Critical Period For Maturation Research Articles

Longitudinal body mass index trajectories at preschool age: children with rapid growth have differential composition of the gut microbiota in the first year of life

Background/ObjectiveThe steep rise in childhood obesity has emerged as a worldwide public health problem. The first 4 years of life are a critical window where long-term developmental patterns of body mass index (BMI) are established and a critical period for microbiota maturation. Understanding how the early-life microbiota relate to preschool growth may be useful for identifying preventive interventions for childhood obesity. We aim to investigate whether longitudinal shifts within the bacterial community between 3 months and 1 year of life are associated with preschool BMI z-score trajectories.MethodsBMI trajectories from birth to 5 years of age were identified using group-based trajectory modeling in 3059 children. Their association with familial and environmental factors were analyzed. Infant gut microbiota at 3 months and 1 year was defined by 16S RNA sequencing and changes in diversity and composition within each BMIz trajectory were analyzed.ResultsFour BMIz trajectories were identified: low stable, normative, high stable, and rapid growth. Infants in the rapid growth trajectory were less likely to have been breastfed, and gained less microbiota diversity in the first year of life. Relative abundance of Akkermansia increased with age in children with stable growth, but decreased in those with rapid growth, abundance of Ruminococcus and Clostridium at 1 year were elevated in children with rapid growth. Children who were breastfed at 6 months had increased levels of Sutterella, and decreased levels of Ruminococcus and Clostridium.ConclusionThis study provides new insights into the relationship between the gut microbiota in infancy and patterns of growth in a cohort of preschool Canadian children. We highlight that rapid growth since birth is associated with bacteria shown in animal models to have a causative role in weight gain. Our findings support a novel avenue of research targeted on tangible interventions to reduce childhood obesity.

Differential Age-dependent Mechanisms of High-frequency Stimulation-induced Potentiation in the Prefrontal Cortex–Basolateral Amygdala Pathway Following Fear Extinction

Post-weaning is a critical period for brain maturation in the rat and is comparable to childhood and adolescences in humans. The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) are two brain regions that continue to mature during post-weaning and establish a critical circuit regulating the acquisition and extinction of conditioned fear. We previously demonstrated that exposure to stress leads to significant differences between adults and PWs in the kinetics of extinction behavior as well as differential effects on long-term potentiation. In the current experiments, we aimed to investigate whether prior fear or extinction learning would elicit differences in the ability to induce electrical LTP in the mPFC-BLA pathway in the adult and PW animals. To that end, we subjected adult and PW rats to auditory fear conditioning and extinction, followed by high-frequency stimulation (HFS) to induce LTP. The results indicate that when the conditioning protocol is adjusted to produce comparable extinction kinetics in both age groups, no LTP can be induced after fear conditioning in the mPFC-BLA pathway. Importantly, after extinction, LTP was successfully induced, and a significant difference was observed in the levels of potentiation between adults and PW rats. Further, freezing levels during extinction positively correlated with the magnitude of LTP only in adult animals. These results suggest that the changes occurring at the synaptic level following fear extinction are dissimilar in adult and PW animals. Our results further strengthen the assertion that PW and adult fear extinction learning may rely on different mechanisms.

Characteristics and birth outcomes of pregnant adolescents compared to older women: An analysis of individual level data from 140,000 mothers from 20 RCTs.

