a significant reduction in AR in MeA on male rats treated with Cd 1 mg/kg. These results show that exposure to high doses of Cd in early postnatal life could alter the correct integration of hormonal signals in the brain areas that regulate and display SIM and MSB in adult male rats.

Early-life stress perturbs the epigenetics of Cd36 concurrent with adult onset of NAFLD in mice

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the U.S. and worldwide. The roles of early postnatal life stress (EPLS) and the fatty acid translocase (CD36) on the pathogenesis of adult-onset NAFLD remain unknown. We hypothesized that EPLS, in the form of neonatal maternal separation (NMS), would predispose mice towards developing adult NAFLD, increase hepatic CD36 expression, and differentially methylate Cd36 promoter concurrently.MethodsNMS was performed on mice from postnatal day 1 to 21 and a high-fat/high-sucrose (HFS) diet was started at 4 weeks of age to generate four experimental groups: Naive-control diet (CD), Naive-HFS, NMS-CD, and NMS-HFS.ResultsNMS alone caused NAFLD in adult male mice at 25 weeks of age. The effects of NMS and HFS were generally additive in terms of NAFLD, hepatic Cd36 mRNA levels, and hepatic Cd36 promoter DNA hypomethylation. Cd36 promoter methylation negatively correlated with Cd36 mRNA levels. Two differentially methylated regions (DMRs) within Cd36 promoter regions appeared to be vulnerable to NMS in the mouse.ConclusionsOur findings suggest that NMS increases the risk of an individual, particularly male, towards NAFLD when faced with a HFS diet later in life.ImpactThe key message of this article is that neonatal maternal separation and a postweaning high-fat/high-sucrose diet increased the risk of an individual, particularly male, towards NAFLD in adult life.What this study adds to the existing literature includes the identification of two vulnerable differentially methylated regions in hepatic Cd36 promoters whose methylation levels very strongly negatively correlated with Cd36 mRNA.The impact of this article is that it provides an early-life environment-responsive gene/promoter methylation model and an animal model for furthering the mechanistic study on how the insults in early-life environment are “transmitted” into adulthood and caused NAFLD.

Maternal neglect alters reward-anticipatory behavior, social status stability, and reward circuit activation in adult male rats.

Adverse early life experiences affect neuronal growth and maturation of reward circuits that modify behavior under reward predicting conditions. Previous studies demonstrate that rats undergoing denial of expected reward in the form of maternal contact (DER-animal model of maternal neglect) during early post-natal life developed anhedonia, aggressive play-fight behaviors and aberrant prefrontal cortex structure and neurochemistry. Although many studies revealed social deficiency following early-life stress most reports focus on individual animal tasks. Thus, attention needs to be given on the social effects during group tasks in animals afflicted by early life adversity. To investigate the potential impact of the DER experience on the manifestation of behavioral responses induced by natural rewards, we evaluated: 1) naïve adult male sexual preference and performance, and 2) anticipatory behavior during a group 2-phase food anticipation learning task composed of a context-dependent and a cue-dependent learning period. DER rats efficiently spent time in the vicinity of and initiated sexual intercourse with receptive females suggesting an intact sexual reward motivation and consummation. Interestingly, during the context-dependent phase of food anticipation training DER rats displayed a modified exploratory activity and lower overall reward-context association. Moreover, during the cue-dependent phase DER rats displayed a mild deficit in context-reward association while increased cue-dependent locomotion. Additionally, DER rats displayed unstable food access priority following food presentation. These abnormal behaviours were accompanied by overactivation of the ventral prefrontal cortex and nucleus accumbens, as assessed by pCREB levels. Collectively, these data show that the neonatal DER experience resulted in adulthood in altered activation of the reward circuitry, interfered with the normal formation of context-reward associations, and disrupted normal reward access hierarchy formation. These findings provide additional evidence to the deleterious effects of early life adversity on reward system, social hierarchy formation, and brain function.

Do preterm infants with Bronchopulmonary dysplasia have a unique postnatal weight gain pattern?

