Form Of Early Life Stress Research Articles

Abstract P353: Sexual dimorphism of blood pressure responses to angiotensin II in rats subjected to early life circadian stress

Various forms of early life stress (ELS) lead to a greater risk of hypertension, but no studies have examined stress produced by circadian disruption. We hypothesize that circadian stress during adolescence will increase sensitivity to a hypertensive stimulus in adulthood recapitulating other models of early life stress (ELS). We exposed male and female rats 1-2 weeks post-weaning to 6-hour phase advances (shifts) in the light/dark cycle each week for 4 weeks. To assess whether the molecular clock contributes to the response to ELS, we performed these studies in both Bmal1 knockout (KO) rats and littermate wildtype (WT) controls, Bmal1 is a core circadian clock transcription factor. At 10-12 weeks of age, baseline mean arterial pressure (MAP) was measured (telemetry) followed by a 2-wk angiotensin II (AngII) infusion (250 ng/kg/min, s.c.). At baseline, non-ELS KO rats of both sexes had lower MAP compared to WT littermates, but this genotype effect was lost in ELS rats. Thus, exposure to circadian stress early in life has only a modest effect on baseline blood pressure in rats lacking Bmal1. AngII increased MAP in all groups but was significantly attenuated in male ELS rats compared to non-ELS controls of both genotypes (p stress = 0.039, p genotype =0.979, p SxG =0.917, 2-way ANOVA), but this attenuation was not evident in female rats (p stress = 0.497, p genotype =0.041, p SxG =0.772). We also observed a significant phase advance in peak MAP in male non-ELS rats of both genotypes that was absent in ELS males (p Genotype =0.030, p AngII <0.001, p AngIIxGT =0.025). In contrast, there were no significant differences in peak MAP time in any female rats. The response to AngII was attenuated in ELS male, but not female rats. These data do not support our original hypothesis that exposure to circadian stress during adolescence induces hypersensitization to Ang II in rats but does reveal an impact on the timing of peak MAP in male rats. We propose that the attenuated MAP response to AngII seen in male rats following exposure to specific types of circadian stress during the post-weaning period may pre-condition rats against a subsequent hypertensive stimulus.

Effects of early-life stress on probabilistic reversal learning and response perseverance in young adults

Early life stress (ELS), including experiences with abuse and neglect, are related to several negative health outcomes in adulthood. One area that has received attention is the increased rate of substance abuse disorder in individuals who had experienced ELS. Given the critical role habitual behavior in the development of substance abuse, ELS may affect the trajectory of neural development such that habitual responding is more dominant than in individuals who did not experience ELS. Here, we examine learning of a probabilistic classification task (the Weather Prediction Task) in healthy young adults who reported significant ELS and those that did not. This task can be learned in a declarative, model-based manner, or in a more habitual, stimulus-response manner. Participants learned to choose the outcome (sun or rain) that was probabilistically associated with each cue combination through reinforcement on each trial. After 100 trials, the probabilities were reversed, and we conceptualized habitual behavior as perseverating responses based on the old probabilities. We also collected information about subjective socio-economic status (sSES), anxiety, depression, and substance use from participants. Using multiple regression, we found that our measure of habitual responding was correlated with reported alcohol use, suggesting that our measure of habit has validity for health behaviors. Furthermore, we found that some forms of early life stress led to greater response perseverance after contingencies were reversed. Overall, the results suggest that childhood adversity may contribute to the development of habit.

Echoes of early-life stress on suicidal behavior in individuals with substance use disorder

Introduction: Psychoactive substances abuse is considered a problematic social factor due its likelihood to cause harmful, self-destructive behaviors to the subjects and the overall society. Stress in an individual's early life may also be a contributing factor to substance abuse as well as suicide attempts. There is a lack of studies examining these factors in people with substance-use disorder. Aim: to identify the relationship between early-life stress and suicide attempts in drug-dependent adults. Methods: This is a predictive correlational study with a cross-sectional approach. The convenience sample consisted of 105 individuals treated at an outpatient unit for addiction treatment. The participants were assessed using the Mini-international Neuropsychiatric Interview, a Childhood Trauma Questionnaire to measure the severity of the different types of early life stress; the Beck Scale for Suicide Ideation was also used. The data were analyzed using descriptive and inferential statistics through univariate and multivariate logistic regression. Results: The analyzed sample included 33 (31.4%) individuals who attempted suicide and were significantly more likely to suffer from emotional, physical, or sexual abuse than those who had never attempted suicide (p <0,05). Conclusions: Different forms of early-life stress are related to attempted suicide in people with substance-use disorder. Further studies are needed to understand the effects of early-life stress on suicide attempts in drug-dependent people.