SummaryBackgroundAdolescence is a critical period of maturation when nutrient needs are high, especially among adolescents entering pregnancy. Using individual-level data from 140,000 participants, we examined socioeconomic, nutrition, and pregnancy and birth outcomes for adolescent mothers (10–19 years) compared to older mothers in low and middle-income countries.MethodsThis study was conducted between March 16, 2018 and May 25, 2021. Data were obtained from 20 randomised controlled trials of micronutrient supplementation in pregnancy. Stratified analyses were conducted by age (10–14 years, 15–17 years, 18–19 years, 20–29 years, 30–39 years, 40+ years) and geographical region (Africa, Asia). Crude and confounder-adjusted means, prevalence and relative risks of pregnancy, nutrition and birth outcomes were estimated using multivariable linear and log-binomial regression models with 95% confidence intervals.FindingsAdolescent mothers comprised 31.6% of our data. Preterm birth, small-for-gestational age (SGA), low birthweight (LBW) and newborn mortality followed a U-shaped trend in which prevalence was highest among the youngest mothers (10–14 years) and then reduced gradually, but increased again for older mothers (40+ years). When compared to mothers aged 20–29 years, there was a 23% increased risk of preterm birth, a 60% increased risk of perinatal mortality, a 63% increased risk of neonatal mortality, a 28% increased risk of LBW, and a 22% increased risk of SGA among mothers 10–14 years. Mothers 40+ years experienced a 22% increased risk of preterm birth and a 103% increased risk of stillbirth when compared to the 20–29 year group.InterpretationThe youngest and oldest mothers suffer most from adverse pregnancy and birth outcomes. Policy and programming agendas should consider both biological and socioeconomic/environmental factors when targeting these populations.FundingBill and Melinda Gates Foundation (Grant No: OP1137750).

Assessing the role of adolescent hormonal contraceptive use on risk for depression: a 3-year longitudinal study protocol

BackgroundThe incidence of depression in human females rises steadily throughout adolescence, a critical period of pubertal maturation marked by increasing levels of gonadal hormones including estrogens and progesterone. These gonadal hormones play a central role in social and emotional development and may also contribute to the increased occurrence of depression in females that begins in early adolescence. In this study, we examine whether and how introducing synthetic estrogen and progestin derivatives through the use of combined hormonal contraceptives (CHC), affects adolescent females’ risk for developing depression. We further assess potential links between CHC use and alterations in stress responses and social-emotional functioning.MethodsUsing a longitudinal cohort design, we will follow a sample of adolescent females over the span of three years. Participants will be assessed at three time points: once when they are between 13 and 15 years of age, and at approximately 18 and 36 months after their initial assessment. Each time point will consist of two online sessions during which participants will complete a clinical interview that screens for key symptoms of mental health disorders, along with a series of questionnaires assessing their level of depressive symptoms and history of contraceptive use. They will also complete a standardized social-evaluative stress test and an emotion recognition task, as well as provide saliva samples to allow for assessment of their circulating free cortisol levels.DiscussionIn this study we will assess the effect of CHC use during adolescence on development of Major Depressive Disorder (MDD). We will control for variables previously found to or proposed to partially account for the observed relationship between CHC use and MDD, including socioeconomic status, age of sexual debut, and CHC-related variables including age of first use, reasons for use, and its duration. In particular, we will discover whether CHC use increases depressive symptoms and/or MDD, whether elevated depressive symptoms and/or MDD predict a higher likelihood of starting CHC, or both. Furthermore, this study will allow us to clarify whether alterations in stress reactivity and social-emotional functioning serve as pathways through which CHC use may result in increased risk of depressive symptoms and/or MDD.

Individual differences in amygdala volumes predict changes in functional connectivity between subcortical and cognitive control networks throughout adolescence

Adolescence is a critical period of structural and functional neural maturation among regions serving the cognitive control of emotion. Evidence suggests that this process is guided by developmental changes in amygdala and striatum structure and shifts in functional connectivity between subcortical (SC) and cognitive control (CC) networks. Herein, we investigate the extent to which such developmental shifts in structure and function reciprocally predict one another over time. 179 youth (9-15 years-old) completed annual MRI scans for three years. Amygdala and striatum volumes and connectivity within and between SC and CC resting state networks were measured for each year. We tested for reciprocal predictability of within-person and between-person changes in structure and function using random-intercept cross-lagged panel models. Within-person shifts in amygdala volumes in a given year significantly and specifically predicted deviations in SC-CC connectivity in the following year, such that an increase in volume was associated with decreased SC-CC connectivity the following year. Deviations in connectivity did not predict changes in amygdala volumes over time. Conversely, broader group-level shifts in SC-CC connectivity were predictive of subsequent deviations in striatal volumes. We did not see any cross-predictability among amygdala or striatum volumes and within-network connectivity measures. Within-person shifts in amygdala structure year-to-year robustly predicted weaker SC-CC connectivity in subsequent years, whereas broader increases in SC-CC connectivity predicted smaller striatal volumes over time. These specific structure function relationships may contribute to the development of emotional control across adolescence.

