Consequences In Later Life Research Articles

Choline Intake and Cognitive Function Among U.S. Older Adults

Choline is an essential nutrient affects brain development in early life. However, evidence is lacking regarding its potential neuroprotective effects in later life from community-based cohorts. This study assessed the relationship between choline intake and cognitive functioning in a sample of older adults 60 years + from the National Health and Nutrition Examination Survey 2011–2012 and 2013–2014 waves (n = 2,796). Choline intake was assessed using two nonconsecutive 24-hour dietary recalls. Cognitive assessments included immediate and delayed word recalls, Animal Fluency, and Digit Symbol Substitution Test. The average daily dietary choline intake was 307.5 mg, and the total intake (including intake from dietary supplements) was 330.9 mg, both below the Adequate Intake level. Neither dietary OR = 0.94, 95% CI (0.75, 1.17) nor total choline intake OR = 0.87, 95% CI (0.70, 1.09) was associated with changes in cognitive test scores. Further investigation adopting longitudinal or experimental designs may shed light on the issue.

Developmental exposure to thyroid disruptors: misprogramming of the brain's stem cells in later life?

Developmental exposure to thyroid disruptors: misprogramming of the brain's stem cells in later life?

Galactose in the Post-Weaning Diet Programs Improved Circulating Adiponectin Concentrations and Skeletal Muscle Insulin Signaling.

Short-term post-weaning nutrition can result in long-lasting effects in later life. Partial replacement of glucose by galactose in the post-weaning diet showed direct effects on liver inflammation. Here, we examined this program on body weight, body composition, and insulin sensitivity at the adult age. Three-week-old female C57BL/6JRccHsd mice were fed a diet with glucose plus galactose (GAL; 16 energy% (en%) each) or a control diet with glucose (GLU; 32 en%) for three weeks, and afterward, both groups were given the same high-fat diet (HFD). After five weeks on a HFD, an oral glucose tolerance test was performed. After nine weeks on a HFD, energy metabolism was assessed by indirect calorimetry, and fasted mice were sacrificed fifteen minutes after a glucose bolus, followed by serum and tissue analyses. Body weight and body composition were not different between the post-weaning dietary groups, during the post-weaning period, or the HFD period. Glucose tolerance and energy metabolism in adulthood were not affected by the post-weaning diet. Serum adiponectin concentrations were significantly higher (p = 0.02) in GAL mice while insulin, leptin, and insulin-like growth factor 1 concentrations were not affected. Expression of Adipoq mRNA was significantly higher in gonadal white adipose tissue (gWAT; p = 0.03), while its receptors in the liver and skeletal muscles remained unaffected. Irs2 expression was significantly lower in skeletal muscles (p = 0.01), but not in gWAT or Irs1 expression (in both tissues). Gene expressions of inflammatory markers in gWAT and the liver were also not affected. Conclusively, galactose in the post-weaning diet significantly improved circulating adiponectin concentrations and reduced skeletal muscle Irs2 expression in adulthood without alterations in fat mass, glucose tolerance, and inflammation.

NMN Supplementation Rescues Fertility and Bone Strength in Chemotherapy-Treated Mice

Background: Cancer survivors often face infertility as a result of ovarian toxicity from cytotoxic chemotherapy drugs, which trigger a cascade of events ultimately causing follicular reserve exhaustion and endocrine disruption. Apart from infertility, this can have severe consequences on women’s health with early-onset menopause and a decline in bone health. For girls with cancer, ovarian tissue cryopreservation (OTC) is the only option for fertility preservation. OTC + transplantation may provide future fertility potential, but it provides minimal/no protection from endocrine failure and osteoporosis. Aim: To assess the effects of the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) on ovarian function, fertility, and late-life bone health. Method: 7-day old female mice were treated +/- cisplatin (2mg/kg). Two weeks later, +/- NMN was delivered in drinking water (2g/L) and sustained throughout life. A breeding trial was conducted at 6 weeks, and to assess late-life effects on bone structure, mice were maintained until euthanasia at 24 months of age. Results: Cisplatin caused a dramatic decline in all fertility endpoints. NMN supplementation rescued breeding performance in cisplatin treated animals by 5-fold (p=0.015), as measured by the cumulative number of pups/female. Given the importance of ovarian function to estrogen release and the risk of osteoporosis, we sought to determine the impacts of these interventions on late-life bone health. Bones were subject to mechanical and structural analysis to assess differences in the onset of osteoporosis. In cisplatin treated animals, NMN rescued cortical bone thickness (femur diaphysis p[Formula: see text]0.0001, femur metaphysis p=0.0081, tibia p=0.0072), bone volume (femur p=0.0015, tibia p=0.0102), and bone density (femur p=0.0463) to control levels, and increased mechanical strength (tibia, p=0.0024). Conclusion: Long-term NMN treatment delivered following chemotherapy protected against subsequent ovarian failure and infertility, and notably improved late-life bone health, possibly due to the prevention of premature ovarian failure.