Human myeloid progenitor glucocorticoid receptor activation causes genomic instability, type 1 IFN- response pathway activation and senescence in differentiated microglia; an early life stress model.

One form of early life stress, prenatal exposure to glucocorticoids (GCs), confers a higher risk of psychiatric and neurodevelopmental disorders in later life. Increasingly, the importance of microglia in these disorders is recognized. Studies on GCs exposure during microglial development have been limited, and there are few, if any, human studies. We established an in vitro model of ELS by continuous pre-exposure of human iPS-microglia to GCs during primitive hematopoiesis (the critical stage of iPS-microglial differentiation) and then examined how this exposure affected the microglial phenotype as they differentiated and matured to microglia, using RNA-seq analyses and functional assays. The iPS-microglia predominantly expressed glucocorticoid receptors over mineralocorticoid receptors, and in particular, the GR-α splice variant. Chronic GCs exposure during primitive hematopoiesis was able to recapitulate in vivo ELS effects. Thus, pre-exposure to prolonged GCs resulted in increased type I interferon signaling, the presence of Cyclic GMP-AMP synthase-positive (cGAS) micronuclei, cellular senescence and reduced proliferation in the matured iPS-microglia. The findings from this in vitro ELS model have ramifications for the responses of microglia in the pathogenesis of GC- mediated ELS-associated disorders such as schizophrenia, attention-deficit hyperactivity disorder and autism spectrum disorder.

Cerebral Erythropoietin Prevents Sex-Dependent Disruption of Respiratory Control Induced by Early Life Stress.

Injuries that occur early in life are often at the root of adult illness. Neonatal maternal separation (NMS) is a form of early life stress that has persistent and sex-specific effects on the development of neural networks, including those that regulate breathing. The release of stress hormones during a critical period of development contributes to the deleterious consequences of NMS, but the role of increased corticosterone (CORT) in NMS-induced respiratory disturbance is unknown. Because erythropoietin (EPO) is a potent neuroprotectant that prevents conditions associated with hyperactivation of the stress neuroaxis in a sex-specific manner, we hypothesized that EPO reduces the sex-specific alteration of respiratory regulation induced by NMS in adult mice. Animals were either raised under standard conditions (controls) or exposed to NMS 3 h/day from postnatal days 3–12. We tested the efficacy of EPO in preventing the effects of NMS by comparing wild-type mice with transgenic mice that overexpress EPO only in the brain (Tg21). In 7-days-old pups, NMS augmented CORT levels ~2.5-fold by comparison with controls but only in males; this response was reduced in Tg21 mice. Respiratory function was assessed using whole-body plethysmography. Apneas were detected during sleep; the responsiveness to stimuli was measured by exposing mice to hypoxia (10% O2; 15 min) and hypercapnia (5% CO2; 10 min). In wild-type, NMS increased the number of apneas and the hypercapnic ventilatory response (HcVR) only in males; with no effect on Tg21. In wild-type males, the incidence of apneas was positively correlated with HcVR and inversely related to the tachypneic response to hypoxia. We conclude that neural EPO reduces early life stress-induced respiratory disturbances observed in males.

A role for gut microbiota in early-life stress-induced widespread muscle pain in the adult rat.

Adult rats that experienced neonatal limited bedding (NLB), a form of early-life stress, experience persistent muscle mechanical hyperalgesia. Since there is a growing recognition that the gut microbiome regulates pain and nociception, and that early-life stress produces a long-lasting impact on the gut microbiome, we tested the hypothesis that persistent muscle hyperalgesia seen in adult NLB rats could be ameliorated by interventions that modify the gut microbiome. Adult NLB rats received probiotics, either Lactobacillus rhamnosus GG (10 billion CFU/150 ml) or De Simone Formulation (DSF) (112.5 billion CFU/150 ml mixture of 8 bacterial species), in their drinking water, or non-absorbable antibiotics, rifaximin or neomycin, admixed with cookie dough, to provide 50 mg/kg. Mechanical nociceptive threshold in the gastrocnemius muscle was evaluated before and at several time points after administration of probiotics or antibiotics. Adult NLB rats fed probiotics L. Rhamnosus or DSF, antibiotics, as well as rats fed non-absorbable antibiotics rifaximin or neomycin, had markedly attenuated muscle mechanical hyperalgesia. We hypothesize that persistent skeletal muscle hyperalgesia produced by NLB stress may be, at least in part, due to a contribution of the gut microbiome, and that modulation of gut microbiome using probiotics or non-absorbable antibiotics, may be novel therapeutic approaches for the treatment of chronic musculoskeletal pain.