Adolescent's Generational Practices, Parent-Child Relationship and Parenting Style of Mothers to their Adolescent Children

Adolescence is a critical period for brain maturation and is described as a stage of vulnerability. Today's adolescents belong to the generation called "Generation Z," also called "Gen Zers," which are people aged 22 and below. These people are identified as unique, unlimited, and ethical. This study assessed the adolescent's generational practices of parent-child relationships and mothers' parenting styles toward their adolescents. The study utilized the descriptive- correlational design conducted in Iligan City, with one hundred twenty mothers selected through purposive and snowball sampling. It used three researcher- made questionnaires, all validated and underwent pilot testing and reliability testing. The researcher gathered data, strictly followed the ethical considerations, and analyzed the data following statistical methods and techniques with the aid of statistical software Minitab: mean, standard deviation, and Pearson’s r. The results then revealed that common generational practice in their generation is that adolescents are commonly interested in their phones and depend on them. In addition, the mother's parent-child relationships and parenting styles are found satisfactory. However, results show no significant relationship between the parenting style and the generational practices of adolescents in lifestyle practices and behavior/attitude and between the parent-child relationship and their parenting style. Keywords : behavior, gadget dependency, generation Z, genital stage, lifestyle

21 Long-Term Ophthalmologic Outcome of Young Adults Born Extremely Preterm

Abstract Primary Subject area Ophthalmology Background Retinopathy of prematurity (ROP) remains the dominant cause of severe visual impairment in childhood in North America and Europe. With the salient improvement in neonatal care since the 1980s, more and more very/extremely premature infants survived and are now reaching adulthood. Premature birth interferes with the critical period of retinal maturation and foveal development. The development of ROP further damages the retina and its vasculature. So far, outcome studies on visual functions and ocular structure in adults born preterm remain scarce. Objectives The first aim of this study is to describe the visual function and retinal structure in a cohort of young adults who were born prematurely. With the recognition of the insidious nature of ROP, we also aimed to investigate if ROP could exert a “second hit” beyond prematurity. Design/Methods This cross-sectional observational study compared visual function of young adults (18-29 years old) born prematurely (< 30 weeks of gestational age [GA]) versus full-term controls. Participants were categorized into three groups: preterm without ROP, preterm with ROP, and term. Comprehensive ophthalmologic examination was performed with blinding to preterm and ROP status. Best corrected visual acuity (BCVA) was assessed with a standardized linear Snellen chart and contrast sensitivity (CS) with the Vistech system. When analyzing BCVA, refractive errors, and contrast sensitivities, we further grouped data based on the strong eyes (better BCVA) and the weak eyes (worse BCVA). Area-under-the-curve (AUC) analysis was performed to gauge the overall CS. Group comparisons were done using ANOVA. Results In this study, 88 individuals born prematurely and 86 individuals born full-term were recruited. Among the strong eyes of the 3 groups, there was no significant difference for BCVA or refractive errors (see image). Among the weak eyes, the preterm with ROP group had the worst BCVA and refractive outcomes, compared to the preterm without ROP and term groups. In the strong eyes, the CS AUC of the preterm with ROP group (16.22 ± 2.69 p<0.0001) was significantly lower than both the preterm without ROP (18.13 ± 2.01) and term (19.55 ± 2.48) groups. In the weak eyes, the AUC of the 3 groups showed a significant and progressive decline from the term group (18.9 ± 2.84) to the preterm without ROP group (18.29 ± 2.14), then to the preterm with ROP group (15.24 ± 2.21). Conclusion In our cohort of young adults born preterm, prematurity alone did not affect their BCVA and refractive errors. However, ROP was independently associated with a lower BCVA, higher refractive errors, and a reduced contrast sensitivity. Our data have shown that prematurity and ROP have independent effects on contrast sensitivity. This study highlights the necessity of long-term ophthalmologic follow-ups for adults who were born prematurely.