Association between antenatal glucocorticoid exposure and the activity of the stress system, cognition, and behavior in 8- to 9-year-old children: A prospective observational study.

Glucocorticoid (GC) -induced fetal programming of the activity of the hypothalamus-pituitary-adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood. Prospective observational study in 31 children whose mothers received single (n=19) or multiple (n=12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+6 weeks of gestation) compared with 38 non-exposed, age-matched children. Primary end point was the activity of the HPAA in response to the Trier Social Stress Test. Secondary end points were changes in autonomic nervous system (ANS) activity, cognitive performance (IQ), attention-deficit/hyperactivity disorder (ADHD) symptoms, and electrocortical activity (EEG). There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM-exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high-frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM-exposed children had lower IQ scores than the unexposed group. BM-exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose-response relation between BM exposure and activity of the ANS and IQ was estimated in post-hoc analyses. Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life-saving therapy, but its prescription may warrant a well-balanced risk-benefit assessment.

Post-Concussion Syndrome and Chronic Traumatic Encephalopathy: Narrative Review on the Neuropathology, Neuroimaging and Fluid Biomarkers.

Traumatic brain injury is a significant public health issue and represents the main contributor to death and disability globally among all trauma-related injuries. Martial arts practitioners, military veterans, athletes, victims of physical abuse, and epileptic patients could be affected by the consequences of repetitive mild head injuries (RMHI) that do not resume only to short-termed traumatic brain injuries (TBI) effects but also to more complex and time-extended outcomes, such as post-concussive syndrome (PCS) and chronic traumatic encephalopathy (CTE). These effects in later life are not yet well understood; however, recent studies suggested that even mild head injuries can lead to an elevated risk of later-life cognitive impairment and neurodegenerative disease. While most of the PCS hallmarks consist in immediate consequences and only in some conditions in long-termed processes undergoing neurodegeneration and impaired brain functions, the neuropathological hallmark of CTE is the deposition of p-tau immunoreactive pre-tangles and thread-like neurites at the depths of cerebral sulci and neurofibrillary tangles in the superficial layers I and II which are also one of the main hallmarks of neurodegeneration. Despite different CTE diagnostic criteria in clinical and research approaches, their specificity and sensitivity remain unclear and CTE could only be diagnosed post-mortem. In CTE, case risk factors include RMHI exposure due to profession (athletes, military personnel), history of trauma (abuse), or pathologies (epilepsy). Numerous studies aimed to identify imaging and fluid biomarkers that could assist diagnosis and probably lead to early intervention, despite their heterogeneous outcomes. Still, the true challenge remains the prediction of neurodegeneration risk following TBI, thus in PCS and CTE. Further studies in high-risk populations are required to establish specific, preferably non-invasive diagnostic biomarkers for CTE, considering the aim of preventive medicine.

ASSOCIATION BETWEEN BULLYING OR PEER VICTIMIZATION AND PSYCHOPATHOLOGY SYMPTOMS AMONG ADOLESCENTS

Bullying or peer victimization is a topic for concern among teenagers and youth of society. It is a common type of interpersonal aggression and usually occurs in many forms, patterns, have several consequences either physical or psychological. Bullying behavior is a severe issue and has short-term as well as long-term impact on individual. However, teenagers who are victimized by the perpetrators may develop the psychopathological symptoms and mental health problems, such as, distress, depression, anxiety, social isolation, etc, which also have some serious effects in later life or adulthood and sometimes leads to suicidal ideation. Therefore, this conceptual paper is aimed to explore the relevant studies about the issues of bullying or peer victimization and its association with psychopathology symptoms among adolescents and children. And also observe what it has impact on later life of individual. Furthermore, this paper also intends to explore about the relevant prevention policies and concern of bullying in society.

