Adverse effects of early-life stress:focus on the rodent neuroendocrine system

Early-life stress is associated with a high prevalence of mental illnesses such as post-traumatic stress disorders,attention-deficit/hyperactivity disorder,schizophrenia,and anxiety or depressive behavior,which constitute major public health problems.In the early stages of brain development after birth,events such as synaptogenesis,neuron maturation,and glial differentiation occur in a highly orchestrated manner,and external stress can cause adverse long-term effects throughout life.Our body utilizes multifaceted mechanisms,including neuroendocrine and neurotransmitter signaling pathways,to appropriately process external stress.Newborn individuals first exposed to early-life stress deploy neurogenesis as a stress-defense mechanism;however,in adulthood,early-life stress induces apoptosis of mature neurons,activation of immune responses,and reduction of neurotrophic factors,leading to anxiety,depression,and cognitive and memory dysfunction.This process involves the hypothalamus-pituitary-adrenal axis and neurotransmitters secreted by the central nervous system,including norepinephrine,dopamine,and serotonin.The rodent early-life stress model is generally used to experimentally assess the effects of stress during neurodevelopment.This paper reviews the use of the early-life stress model and stress response mechanisms of the body and discusses the experimental results regarding how early-life stress mediates stress-related pathways at a high vulnerability of psychiatric disorder in adulthood.

Distinct neuronal excitability alterations of medial prefrontal cortex in early-life neglect model of rats

Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.

Early-life galacto-oligosaccharides supplementation alleviates the small intestinal oxidative stress and dysfunction of lipopolysaccharide-challenged suckling piglets

Background:Galacto-oligosaccharides(GOS)are non-digestible food ingredients that promote the growth of beneficial bacteria in the gut.This study investigated the protective effect of the early-life GOS supplement on the piglets’gut function against the oxidative stress induced by lipopolysaccharide(LPS)-challenge.Methods:Eighteen neonatal piglets were assigned to three groups including CON,LPS and LPS+GOS groups.The piglets in CON group and LPS group received physiological saline,while those in LPS+GOS group received GOS solution for 13 d after birth.On d 14,the piglets in LPS group and LPS+GOS group were injected with LPS solutions,while the piglets in CON group were injected with the same volume of physiological saline.Results:The results showed that the early-life GOS supplement blocked the LPS-induced reactive oxygen species(ROS)secretion,malondialdehyde(MDA)production and the increase of pro-apoptotic factor expression.Meanwhile,the early-life GOS supplement improved the activities of antioxidant enzymes,disaccharidase enzymes activities,and digestive enzymes activities,and increased the mRNA abundance of the gene related to nutrient digestion and absorption and the relative protein expression of tight junction.The study also showed that the early-life GOS supplement improved the expression of Hemeoxygenase-1(HO-1)and NAD(P)H/quinone acceptor oxidoreductase-1(NQO-1),and activated the AMP-activated protein kinase(AMPK).Conclusions:These results suggested that GOS enhanced the gut function,reduced the ROS production and proapoptotic factors gene expression,and activated the AMPK signaling pathway in LPS-challenged piglets.

Neuroprotection and recovery from early-life adversity: considerations for environmental enrichment

In the laboratory,environmental enrichment（EE）is used as a protocol to understand the functional,behavioral and molecular mechanisms that underlie neural plasticity（van Praag et al.,2000;Sale et al.,2014）.In addition,it is utilized to provide supplementary resources to animals in order to maintain their well-being and to preserve the scientific validity of the study at hand（see http：//www.nap.edu/catalog/12910/guide-for-thecare-and-use-of-laboratory-animals-eighth）.

Fetal lung growth predicts the risk for early-life respiratory infections and childhood asthma

Background Early-life respiratory infections and asthma are major health burdens during childhood.Markers predicting an increased risk for early-life respiratory diseases are sparse.Here,we identified the predictive value of ultrasound-monitored fetal lung growth for the risk of early-life respiratory infections and asthma.Methods Fetal lung size was serially assessed at standardized time points by transabdominal ultrasound in pregnant women participating in a pregnancy cohort.Correlations between fetal lung growth and respiratory infections in infancy or early-onset asthma at five years were examined.Machine-learning models relying on extreme gradient boosting regressor or classifier algorithms were developed to predict respiratory infection or asthma risk based on fetal lung growth.For model development and validation,study participants were randomly divided into a training and a testing group,respectively,by the employed algorithm.Results Enhanced fetal lung growth throughout pregnancy predicted a lower early-life respiratory infection risk.Male sex was associated with a higher risk for respiratory infections in infancy.Fetal lung growth could also predict the risk of asthma at five years of age.We designed three machine-learning models to predict the risk and number of infections in infancy as well as the risk of early-onset asthma.The models’R2 values were 0.92,0.90 and 0.93,respectively,underscoring a high accuracy and agreement between the actual and predicted values.Influential variables included known risk factors and novel predictors,such as ultrasound-monitored fetal lung growth.Conclusion Sonographic monitoring of fetal lung growth allows to predict the risk for early-life respiratory infections and asthma.