Objectives To investigate the weight gain pattern of preterm infants with bronchopulmonary dysplasia (BPD) during the hospital stay using weekly weight assessment methods. Methods This single-center, retrospective, cohort study was carried out in Zekai Tahir Burak Maternal Health Education and Research Hospital between 2014 and 2018. One hundred fifty-one preterm infants <32 weeks of gestation and <1500 g of birth weight with BPD were compared to 251 babies without BPD in terms of weekly weight gain, standard deviation score (SDS), and fall in weight SDS till discharge. Results Mean body weight was significantly lower in babies with BPD in all weeks except postnatal week (PW) 8. The groups had similar daily weight gain between birth and discharge (p = .78). Infants with BPD had lower weight SDS on postnatal day (PD) 14 and 21, and discharge, however similar on PD 28. The fall in SDS between PW 4 and discharge was significantly higher in the BPD group. Infants with BPD had higher fall in weight SDS between birth and discharge (p = .022). Discharge weight SDS was associated with gestational age and weight SDS on PW 4 in the whole cohort. Conclusion Infants with BPD showed a unique and unsteady pattern of growth compromise during the NICU course, most explicitly in early postnatal life and between PD 28-discharge. Future studies should consider not only the early postnatal life but also the period after four weeks of life till discharge to design an optimal nutrition strategy and decent growth for preterm infants with BPD.

Sodium and Growth in Preterm Infants: A Review.

This article is intended to review the relationship between sodium homeostasis and growth, outline reasons why preterm infants may become sodium deficient, and share data from our group and others regarding the potential benefits of dietary sodium supplementation. Despite tremendous efforts over the past 20 years to optimize neonatal nutrition, postnatal growth failure in preterm infants remains a significant problem. Compelling associations have been identified between in-hospital growth failure and cardiometabolic and neurodevelopmental disorders, heightening the need to further identify the optimal nutritional needs of preterm infants. The impact of sodium deficiency may have on somatic growth is poorly studied and reported upon within the human literature. In contrast, animal studies dating back almost 100 years highlight the nutritional importance of dietary sodium. Sodium homeostasis during early postnatal life is understudied and underappreciated by neonatologists. Insufficient sodium intake during early life is likely a critical yet underappreciated contributor to growth failure. Total body sodium depletion may be an important risk factor driving complications of premature birth. Increased awareness of sodium homeostasis in preterm infants may improve outcomes in this population. Sodium intake recommendations are provided based on the interpretation of currently available literature.

A consequence of immature breathing induces persistent changes in hippocampal synaptic plasticity and behavior: a role of prooxidant state and NMDA receptor imbalance.

Underdeveloped breathing results from premature birth and causes intermittent hypoxia during the early neonatal period. Neonatal intermittent hypoxia (nIH) is a condition linked to the increased risk of neurocognitive deficit later in life. However, the mechanistic basis of nIH-induced changes to neurophysiology remains poorly resolved. We investigated the impact of nIH on hippocampal synaptic plasticity and NMDA receptor (NMDAr) expression in neonatal mice. Our findings indicate that nIH induces a prooxidant state that leads to an imbalance in NMDAr subunit composition favoring GluN2B over GluN2A expression and impairs synaptic plasticity. These consequences persist in adulthood and coincide with deficits in spatial memory. Treatment with an antioxidant, manganese (III) tetrakis (1-methyl-4-pyridyl)porphyrin (MnTMPyP), during nIH effectively mitigated both immediate and long-term effects of nIH. However, MnTMPyP treatment post-nIH did not prevent long-lasting changes in either synaptic plasticity or behavior. In addition to demonstrating that the prooxidant state has a central role in nIH-mediated neurophysiological and behavioral deficits, our results also indicate that targeting the prooxidant state during a discrete therapeutic window may provide a potential avenue for mitigating long-term neurophysiological and behavioral outcomes that result from unstable breathing during early postnatal life.

Diabetes incidence in Austria: The role of famines on diabetes and related NCDs

Undernutrition in early life associates with increased risk for type 2 diabetes in later life. Whether similar associations hold for other diseases remains unclear. We aim to quantify how perinatal exposure to famines relates to the risk of becoming incident with type 2 diabetes in later life. Using population-wide medical claims data for Austrians aged >50y, yearly diabetes incidence was measured in an epidemiological progression model. We find incidence rates that increase from 2013 to 2017 and observe two famine-related birth cohorts of 5,887 patients with incidence rate increases for diabetes of up to 78% for males and 59% for females compared to cohorts born two years earlier. These cohorts show increased risks for multiple other diagnoses as well. Public health efforts to decrease diabetes must not only focus on lifestyle factors but also emphasize the importance of reproductive health and adequate nutrition during pregnancy and early postnatal life.