Intergenerational Socioeconomic Mobility and Cognitive Impairment in Chinese Older Adults: Does Gender Matter?

The prevalence of dementia among older adults in mainland China is projected to increase rapidly in the next few decades. This study aimed to examine the impact of intergenerational socioeconomic mobility on the risk of cognitive impairment in a cohort of Chinese older adults, with a focus on potential gender differences. Data were derived from the 2011 wave of the Chinese Longitudinal Healthy Longevity Survey. Socioeconomic mobility in this study includes three dimensions: occupational mobility, educational mobility, and residential mobility. Cognitive impairment was assessed using the Chinese version of Mini-Mental State Examination. The final sample included 6,233 older adults aged 80 years and above. Logistic regression models were performed to assess the impact of the three dimensions of socioeconomic mobility on the risk of cognitive impairment in older men and women. For men, those with stable high occupational status across generations had the lowest risk of cognitive impairment. For women, those who received no education and lived in rural areas across generations had the highest risk of cognitive impairment. These findings lend support to the cumulative risk theory, which highlights the accumulation of risk factors that places individuals in jeopardy for negative health consequences in later life. The findings have implications for advancing supportive policies and practices related to maximizing the benefits of education and occupation for cognition in later life, especially for women in rural China.

Childhood obesity and adverse cardiometabolic risk in large for gestational age infants and potential early preventive strategies: a narrative review.

Accumulating evidence indicates that obesity and cardiometabolic risks become established early in life due to developmental programming and infants born as large for gestational age (LGA) are particularly at risk. This review summarizes the recent literature connecting LGA infants and early childhood obesity and cardiometabolic risk and explores potential preventive interventions in early infancy. With the rising obesity rates in women of childbearing age, the LGA birth rate is about 10%. Recent literature continues to support the higher rates of obesity in LGA infants. However, there is a knowledge gap for their lifetime risk for adverse cardiometabolic outcomes. Potential factors that may modify the risk in early infancy include catch-down early postnatal growth, reduction in body fat growth trajectory, longer breastfeeding duration, and presence of a healthy gut microbiome. The early postnatal period may be a critical window of opportunity for active interventions to mitigate or prevent obesity and potential adverse metabolic consequences in later life. A variety of promising candidate biomarkers for the early identification of metabolic alterations in LGA infants is also discussed. IMPACT: LGA infants are the greatest risk category for future obesity, especially if they experience rapid postnatal growth during infancy. Potential risk modifying secondary prevention strategies in early infancy in LGA infants include catch-down early postnatal growth, reduction in body fat growth trajectory, longer breastfeeding duration, and presence of a healthy gut microbiome. LGA infants may be potential low-hanging fruit targets for early preventive interventions in the fight against childhood obesity.

Estimating the late-life effects of social and emotional skills in childhood using midlife mediators

Social and emotional skills are known to affect health and non-health outcomes, but there is limited evidence on whether these skills in childhood affect late life outcomes because of a shortage of long-running datasets containing this information. We develop a three-stage procedure and use it to estimate the effect of childhood social and emotional skills on health and labour market outcomes in late-life. This procedure makes use of mediators in midlife which are shown to be predicted by childhood skills in one dataset and to predict late-life outcomes in another dataset. We use this method to combine estimates from the National Child Development Survey and the British Household Panel Survey. We find that childhood skills predict marital status, education, home ownership, income and health at age 46 years and these midlife variables predict levels of quality-adjusted life years and labour income accumulated by age 63 years. The combined estimates suggest a standard deviation increase in average Bristol Social Adjustment Guide total score at ages 7 and 11 is associated with 4.2% (standard error = 0.6%) additional quality-adjusted life years and more than 9.9% (£14,539, standard error = £2072) additional accumulated pre-tax earnings by age 63 years. Therefore, childhood interventions to increase social and emotional skills would be expected to reduce future healthcare costs and increase wealth. Our three-stage methodology can be used to predict the life-course effects of investments in childhood skills by combining results from datasets across population cohorts.