Sexual dimorphic role of the glucocorticoid receptor in chronic muscle pain produced by early-life stress.

Fibromyalgia and other chronic musculoskeletal pain syndromes are associated with stressful early life events, which can produce a persistent dysregulation in the hypothalamic-pituitary adrenal (HPA) stress axis function, associated with elevated plasm levels of corticosterone in adults. To determine the contribution of the HPA axis to persistent muscle hyperalgesia in adult rats that had experienced neonatal limited bedding (NLB), a form of early-life stress, we evaluated the role of glucocorticoid receptors on muscle nociceptors in adult NLB rats. In adult male and female NLB rats, mechanical nociceptive threshold in skeletal muscle was significantly lower than in adult control (neonatal standard bedding) rats. Furthermore, adult males and females that received exogenous corticosterone (via dams’ milk) during postnatal days 2–9, displayed a similar lowered mechanical nociceptive threshold. To test the hypothesis that persistent glucocorticoid receptor signaling in the adult contributes to muscle hyperalgesia in NLB rats, nociceptor expression of glucocorticoid receptor (GR) was attenuated by spinal intrathecal administration of an oligodeoxynucleotide (ODN) antisense to GR mRNA. In adult NLB rats, GR antisense markedly attenuated muscle hyperalgesia in males, but not in females. These findings indicate that increased corticosterone levels during a critical developmental period (postnatal days 2–9) produced by NLB stress induces chronic mechanical hyperalgesia in male and female rats that persists in adulthood, and that this chronic muscle hyperalgesia is mediated, at least in part, by persistent stimulation of glucocorticoid receptors on sensory neurons, in the adult male, but not female rat.

Early life stress alters transcriptomic patterning across reward circuitry in male and female mice

Abuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brain’s transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

Early Life Stress Delays Sexual Maturation in Female Mice.

In humans, some forms of early life stress (ELS) have been linked with precocious puberty, altered brain maturation, and increased risk for a variety of forms of pathology. Interestingly, not all forms of ELS have been found to equally impact these metrics of maturation. In recent work, we have found that ELS in the form of limited bedding (LB) from P4 to P11, was associated with precocious hippocampus maturation in males and increased risk for depressive-like pathology and attentional disturbance in female mice. Here, we sought to test whether ELS in the form of LB also impacted the timing of sexual maturation in female mice. To establish rate of somatic and sexual development, distinct cohorts of mice were tested for weight gain, timing of vaginal opening, and development of estrous cycling. ELS animals weighed significantly less than controls at every timepoint measured. Onset of vaginal opening was tracked from P21 to 40, and ELS was found to significantly delay the onset of vaginal opening. To test the impact of ELS on estrous cycle duration and regularity, vaginal cytology was assessed in independent groups of animals using either a continuous sampling (daily from P40 to P57) or random sampling approach (single swab at P35, P50, or P75). ELS did impact measures of estrous cycling, but these effects were dependent upon the sampling method used. We also tested the impact of ELS on anxiety-like behaviors over development and across the estrous cycle. We observed a developmental increase in anxiety-like behavior in control but not ELS mice. No effect of estrous cycle stage was found on anxiety-like behavior for either group of mice. Together these results provide evidence that ELS in the form of LB delays somatic and sexual development. Additional work will be required to determine the mechanism by which ELS impacts these measures, and if these effects are common to other models of ELS in rodents.

Early Attachment Disruption, Inflammation, and Vulnerability for Depression in Rodent and Primate Models.

Early experiments in nonhuman primates established the relation between disruption of filial attachment and depressive-like outcomes. Subsequent studies in rats and mice have been instrumental in linking depressive-like outcomes to disturbances in maternal behavior. Another aspect of attachment disruption, absence of the attachment object per se, may be studied more effectively in a different laboratory rodent—the guinea pig. Here, we discuss the rationale for using guinea pigs for this work. We then review guinea pig studies providing evidence for inflammatory mechanisms mediating both depressive-like behavior during separation as well as sensitization of stress responsiveness such as is thought to lead to increased vulnerability to depression at later ages. Finally, we discuss recent complementary work in adult monkeys that suggests cross-species generalizability of broad principles derived from the guinea pig experiments. Overall, the findings provide experimental support for human research implicating inflammatory mechanisms in the development of increased stress responsiveness and vulnerability to depression following attachment disruption and other forms of early-life stress. Specifically, the findings suggest inflammatory mechanisms may set in motion a cascade of underlying processes that mediate later increased stress responsiveness and, therefore, depression susceptibility.