FGF18 modulates CTGF mRNA expression in cumulus-oocyte complexes and early bovine embryos: preliminary data.

The Hippo pathway is involved in the proliferation of intrafollicular cells and in early embryonic development, mainly because effectors of this pathway are key transcription regulators of genes such as CTGF and CYR61, which are involved in cell proliferation. Recent studies by our group found that fibroblast growth factor 18 (FGF18) is present in the fallopian tube during early embryonic development, leading to the hypothesis that FGF18 may have a role during embryonic development. Therefore, the aim of the following study was to determine whether FGF18 modulates the expression of Hippo pathway target genes, CTGF and CYR61, during oocyte maturation and early embryonic development. Three experiments were carried out, with in vitro maturation (IVM) of cumulus-oocyte complexes (COCs) and embryo culture. In experiment one, FGF18 (100 ng/ml) induced an increase (P < 0.05) in CTGF gene expression at 12 h post-exposure. In experiment two, FGF18 (100 ng/ml) induced a reduction (P < 0.05) in CTGF expression at 3 h post-exposure. In the third experiment, day 7 embryos exposed to FGF18 during oocyte IVM expressed greater CTGF mRNA abundance, whereas FGF18 exposure during embryo in vitro embryo culture did not alter CTGF expression in comparison with untreated controls. The preliminary data presented here show that FGF18 modulates CTGF expression in critical periods of oocyte nuclear maturation, cumulus expansion and early embryonic development in cattle.

Age-Related Variations in Regional White Matter Volumetry and Microstructure During the Post-adolescence Period: A Cross-Sectional Study of a Cohort of 1,713 University Students.

Human brain white matter undergoes a protracted maturation that continues well into adulthood. Recent advances in diffusion-weighted imaging (DWI) methods allow detailed characterizations of the microstructural architecture of white matter, and they are increasingly utilized to study white matter changes during development and aging. However, relatively little is known about the late maturational changes in the microstructural architecture of white matter during post-adolescence. Here we report on regional changes in white matter volume and microstructure in young adults undergoing university-level education. As part of the MRi-Share multi-modal brain MRI database, multi-shell, high angular resolution DWI data were acquired in a unique sample of 1,713 university students aged 18–26. We assessed the age and sex dependence of diffusion metrics derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in the white matter regions as defined in the John Hopkins University (JHU) white matter labels atlas. We demonstrate that while regional white matter volume is relatively stable over the age range of our sample, the white matter microstructural properties show clear age-related variations. Globally, it is characterized by a robust increase in neurite density index (NDI), and to a lesser extent, orientation dispersion index (ODI). These changes are accompanied by a decrease in diffusivity. In contrast, there is minimal age-related variation in fractional anisotropy. There are regional variations in these microstructural changes: some tracts, most notably cingulum bundles, show a strong age-related increase in NDI coupled with decreases in radial and mean diffusivity, while others, mainly cortico-spinal projection tracts, primarily show an ODI increase and axial diffusivity decrease. These age-related variations are not different between males and females, but males show higher NDI and ODI and lower diffusivity than females across many tracts. These findings emphasize the complexity of changes in white matter structure occurring in this critical period of late maturation in early adulthood.

Cerebellum and Prematurity: A Complex Interplay Between Disruptive and Dysmaturational Events.