Hypertensive disorders of pregnancy and alterations in brain metabolites in preterm infants: A multi-voxel proton MR spectroscopy study

BackgroundInfants born to mothers with hypertensive disorders of pregnancy (HDP) have adverse neurodevelopmental consequences in later life. Magnetic resonance spectroscopy (MRS) is used to predict subsequent neurodevelopment in the field of perinatology. AimWe aimed to determine whether exposure to HDP in utero leads to alterations in brain metabolites in preterm infants using multi-voxel proton MRS at term-equivalent age. Study designRetrospective cohort study. SubjectsA total of 103 preterm infants born before 34 weeks of gestation at Nagoya University Hospital between 2010 and 2018 were eligible. Twenty-seven infants were born to mothers with HDP (HDP group), and 76 were born to mothers without HDP (non-HDP group). Outcome measuresThe peak area ratios of N-acetylaspartate (NAA)/choline (Cho), NAA/creatine (Cr), and Cho/Cr were evaluated at 10 designated regions of interest (bilateral frontal lobes, basal ganglia, thalami, temporal lobes, and occipital lobes). ResultsThe peak area ratios of NAA/Cho and NAA/Cr in the bilateral thalami were significantly higher in the HDP group than in the non-HDP group after adjustment for covariates (postmenstrual age at MRS assessment and infant sex). No significant differences were observed in other regions. Preeclampsia, abnormal umbilical artery blood flow, and fetal growth restrictions were significantly associated with increased NAA/Cho and NAA/Cr ratios in the thalami. ConclusionsBased on the evidence that NAA/Cho and NAA/Cr ratios constantly increase with postmenstrual age in normal brain development, exposure to maternal HDP in utero may accelerate brain maturation and increase neuronal activity in preterm infants.

The mutual patterning between the developing nephron and its covering tissues\u2014valid reasons to rethink the search for traces left by impaired nephrogenesis

BackgroundThe impairment of nephrogenesis can cause the termination of nephron formation in preterm and low birth weight babies. This leads to oligonephropathy with severe health consequences in later life. Although many clinical parameters are known, surprisingly little information is available regarding the initial damage on the developing nephron. Equally astounding, the first morphological data regarding the specifics of nephron formation in the nephrogenic zone of the fetal human kidney during late gestation has only been published within the past few years. In this context, it was observed that each stage of nephron anlage is surrounded by a specific set of tissues. Although highly relevant for the normal progress of nephron formation, the mutual patterning has not been systematically described.ResultsTo contribute, the different stages of nephron anlage in the nephrogenic zone of the fetal human kidney during late gestation were screened by the optical microscope and documented by images. Following this, magnifications (28 × 18 cm) were produced to trace the contours of the developing nephron and its covering tissues. The resulting sketches, almost true to scale, were scanned, edited, and processed by a design program. As a base, first the individual position, size, and shape of the nephrogenic niche, pretubular aggregate, renal vesicles, comma- and S-shaped bodies are presented. Secondly, their structural relations to the renal capsule, collecting duct ampulla, perforating radiate artery, and expanding interstitium are shown. Third of all, the focus is on less considered configurations, such as site-specific approximation, local distancing, punctual adhesion, integration, separation, delamination, formation of congruent and divergent surfaces, and folding and opening of interstitial clefts.ConclusionsThe present contribution illuminates the mutual patterning between the developing nephron and its covering tissues. It is indispensable to know about the microanatomical relations, in order to identify whether the noxae impairing nephrogenesis targets only the developing nephron or also its covering tissues as interacting and controlling instances.