A person-centered approach to the assessment of early life stress: Associations with the volume of stress-sensitive brain regions in early adolescence.

Researchers are becoming increasingly interested in linking specific forms of early life stress (ELS) to specific neurobiological markers, including alterations in the morphology of stress-sensitive brain regions. We used a person-centered, multi-informant approach to investigate the associations of specific constellations of ELS with hippocampal and amygdala volume in a community sample of 211 9- to 13-year-old early adolescents. Further, we compared this approach to a cumulative risk model of ELS, in which ELS was quantified by the total number of stressors reported. Using latent class analysis, we identified three classes of ELS (labeled typical/low, family instability, and direct victimization) that were distinguished by experiences of family instability and victimization. Adolescents in the direct victimization class had significantly smaller hippocampal volume than did adolescents in the typical/low class; ELS classes were not significantly associated with amygdala volume. The cumulative risk model of ELS had a poorer fit than did the person-centered model; moreover, cumulative ELS was not significantly associated with hippocampal or amygdala volume. Our results underscore the utility of taking a person-centered approach to identify alterations in stress-sensitive brain regions based on constellations of ELS, and suggest victimization is specifically associated with hippocampal hypotrophy observed in early adolescence.

17. Lifelong Transcriptional, Epigenetic, and Neurophysiological Consequences of Early Life Stress in Mouse Brain Reward Circuitry

Abuse, neglect, and other forms of early life stress (ELS) increase risk for depression. We recently established a “two-hit” stress paradigm in male and female mice, and found a sensitive period for postnatal stress to increase risk that stress in adulthood results in depression-like behavior. We sought to understand the long-lasting consequences of ELS on reward circuitry at transcriptional, epigenetic, and neurophysiological levels.

6.2 Harsh Physical Punishment and Aggression: Neurobiological Mediators and Influences of Other Forms of Environmental Risk

Consistent links exist between harsh physical punishment during childhood and risk for later aggressive and violent behavior in adolescence. Recent work has focused on how changes in brain regions such as the amygdala may mediate the linkage between harsh physical punishment and later aggression and violence. Past research has found that forms of early life stress, such as child maltreatment, are related to higher amygdala activity to facial displays of threat, but few links have been reported between amygdala activity and problem behavior in these sample groups.

Early Life Stress: Effects on the Regulation of Anxiety Expression in Children and Adolescents.

This study examined children's (N = 79; 9-10 years) and adolescents' (N = 82; 15-16 years) ability to regulate their emotion expressions of anxiety as they completed a modified version of the Trier Social Stress Test for Children (TSST-C). Approximately half in each age group were internationally adopted from institutional care (N = 79) and half were non-adopted, age-matched peers (N = 82). Institutional care was viewed as a form of early life stress. Coders who were reliable and blind to group status watched videos of the session to assess anxiety expressions using the Child and Adolescent Stress and Emotion Scale developed for this study. Children exhibited more expressions of anxiety than adolescents, and youth adopted from institutions showed more expressions of anxiety than their non-adopted counterparts. The role of early life stress on observed anxiety expressions remained significant after controlling for differences in age, physiological stress responses measured through salivary cortisol reactivity, and self-reports of stress during the TSST-C. This suggests possible deficits in the regulation of expressive behavior for youth with early life stress histories, which cannot be explained by experiencing the task as more stressful.

Effects of early life social stress on endocrinology, maternal behavior, and lactation in rats

Exposure to early life stress is a predictor of mental health disorders, and two common forms of early life stress are social conflict and impaired maternal care, which are predominant features of postpartum mood disorders. Exposure of lactating female rats to a novel male intruder involves robust social conflict and induces deficits in maternal care towards the F1 offspring. This exposure is an early life social stressor for female F1 pups that induces inefficient lactation associated with central changes in oxytocin (OXT), prolactin (PRL), and arginine vasopressin (AVP) gene expression in adult F1 females.The mothers of the rats in the current study were either allowed to raise their pups without exposure to a social stressor (control), or presented with a novel male intruder for 1h each day on lactation days 2–16 (chronic social stress). The effects of this early life chronic social stress (CSS) exposure on subsequent peripheral endocrinology, maternal behavior, and physiology were assessed.Exposure of female pups to early life CSS resulted in persistent alterations in maternal endocrinology at the end of lactation (attenuated prolactin and elevated corticosterone), depressed maternal care and aggression, increased restlessness and anxiety-related behavior, impaired lactation, and decreased saccharin preference. The endocrine and behavioral data indicate that early life CSS has long-term effects which are similar to changes seen in clinical populations of depressed mothers and provide support for the use of the chronic social stress paradigm as an ethologically relevant rodent model for maternal disorders such as postpartum depression and anxiety.