The Nucleus Accumbens CRH–CRHR1 System Mediates Early-Life Stress-Induced Sleep Disturbance and Dendritic Atrophy in the Adult Mouse

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood,one of which is sleep disturbance.As the corticotropin-releasing hormone(CRH)–corticotropin-releasing hormone receptor 1(CRHR1)system and nucleus accumbens(NAc)play important roles in both stress responses and sleep-wake regulation,in this study we investigated whether the NAc CRH–CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice.Using the limited nesting and bedding material paradigm from postnatal days 2 to 9,we found that early-life stress disrupted sleep-wake behaviors during adulthood,including increased wakefulness and decreased non-rapid eye movement(NREM)sleep time during the dark period and increased rapid eye movement(REM)sleep time during the light period.The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure.Importantly,Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology,whereas NAc Crhr1 knockdown reversed these effects(including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy).Together,our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc,and highlight the critical role of the NAc CRH–CRHR1 system in modulating these negative outcomes evoked by early-life stress.

Early-life nutrition and metabolic disorders in later life:a new perspective on energy metabolism

Type 2 diabetes mellitus and metabolic disorders have become an epidemic globally.However,the pathogenesis remains largely unclear and the prevention and treatment are still limited.In addition to environmental factors during adulthood,early life is the critical developmental window with high tissue plasticity,which might be modified by external environmental cues.Substantial evidence has demonstrated the vital role of early-life nutrition in programming the metabolic disorders in later life.In this review,we aim to overview the concepts of fetal programming and investigate the effects of early-life nutrition on energy metabolism in later life and the potential epigenetic mechanism.The related studies published on PubMed database up to March 2020 were included.The results showed that both maternal overnutrition and undernutrition increased the riskes of metabolic disorders in offspring and epigenetic modifications,including DNA methylation,miRNAs,and histone modification,might be the vital mediators.The beneficial effects of early-life lifestyle modifications as well as dietary and nutritional interventions on these deleterious metabolic remolding were initially observed.Overall,characterizing the early-life malnutrition that reshapes metabolic disease trajectories may yield novel targets for early prevention and intervention and provide a new point of view to the energy metabolism.

Early-life stress alters sleep structure and the excitatory-inhibitory balance in the nucleus accumbens in aged mice

Background:Exposure to adverse experiences in early life may profoundly reshape the neurodevelopmental trajectories of the brain and lead to long-lasting behavioral and neural alterations.One deleterious effect of early-life stress that manifests in later life is sleep disturbance,but this has not been examined in aged mice and the underlying neural mechanisms remain unknown.Considering the important role of the nucleus accumbens (NAc) in the sleep-wake regulation,this study aimed to assess the effects of early-life stress on the sleep behaviors in aged mice and the potential involvement of the NAc in stress-induced sleep abnormalities.Methods:Twenty aged male C57BL/6 mice (>16 months,n =10 per group) were used in this study.During post-natal days 2 to 9,dams were provided with either sufficient (control) or a limited nesting and bedding materials (stressed).When the mice were 16 to 17 months old,their sleep-wake behaviors were recorded over 24 h using electroencephalogram and electromyelogram.The amount of each sleep-wake stage,mean duration,and stage transition was analyzed.Then,five animals were randomly chosen from each group and were used to measure the expression levels of vesicular glutamate transporter-1 (VGluT1) and vesicular transporters of γ-aminobutyric acid (VGAT) in the NAc using immunohistochemistry.Group comparisons were carried out using Student t test or analysis of variances when appropriate.Results:Compared with the control mice,the early-life stressed aged mice spent less time awake over 24 h (697.97 ± 77.47 min vs.631.33 ± 34.73 min,t17 =2.376,P =0.030),accordingly,non-rapid eye movement sleep time was increased (667.37 ± 62.07 min vs.723.54 ± 39.21 min,t17 =2.326,P =0.033) and mean duration of rapid eye movement sleep was prolonged (73.00 ± 8.98 min vs.89.39 ± 12.69 min,t17 =3.277,P =0.004).Meanwhile,we observed decreased VGluT1/VGAT ratios in the NAc in the stressed group (F(1,16) =81.04,P < 0.001).Conclusion:Early adverse experiences disrupt sleep behaviors in aged mice,which might be associated with the excitatory-inhibitory imbalance in the NAc.