The cerebellum plays a critical regulatory role in motor coordination, cognition, behavior, language, memory, and learning, hence overseeing a multiplicity of functions. Cerebellar development begins during early embryonic development, lasting until the first postnatal years. Particularly, the greatest increase of its volume occurs during the third trimester of pregnancy, which represents a critical period for cerebellar maturation. Preterm birth and all the related prenatal and perinatal contingencies may determine both dysmaturative and lesional events, potentially involving the developing cerebellum, and contributing to the constellation of the neuropsychiatric outcomes with several implications in setting-up clinical follow-up and early intervention.

Transient developmental imbalance of cortical interneuron subtypes presages long-term changes in behavior.

SummaryCortical GABAergic interneurons are generated in large numbers in the ganglionic eminences and migrate into the cerebral cortex during embryogenesis. At early postnatal stages, during neuronal circuit maturation, autonomous and activity-dependent mechanisms operate within the cortex to adjust cell numbers by eliminating naturally occurring neuron excess. Here, we show that when cortical interneurons are generated in aberrantly high numbers—due to a defect in precursor cell proliferation during embryogenesis—extra parvalbumin interneurons persist in the postnatal mouse cortex during critical periods of cortical network maturation. Even though cell numbers are subsequently normalized, behavioral abnormalities remain in adulthood. This suggests that timely clearance of excess cortical interneurons is critical for correct functional maturation of circuits that drive adult behavior.

Geochronology, geochemistry and petrogenesis of the Neoarchean magmatism in the Jiefangyingzi area, northern North China Craton: Implications for crustal growth and tectonic affinity

The Bayan Obo-Duolun-Chifeng-Kaiyuan fault is considered as the craton-orogen boundary between the northern North China Craton (NCC) and the Central Asian Orogenic Belt (CAOB). However, locations of this boundary from Duolun, Chifeng to Kaiyuan have not been well constrained. The Jiefangyingzi area northeast to Chifeng is located at the junction of the Bainaimiao arc belt and northern NCC, and has long been regarded as part of the Bainaimiao arc belt of the CAOB. This paper presents new LA-ICP-MS zircon U-Pb geochronological, whole-rocks geochemical and Nd-Hf isotopic data of some recently identified Neoarchean magmatic rocks from the Jiefangyingzi area. These rocks consist mainly of amphibolites, dioritic gneisses, quartz dioritic gneisses, tonalitic gneisses and trondhjemitic gneisses formed at 2569–2536 Ma and minor amphibole plagioclase gneisses formed at ca. 2640 Ma, and are distributed in an east–west belt that is about 13 km long and 1.5 km wide. Geochemical and Nd-Hf isotopic compositions suggest that the amphibolites were derived from partial melting of a depleted mantle that was metasomatized by subduction-derived fluids with significant crustal contamination, and the dioritic gneisses were generated by partial melting of mantle peridotite metasomatized by slab-melts. The quartz dioritic and tonalitic gneisses originated from high degree partial melting of the subducted oceanic crust with garnet-bearing amphibolite facies in the residue, while the trondhjemitic gneisses originated from low degree partial melting of the thickened mafic lower crust with eclogite facies in the residue due to underplating of mafic magmas. The occurrences of Neoarchean basement rocks, combined with previous Nd-Hf isotopic data of the late Paleozoic magmatic rocks, suggest that the Jiefangyingzi area has a tectonic affinity with the Eastern Block of the NCC rather than the CAOB, and the craton-orogen boundary between the northern NCC and the CAOB should be situated in places north to the Jiefangyingzi area. Our results support that the late Neoarchean (2.6–2.5 Ga) is also a period of crustal growth as well as extensive reworking of the 2.9–2.7 Ga ancient crust in the northwestern margin of the Eastern Block of the NCC. In addition, the transition from tonalite-trondhjemite-granodiorite (TTG) and other potassium-poor granitoid gneisses to crustal-derived potassium-rich granitoid gneisses at the end of Neoarchean (ca. 2.53 Ga) marked the initial cratonization of the NCC and ca. 2.53 Ga is a critical transformation period of maturation of the continental crust in the NCC.