Alterations in the Epigenetic Landscape Underlying Later-Life Health Effects Due to In-utero Exposure to Endocrine Disrupting Chemicals: A Review of Outcomes from Mice to Men

Widespread persistence of Endocrine Disrupting Chemicals (EDCs) in the environment has mandated the need to study their potential long-term effects on human health, after acute as well aschronic exposures. The particular focus is on in utero exposure to EDCs in rodent models to look at altered epigenetic programming to result in transgenerational effects in later life of the offspring. This potentially contributes to reproductive and immune dysfunctions, obesity, cancer, and altered brain development and neurobehavioral outcomes. The literature to date establishes the transgenerational effects associated with in utero exposure to EDCs in rodent models. Hence, the aim of this review is to provide a comprehensive overview of epigenetic programming and its regulation in mammals, specially focussing on epigenetic plasticity and susceptibility to exogenous endocrine-active chemicals, EDCs, during the early developmental period, and carried forward to later life using rodent models. The available reports suggest that the key mechanism behind the long-term impact of EDCs is caused by alterations in the epigenetic programming machinery, leading to dysregulated gene expression during adult life. Studies have reported the effect of prenatal exposure to EDCs in the ovarian microRNA expression and function, highlighting ovary as an organ undergoing in utero programming. It ascertains the heightened sensitivity of the organ to exogenous hormone-active compounds, particularly during early development. In addition to this, another key aspect in this review is increased susceptibility of the brain when exposed to even minute quantities of EDCs during embryonic development, resulting in profound alterations in the structural organization of the brain and neurobehavior. Detailed analyses of variables such as folic acid and phytoestrogen content in maternal diet need to be considered as crucial factors while designing experiments and therapeutic interventions. Apart from this, appropriate animal handling during the experimental procedures to eliminate stress in animal models to ensure unbiased results is recommended.

Predictors of Emotional and Behavioural Problems amongst Children of North East India

Mental health problems in early childhood have negative consequences in later life, and risk factors put an extra burden on their health outcome. Hence, researchers aimed to determine the predictors of emotional and behavioural problems amongst the children. A quantitative approach and cross-sectional descriptive design was used to conduct this study amongst 100 parents of children who attended a Tertiary Mental Healthcare Institute of North East India. Participants were selected by using systematic random sampling technique. Data were collected by using Socio Demographic Proforma, Alabama Parenting Questionnaire and Strengths and Difficulties Questionnaire. Data were analyzed by using stepwise multiple linear regression techniques to determine predictors of emotional and behavioural problems amongst the children. Findings revealed that age of the child and inconsistent discipline are the significant predictors of the emotional problems, poor monitoring/supervision is the significant predictor of conduct problems, age of the child, poor monitoring/supervision and inconsistent discipline are significant predictors of hyperactivity; gender of the child is the significant predictor of peer problems and poor monitoring/supervision and corporal punishment are the significant predictors of the total difficulties. Findings also revealed that positive involvement is the significant predictor of pro-social behaviour. These findings confirmed that negative parenting practices, age and gender of the child are the risk factors for the emotional and behavioural problems amongst the children. Therefore, health professionals working with children need to consider these factors in planning a comprehensive intervention package for better outcome.

Maternal Vegetable and Fruit Consumption during Pregnancy and Its Effects on Infant Gut Microbiome.

Maternal nutrition intake during pregnancy may affect the mother-to-child transmission of bacteria, resulting in gut microflora changes in the offspring, with long-term health consequences in later life. Longitudinal human studies are lacking, as only a small amount of studies showing the effect of nutrition intake during pregnancy on the gut microbiome of infants have been performed, and these studies have been mainly conducted on animals. This pilot study explores the effects of high or low fruit and vegetable gestational intake on the infant microbiome. We enrolled pregnant women with a complete 3-day dietary record and received postpartum follow-up. The 16S rRNA gene sequence was used to characterize the infant gut microbiome at 2 months (n = 39). Principal coordinate analysis ordination revealed that the infant gut microbiome clustered differently for high and low maternal fruit and vegetable consumption (p < 0.001). The linear discriminant analysis effect size and feature selection identified 6 and 17 taxa from both the high and low fruit and vegetable consumption groups. Among the 23 abundant taxa, we observed that six maternal intake nutrients were associated with nine taxa (e.g., Erysipelatoclostridium, Isobaculum, Lachnospiraceae, Betaproteobacteria, Burkholderiaceae, Sutterella, Clostridia, Clostridiales, and Lachnoclostridium). The amount of gestational fruit and vegetable consumption is associated with distinct changes in the infant gut microbiome at 2 months of age. Therefore, strategies involving increased fruit and vegetable consumption during pregnancy should be employed for modifying the gut microbiome early in life.