Prenatal alcohol exposure alters mRNA expression for stress peptides, glucocorticoid receptor function and immune factors in acutely stressed neonatal brain.

The amygdala, hippocampus and hypothalamus are critical stress regulatory areas that undergo functional maturation for stress responding initially established during gestational and early postnatal brain development. Fetal alcohol spectrum disorder (FASD), a consequence of prenatal alcohol exposure (PAE), results in cognitive, mood and behavioral disorders. Prenatal alcohol exposure negatively impacts components of the brain stress response system, including stress-associated brain neuropeptides and glucocorticoid receptors in the amygdala, hippocampus and hypothalamus. While PAE generates a unique brain cytokine expression pattern, little is known about the role of Toll-like receptor 4 (TLR4) and related proinflammatory signaling factors, as well as anti-inflammatory cytokines in PAE brain stress-responsive regions. We hypothesized that PAE sensitizes the early brain stress response system resulting in dysregulated neuroendocrine and neuroimmune activation. A single, 4-h exposure of maternal separation stress in male and female postnatal day 10 (PND10) C57Bl/6 offspring was utilized. Offspring were from either prenatal control exposure (saccharin) or a limited access (4 h) drinking-in-the-dark model of PAE. Immediately after stress on PND10, the hippocampus, amygdala and hypothalamus were collected, and mRNA expression was analyzed for stress-associated factors (CRH and AVP), glucocorticoid receptor signaling regulators (GAS5, FKBP51 and FKBP52), astrocyte and microglial activation, and factors associated with TLR4 activation including proinflammatory interleukin-1β (IL-1β), along with additional pro- and anti-inflammatory cytokines. Select protein expression analysis of CRH, FKBP and factors associated with the TLR4 signaling cascade from male and female amygdala was conducted. The female amygdala revealed increased mRNA expression in stress-associated factors, glucocorticoid receptor signaling regulators and all of the factors critical in the TLR4 activation cascade, while the hypothalamus revealed blunted mRNA expression of all of these factors in PAE following stress. Conversely, far fewer mRNA changes were observed in males, notably in the hippocampus and hypothalamus, but not the amygdala. Statistically significant increases in CRH protein, and a strong trend in increased IL-1β were observed in male offspring with PAE independent of stressor exposure. Prenatal alcohol exposure creates stress-related factors and TLR-4 neuroimmune pathway sensitization observed predominantly in females, that is unmasked in early postnatal life by a stress challenge.

Echocardiographic assessment of brain sparing in small-for-gestational age infants and association with neonatal outcomes

Brain sparing is an adaptive phenomenon (redistribution of blood flow to the brain) observed in fetuses exposed to chronic hypoxia, who are at risk of intrauterine growth restriction. Here, we assessed the blood flow distribution during the early neonatal period (< 7 days of life) using echocardiography, and evaluated the impact of brain-sparing on postnatal course and neurodevelopmental outcomes. This retrospective study included 42 small-for-gestational age (SGA) infants [further classified into asymmetric SGA (a-SGA, n = 21) and symmetric SGA (s-SGA, n = 21) groups according to their birth head circumference percentiles], and 1: 2 matched appropriate-for-gestational age (AGA) infants (n = 84) admitted to the neonatal intensive care unit. Left ventricular (LV) stroke volume, LV cardiac output (LVCO), upper body blood flow (UBBF), and UBBF/LVCO ratio (%) were significantly higher in both a-SGA and s-SGA infants than in AGA infants. Both a-SGA and s-SGA groups consisted predominantly of infants with higher UBBF/LVCO (%). A UBBF/LVCO ≥ 58.2% (3rd interquartile range) was associated with a later need for rehabilitative therapy after discharge. In summary, brain-sparing effect may continue during the early postnatal life in SGA infants, and may be a promising marker to detect future adverse neurodevelopmental outcomes.