Developmental trajectories of global motion and global form perception from 4 years to adulthood

Literature on the development of global motion and global form perception demonstrated their asynchronous developmental trajectories. However, former studies have failed to clearly establish the critical period of maturation for these specific abilities. This study aimed to analyze the developmental trajectories of global motion and global form discrimination abilities by controlling for basic visual functions and general cognitive ability and to present the global motion and global form normative scores. A sample of 456 children and adolescents (4–17 years of age) and 76 adults recruited from the Italian and Swedish general population participated in the study. Motion and form perception were evaluated by the motion coherence test and form coherence test, respectively. Raven’s matrices were used to assess general cognitive ability, the Lea Hyvärinen chart test was used for full- and low-contrast visual acuity, and the TNO test was used for stereopsis. General cognitive ability and basic visual functions were strongly related to motion and form perception development. Global motion perception had an accelerated maturation compared with global form perception. For motion perception, an analysis of the oblique effect’s development showed that it is present at 4 years of age. The standardized scores of global motion and form coherence tests can be used for clinical purposes.

Effect of Prosody of Rhythmic Yoga-Based Recitation on Positive and Negative Affect among Adolescents: A Four-Armed Comparative Study

Background: Adolescence is a critical period of maturation and immense emotional and behavioral changes. Yoga-based rhythmic recitations have been established to improve emotional personality features. Aim: The current four-arm comparative study attempted to appreciate the rhythmic recitations/prosody on Emotional personality among adolescents. Method: 138 adolescents (age 12.11 ± 0.76 years) satisfying inclusion and exclusion criteria were recruited and randomly allocated into four groups i.e., Humming the recitation following a Chanda (HR), Chanting a mantra (CM), Reading an English phrase, and Silent sitting, based on sections of their respective grades. Group intervention was done for 5 minutes, 3 times a day, for 30 days. According to their allocated group was provided. Subjects were assessed with positive and negative Affect Schedules (PANAS) at baseline and post-intervention. Result: There was no difference in both domains of PANAS in within group analysis. However, the positive affect was statistically significant when compared between the groups (p&gt;0.01). A post-hoc analysis revealed the superiority of the CM and HM groups in positive affect alone when compared with other two groups. Conclusion: There was no statistical difference between CM and HM groups in both domains of PANAS. A humming prosody and mantra chanting demonstrated a similar effect on the amelioration of a positive Emotional personality among adolescents.

Characteristics and Birth Outcomes of Pregnant Adolescents Compared to Older Women: An Analysis of Individual Level Data from 140,000 Mothers From 20 RCTs

Background: Adolescence is a critical period of maturation when nutrient needs are high, especially among adolescents entering pregnancy. Using individual-level data from 140,000 participants, we examined socioeconomic, nutrition, and pregnancy and birth outcomes for adolescent mothers (10-19 years) compared to older mothers in low and middle-income countries. Methods: Data were obtained from 20 randomized controlled trials of micronutrient supplementation in pregnancy. Stratified analyses were conducted by age (10-14 years, 15-17 years, 18-19 years, 20-29 years, 30-39 years, 40+ years) and geographical region (Africa, Asia). Crude and confounder-adjusted means, prevalence and relative risks of pregnancy, nutrition and birth outcomes were estimated using multivariable linear and log-binomial regression models with 95% confidence intervals. Findings: Adolescent mothers comprised 31.6% of our data. Preterm birth, small-for-gestational age (SGA), low birthweight (LBW) and newborn mortality followed a U-shaped trend in which prevalence was highest among the youngest mothers (10-14 years) and then reduced gradually, but increased again for older mothers (40+ years). When compared to mothers aged 20-29, there was a 23% increased risk of preterm birth, a 60% increased risk of perinatal mortality, a 63% increased risk of neonatal mortality, a 28% increased risk of LBW, and a 22% increased risk of SGA among mothers 10-14 years. Mothers 40+ experienced a 22% increased risk of preterm birth and a 103% increased risk of stillbirth when compared to the 20-29 year group. Interpretation: The youngest and oldest mothers suffer most from adverse pregnancy and birth outcomes. Policy and programming agendas should consider both biological and socioeconomic/environmental factors when targeting these populations. Funding Information: Bill & Melinda Gates Foundation. Grant #: OP1137750 Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: Ethics approval for this study was obtained from the Research Ethics Board at the Hospital for Sick Children (Canada). The institutions that implemented the primary trials were responsible for obtaining ethical clearance, which guaranteed informed consent and confidentiality of participants’ information.