Influence of innate immune activation on endocrine and metabolic pathways in infancy.

Prematurity is the leading cause of neonatal morbidity and mortality worldwide. Premature infants often require extended hospital stays, with increased risk of developing infection compared with term infants. A picture is emerging of wide-ranging deleterious consequences resulting from innate immune system activation in the newborn infant. Those who survive infection have been exposed to a stimulus that can impose long-lasting alterations into later life. In this review, we discuss sepsis-driven alterations in integrated neuroendocrine and metabolic pathways and highlight current knowledge gaps in respect of neonatal sepsis. We review established biomarkers for sepsis and extend the discussion to examine emerging findings from human and animal models of neonatal sepsis that propose novel biomarkers for early identification of sepsis. Future research in this area is required to establish a greater understanding of the distinct neonatal signature of early and late-stage infection, to improve diagnosis, curtail inappropriate antibiotic use, and promote precision medicine through a biomarker-guided empirical and adjunctive treatment approach for neonatal sepsis. There is an unmet clinical need to decrease sepsis-induced morbidity in neonates, to limit and prevent adverse consequences in later life and decrease mortality.

A cohort study of the association between prenatal arsenic exposure and age at menarche in a rural area, Bangladesh

BackgroundMillions of individuals worldwide, particularly in Bangladesh, are exposed to arsenic, mainly through drinking water from tube wells. Arsenic is a reproductive toxicant, but there is limited knowledge of whether it influences pubertal development. ObjectivesWe evaluated the association between prenatal arsenic exposure and age at menarche. MethodsThis prospective study was based on data from two studies conducted in Matlab, Bangladesh—the Maternal and Infant Nutrition Interventions in Matlab (MINIMat) trial and the Health Consequences of Arsenic in Matlab (AsMat) study. We included 809 MINIMat girls who participated in assessing age at menarche from July 2016 to June 2017 and had prenatal arsenic exposure data through the AsMat study via measurements in tube well water used by the mothers during pregnancy. The exposure was categorized into <10, 10–49, 50–99, 100–199, and ≥200 µg/L. We used Kaplan-Meier and Cox proportional hazards analyses with adjustment for potential confounders to evaluate the association between arsenic exposure and age at menarche. The results were presented by adjusted hazards ratio (aHR) with a 95% confidence interval (CI). ResultsThe median arsenic concentration in tube well water consumed by pregnant women was 80 µg/L (interquartile range 2–262 µg/L), and 55% drank water with concentrations above Bangladesh’s acceptable value of 50 µg/L. The median age at menarche was 13.0 years. The unadjusted analysis revealed 3.2 months delay in menarche for girls exposed to arsenic concentrations ≥200 µg/L compared with the girl exposed to arsenic concentrations <10 µg/L. Girls exposed to the same higher arsenic concentrations were 23% (aHR 0.77, 95% CI: 0.63–0.95) less likely to have reached menarche than girls exposed to low arsenic concentrations. ConclusionsIncreased levels of prenatal arsenic exposure were associated with older age at menarche. This delay may indicate endocrine disruptions that could potentially result in adverse health consequences in later life. This finding, along with other severe adverse health reinforces the need for arsenic mitigation at the population level.

MiR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans.