Juvenile survival curves in a solitary ground squirrel with a prolonged hibernation:effects of individual characteristics,environment,and maternal investment

Juvenile survival is a key life-history influence on population dynamics and adaptive evolution.We analyzed the effects of individual chara-cteristics,early environment,and maternal investment on juvenile survival in a large solitary hibernating rodent-yellow ground squirrel Spermophilus fulvus using Cox mixed-effects models.Only 48%of weaned pups survived to dispersal and 17%survived to hibernation.Early life expectancy was primarily determined by individual characteristics and,to a lesser extent,by the early environment.The strongest and pos-itive predictor of juvenile survival was body mass which crucially affected mortality immediately after weaning.Males suffered higher mortality than females after the onset of dispersal;however,the overall difference between sexes was partly masked by high rates of mortality in the first days after emergence in both sexes.Later emerged juveniles had lower life expectancy than the earliest pups.The overall effect of local juvenile density was positive.Prolonged lactation did not enhance juvenile survival:Pups nursed longer survived shorter than the young nursed for a shorter period.Our findings support the hypothesis that females of S.fulvus cannot effectively regulate maternal expenditures to mitigate the effects of unfavorable conditions on their offspring.The strategy to deal with seasonal time constraints on life history in female S.fulvus suggests an early termination of maternal care at the cost of juvenile quality and survival.This female reproductive strategy corresponds to a"fast-solitary"life of folivorous desert-dwelling S.fulvus and other solitary ground squirrels with prolonged hibernation.

Perinatal variation and covariation of oxidative status and telomere length in yellow-legged gull chicks

The perinatal period is critical to survival and performance of many organisms.In birds,rapid postnatal growth and sudden exposure to aerial oxygen around hatching markedly affect the chick redox status,with potentially negative consequences on physiology mediated by oxidative stress.In addition,telomere length(TL)undergoes reduction during birds’early life,partly depending on oxidative status.However,relatively few studies have focused specifically on the changes in oxidative status and TL that occur immediately after hatching.In this study of the yellow-legged gull Larus michahellis,we found that chicks undergo a marked increase in plasma total antioxidant capacity and a marked decrease in the concentration of pro-oxidant molecules during the first days after hatching.In addition,TL in erythrocytes decreased by 1 standard deviation over the 4days post-hatching.Body mass and tarsus length covaried with total antioxidant capacity and concentration of pro-oxidants in a complex way,that partly depended on sex and laying order,suggesting that oxidative status can affect growth.Moreover,TL positively covaried with the concentration of pro-oxidant molecules,possibly because retention of high concentrations of pro-oxidant molecules results from mechanisms of prevention of their negative effects,including reduction in TL.Thus,this study shows that chicks undergo marked variation in oxidative status,which predicts growth and subsequent TL,prompting for more studies of the perinatal changes in the critical posthatching stages.

Learning strategies and the social brain:Missing elements in the link between developmental stress,song and cognition?

Bird songs may advertise aspects of cognition because song learning and learning speed in cognitive tasks are both affected by early-life environments.However,such relationships remain ambiguous in the literature.Here,I discuss 2 lines of research that may help to demystify links between song learning and cognition.First,learn­ing strategies should be considered when assessing performance to ensure that individual differences in learning ability are not masked by individual differences in learning strategies.Second,song characteristics should be as­sociated with social behavior because songs have a social purpose and,consequently,should be strongly related at functional and neural levels.Finally,if song learning and cognitive abilities are correlated because they de­velop concurrently and/or share or compete for the same resources,I discuss ways glucocorticoids may link ear­ly-life stress,song learning and cognitive ability,focusing particularly on oxidative stress as a potential mecha­nism.

Early life investment in antlers and body growth reflects adult performance in roe deer population under supplementary feeding conditions

Recent research has challenged the idea that cervid antlers are such costly traits,supporting the assertion early-life antler investment is an honest signal of adult phenotypic quality.However,inferences were made based on antler measurements while growing(velvet)and thus,studies on fully-formed clean antlers are needed to avoid possible bias caused by the inter-individual variation in antler growth phenology.We studied a semi-captive population of European roe deer inhabiting a sub-Mediterranean area(Valsemana research station)and living under optimal conditions(ad libitum food supply and veterinary care).Based on repeated measurements taken from 146 individuals,we assessed whether allocation to secondary sexual traits during early life affected body mass or antler development during adulthood.Furthermore,we evaluated which body measurements better predicted future male quality.Additionally,using 488 individuals,we described age-class-specific variation in male body measurements and assessed the decline in antler size between adult and senescent stages(i.e.magnitude of senescence).Results agree with the assertion that there is no negative effect of a high investment in antler during early life on adult antler size or body mass,but we suggest the use of clean antlers as a more robust and reliable measure.The variables that better predicted body mass during adulthood were yearling body mass and body size at 6 months.Antler score between 10 and 18 months resulted in the best indicator of adult antler size.Finally,we support the idea that the magnitude of senescence in antler size is smaller in environments with higher resource availability during winter.