Regulation of glutamate signaling in the extended amygdala by adolescent alcohol exposure.

Adolescence is a critical period for brain development and behavioral maturation, marked by increased risk-taking behavior and the initiation of drug use. There are significant changes in gray matter volume and pruning of synapses along with a shift in excitatory to inhibitory balance which marks the maturation of cognition and decision-making. Because of ongoing brain development, adolescents are particularly sensitive to the detrimental effects of drugs, including alcohol, which can cause long-lasting consequences into adulthood. The extended amygdala is a region critically implicated in withdrawal and negative affect such as anxiety and depression. As negative affective disorders develop during adolescence, the effects of adolescent alcohol exposure on extended amygdala circuitry needs further inquiry. Here we aim to provide a framework to discuss the existing literature on the extended amygdala, the neuroadaptations which result from alcohol use, and the intersection of factors which contribute to the long-lasting effects of this exposure.

Independent associations of women's age at marriage and first pregnancy with their height in rural lowland Nepal.

In many South Asian communities, the majority of women are married during adolescence and reproduce before 20 years. Early reproduction may adversely affect maternal nutrition and linear growth, however whether early marriage has similar effects is unknown. Shorter women might also be preferentially chosen for earlier marriage. We hypothesized that early marriage and early pregnancy may each be associated with women's shorter height, independent of any selection effects. We analyzed cross-sectional data on 7,146 women aged 20-30 years from rural lowland Nepal. Linear regression models tested associations of early marriage and early reproduction with height, adjusting for women's education and husbands' characteristics (education and wealth) that might index preferential selection of short young women for marriage. Median ages at marriage and first pregnancy were 15 and 18 years, respectively, with 20% pregnant <16 years. Both early marriage and early pregnancy were independently associated with shorter stature, accounting for a decrement of 1.4 cm, which decreased to 1 cm after adjusting for women's education. Effects of early marriage and reproduction persisted after adjusting for the tendency of poorer and less educated men to marry young and short women, indicating a role for social selection. The decrements in height associated with early marriage and reproduction are indicative of broader adverse effects on maternal metabolism during a "critical period" of growth and maturation in the life-course of women. Although the magnitudes of effect are relatively small, they affect large numbers of women in this population.

A history of juvenile mild malaria exacerbates chronic stress-evoked anxiety-like behavior, neuroinflammation, and decline of adult hippocampal neurogenesis in mice

Children residing in high malaria transmission regions are particularly susceptible to malaria. This early-life window is also a critical period for development and maturation of the nervous system, and inflammatory insults during this period may evoke a persistent increase in vulnerability for psychopathology. We employed a two-hit model of juvenile mild malaria and a two-week chronic unpredictable mild stress (CUMS) regime, commencing 60 days post-parasite clearance, to assess whether a history of juvenile infection predisposed the mice towards mood-related behavioral alterations and neurocognitive deficits. We showed that adult mice with a history of juvenile malaria (A-H/JMAL) exhibited heightened CUMS-associated anxiety-like behavior, with no observable change in cognitive behavior. In contrast, mice with a history of adult malaria did not exhibit such enhanced stress vulnerability. At baseline, A-H/JMAL mice showed increased activated microglia within the hippocampal dentate gyrus subfield. This was accompanied by a decrease in proliferating neuronal progenitors, with total number of immature hippocampal neurons unaltered. This neuroinflammatory and neurogenic decline was further exacerbated by CUMS. At day-14 post-CUMS, hippocampi of A-H/JMAL mice showed significantly higher microglial activation, and a concomitant decrease in progenitor proliferation and number of immature neurons. Taken together, these results suggest that a history of juvenile mild malaria leaves a neuroinflammatory mark within the hippocampal niche, and this may contribute to a heightened stress response in adulthood. Our findings lend credence to the idea that the burden of malaria in early-life results in sustained CNS changes that could contribute to increased vulnerability to adult-onset neuronal insults.