Neuroanatomical Correlates of Childhood Sexual Abuse: Identifying Biological Substrates for Environmental Effects on Clinical Phenotypes

Neuroanatomical Correlates of Childhood Sexual Abuse: Identifying Biological Substrates for Environmental Effects on Clinical Phenotypes

Effects of early life social stress on maternal behavior and neuroendocrinology

Maternal mood disorders such as depression and chronic anxiety can negatively affect the lives of both mothers and their adult offspring. An active focus of maternal depression and anxiety research has been the role of chronic social stress in the development of these disorders. Chronic exposure to social stress is common in humans, especially in lactating mothers, and postpartum mood disorders have been correlated with high levels of social conflict and low levels of social support. Recent studies have described an effective and ethologically relevant chronic social stress (CSS) based rodent model for postpartum depression and anxiety. Since CSS attenuates maternal behavior and impairs both dam and offspring growth, it was hypothesized that CSS is an ethologically relevant form of early life stress for the developing female offspring and may have effects on subsequent adult maternal behavior and neuroendocrinology. Dams exposed to early life CSS as infants display substantial increases in pup retrieval and nursing behavior that are specifically associated with attenuated oxytocin, prolactin, and vasopressin gene expression in brain nuclei involved in the control of maternal behavior. Since the growth patterns of both groups were similar despite substantial increases in nursing duration, the early life CSS dams exhibited an attenuated nursing efficiency. It is concluded that early life CSS has long term effects on the neuroendocrinology of maternal care (oxytocin and prolactin) which results in decreased nursing efficiency in the adult dams. The data support the use of early life CSS as an effective model for stress-induced impairments in nursing, such as those associated with postpartum depression and anxiety.

Early life stress increases anxiety-like behavior in Balbc mice despite a compensatory increase in levels of postnatal maternal care

A better understanding of the molecular and cellular mechanisms by which early life stress (ELS) modifies brain development and adult behavior is necessary for diagnosing and treating psychopathology associated with exposure to ELS. For historical reasons, most of the work in rodents has been done in rats and attempts to establish robust and reproducible paradigms in the mouse have proven to be challenging. Here we show that under normal rearing conditions, increased levels of postnatal maternal care are associated with a decrease in anxiety-like behavior in BALB/cByj offspring. Brief daily pup-dam separation (BDS) during the postnatal period was associated with increased postnatal maternal care but was surprisingly associated with increased anxiety-like behavior in adult offspring, providing the first example in which offspring receiving higher levels of postnatal maternal care are more anxious in adulthood. Plasma corticosterone levels were elevated in BDS pups even 3 h after the pups were reunited with the dam, suggesting that this paradigm represents a form of early life stress. We also show that levels of total RNA and DNA in the hippocampus reach a peak at postnatal day 14 and that exposure to BDS seems to inhibit this developmental growth spurt. We propose that exposure to stress during the postnatal period overrides the ability of high levels of postnatal maternal care to program anxiety-like behavior by inhibiting the normal growth spurt that characterizes this period.

Early Life Stress Alters Behavior, Immunity, and Microbiota in Rats: Implications for Irritable Bowel Syndrome and Psychiatric Illnesses

Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.

Neonatal endotoxin exposure modifies the acoustic startle response and circulating levels of corticosterone in the adult rat but only following acute stress

A variety of early life stressors have consistently been implicated in the development of psychopathology in adulthood. The current study investigates a rarely considered form of early life stress, bacterial infection, for its ability to induce psychopathology-like symptoms in adult rat. Specifically, neonatal rats were exposed to a simulated bacterial infection. In adulthood the acoustic startle response of these animals was evaluated both prior to and following exposure to restraint stress. Our results indicate that animals neonatally exposed to infection exhibit a significantly exaggerated acoustic startle response but only following exposure to stress. Additionally, we observed that adult animals neonatally exposed to infection, exhibited increased production of circulating corticosterone following stress, indicating potentiated hypothalamic pituitary adrenal axis activity as well as altered novelty seeking behaviour and locomotor activity. These results extend upon existing pre-clinical findings that indicate certain stressful early life events can predispose the adult animal to exhibit abnormal behaviour in adulthood.