Studying the evolutionary processes that shaped aging offers a path for understanding the causes of aging. The antagonistic pleiotropy theory for the evolution of aging proposes that the inverse correlation between age and natural selection strength allows positive selection of gene variants with early-life beneficial contributions to fitness despite detrimental late-life consequences. However, mechanistic understanding of how this principle manifests in aging is still lacking. We previously identified antagonistic pleiotropy in the function of the Caenorhabditis elegans JNK homolog KGB-1, which provided stress protection in developing larvae, but sensitized adults to stress and shortened their lifespan. To a large extent, KGB-1’s contributions depended on age-dependent and opposing regulation of the stress-protective transcription factor DAF-16, but the underlying mechanisms remained unknown. Here, we describe a role for the microRNA miR-71 in mediating effects of KGB-1 on DAF-16 and downstream phenotypes. Fluorescent imaging along with genetic and survival analyses revealed age-dependent regulation of mir-71 expression by KGB-1—upregulation in larvae, but downregulation in adults—and showed that mir-71 was required both for late-life effects of KGB-1 (infection sensitivity and shortened lifespan), as well as for early life resistance to cadmium. While mir-71 disruption did not compromise development under protein-folding stress (known to depend on KGB-1), disruption of the argonaute gene alg-1, a central component of the microRNA machinery, did. These results suggest that microRNAs play a role in mediating age-dependent antagonistic contributions of KGB-1 to survival, with mir-71 playing a central role and additional microRNAs potentially contributing redundantly.

Trajectories of Mother-Infant Communication: An Experiential Measure of the Impacts of Early Life Adversity.

Caretaking stability in the early life environment supports neurobehavioral development, while instability and neglect constitute adverse environments that can alter maturational processes. Research in humans suggests that different types of early life adversity (ELA) can have differential effects on caretaker relationships and later cognitive and social development; however, identifying mechanistic underpinnings will require animal models with translational validity. Two common rodent models, maternal separation (MS) and limited bedding (LB), influence the mother-infant relationship during a critical window of development. We hypothesized that these paradigms may affect the development of communication strategies on the part of the pup. Ultrasonic vocalizations (USVs) are a care-eliciting mechanism and ethologically relevant response to stressors in the rat pup. USV emission rates and acoustic parameters change throughout early development, presenting the opportunity to define developmental milestones in USVs that would reflect neurobehavioral aberrations if disrupted. This study investigated the effects of MS or LB on the dam-pup relationship by quantifying pup USVs, maternal behavior, and the relationship between the two. First, we used a generalized additive model approach to establish typical developmental trajectories of USV acoustic properties and determine windows of change in MS or LB rearing. Additionally, we quantified maternal behaviors and the predictability of maternal care sequences using an entropy rate calculation. MS and LB each shifted the developmental trajectories of USV acoustic parameters and call types in a sex-specific manner. MS more often impacted male USVs, while LB impacted female USVs. MS dams spent more time passive nursing, and LB dams spent more time on the nest. The predictability of maternal care was associated with the rate of USV emissions exclusively in females. Taken together, findings demonstrate sex- and model-specific effects of rearing environments on a novel developmental trajectory involving the mother-infant relationship, facilitating the translation of animal ELA paradigms to assess later-life consequences.

White matter changes following experimental pediatric traumatic brain injury: an advanced diffusion-weighted imaging investigation.

Pediatric traumatic brain injury (pTBI) is a major community health concern. Due to ongoing maturation, injury to the brain at a young age can have devastating consequences in later life. However, how pTBI affects brain development, including white matter maturation, is still poorly understood. Here, we used advanced diffusion weighted imaging (DWI) to assess chronic white matter changes after experimental pTBI. Mice at post-natal day 21 sustained a TBI using the controlled cortical impact model and magnetic resonance imaging (MRI) was performed at 6 months post-injury using a 4.7T Bruker scanner. Four diffusion shells with 81 directions and b-values of 1000, 3000, 5000, and 7000s/mm2 were acquired and analyzed using MRtrix3 software. Advanced DWI metrics, including fiber density, fiber cross-section and a combined fiber density and cross-section measure, were investigated together with three track-weighted images (TWI): the average pathlength map, mean curvature and the track density image. These advanced metrics were compared to traditional diffusion tensor imaging (DTI) metrics which indicated that TBI injured mice had reduced fractional anisotropy and increased radial diffusivity in the white matter when compared to age-matched sham controls. Consistent with previous findings, fiber density and TWI metrics appeared to be more sensitive to white matter changes than DTI metrics, revealing widespread reductions in fiber density and TWI metrics in pTBI mice compared to sham controls. These results provide additional support for the use of advanced DWI metrics in assessing white matter degeneration following injury and highlight the chronic outcomes that can follow pTBI.