Exposure to bacterial lipopolysaccharide in early life affects the expression of ionotropic glutamate receptor genes and is accompanied by disturbances in long-term potentiation and cognitive functions in young rats

Infections in childhood play an essential role in the pathogenesis of cognitive and psycho-emotional disorders. One of the possible mechanisms of these impairments is changes in the functional properties of NMDA and AMPA glutamate receptors in the brain. We suggest that bacterial infections during the early life period, which is critical for excitatory synapse maturation, can affect the subunit composition of NMDA and AMPA receptors. In the present study, we investigated the effect of repetitive lipopolysaccharide (LPS) intraperitoneal (i.p.) administration (25 μg/kg/day on P14, 16, and 18), mimicking an infectious disease, on the expression of subunits of NMDA and AMPA receptors in young rats. We revealed a substantial decrease of GluN2B subunit expression in the hippocampus at P23 using Western blot analysis and real-time polymerase chain reaction assay. Moderate changes were also found in GluN1, GluN2A, and GluA1 mRNA expression. The LPS-treated rats exhibited decreased exploratory and locomotor activity in the open field test and the impairment of spatial learning in the Morris water maze. Behavioral impairments were accompanied by a significant reduction in long-term hippocampal synaptic potentiation. Our data indicate that LPS-treatment in the critical period for excitatory synapse maturation alters ionotropic glutamate receptor gene expression, disturbs synaptic plasticity, and alters behavior.

Molecular, physiological and behavioral characterization of the heterozygous Df[h15q13]/+ mouse model associated with the human 15q13.3 microdeletion syndrome

The human 15q13.3 microdeletion syndrome (DS) is caused by a heterozygous microdeletion (MD) affecting six genes: FAN1; MTMR10; TRPM1; KLF13; OTUD7A; and CHRNA7. Carriers are at risk for intellectual disability, epilepsy, autism spectrum disorder, and schizophrenia. Here we used the Df[h15q13]/+ mouse model with an orthologous deletion to further characterize molecular, neurophysiological, and behavioral parameters that are relevant to the 15q13.3 DS. First, we verified the expression and distribution of the α7 nicotinic acetylcholine receptor (nAChR), a gene product of the CHRNA7, in cortical and subcortical areas. Results revealed similar mRNA distribution pattern in wildtype (WT) and heterozygous (Het) mice, with about half the number of α7 nAChR binding sites in mutants. Hippocampal recordings showed similar input/output responses of field excitatory post-synaptic potentials and theta-burst induced long-term potentiation in WT and Het mice. Het males exhibited impaired spatial learning acquisition in the Barnes Maze. Indicative of increased seizure susceptibility, Het mice developed secondary seizures after 6-Hz corneal stimulation, and had significantly increased sensitivity to the chemoconvulsant pentylenetetrazol resulting in increased spiking in hippocampal EEG recordings. Basal mRNA expression of brain derived neurotrophic factor and activity regulated immediate early genes (c-fos, Arc, Erg-1 and Npas4) during adolescence, a critical period of brain maturation, was unaffected by genotype. Thus, the MD did not show gross neuroanatomical, molecular, and neurophysiological abnormalities despite deficits in spatial learning and increased susceptibility to seizures. Altogether, our results verify the phenotypic profile of the heterozygous Df[h15q13]/+ mouse model and underscore its translational relevance for human 15q13.3 DS.