Influence Of Early Life Stress Research Articles

Influence of Early-Life Stress on the Excitability of Dynorphin Neurons in the Adult Mouse Dorsal Horn

While early-life adversity has been associated with a higher risk of developing chronic pain in adulthood, the cellular and molecular mechanisms by which chronic stress during the neonatal period can persistently sensitize developing nociceptive circuits remain poorly understood. Here, we investigate the effects of early-life stress (ELS) on synaptic integration and intrinsic excitability in dynorphin-lineage (DYN) interneurons within the adult mouse superficial dorsal horn (SDH), which are important for inhibiting mechanical pain and itch. The administration of neonatal limited bedding between postnatal days (P)2 and P9 evoked sex-dependent effects on spontaneous glutamatergic signaling, as female SDH neurons exhibited a higher amplitude of miniature excitatory postsynaptic currents (mEPSCs) after ELS, while mEPSC frequency was reduced in DYN neurons of the male SDH. Furthermore, ELS decreased the frequency of miniature inhibitory postsynaptic currents selectively in female DYN neurons. As a result, ELS increased the balance of spontaneous excitation versus inhibition (E:I ratio) in mature DYN neurons of the female, but not male, SDH network. Nonetheless, ELS weakened the total primary afferent-evoked glutamatergic drive onto adult DYN neurons selectively in females, without modifying afferent-evoked inhibitory signaling onto the DYN population. Finally, ELS failed to significantly change the intrinsic membrane excitability of mature DYN neurons in either males or females. Collectively, these data suggest that ELS exerts a long-term influence on the properties of synaptic transmission onto DYN neurons within the adult SDH, which includes a reduction in the overall strength of sensory input onto this important subset of inhibitory interneurons. PerspectiveThis study suggests that chronic stress during the neonatal period influences synaptic function within adult spinal nociceptive circuits in a sex-dependent manner. These findings yield new insight into the potential mechanisms by which early-life adversity might shape the maturation of pain pathways in the central nervous system (CNS).

Early life stress modulates the genetic influence on brain structure and cognitive function in children

The enduring influence of early life stress (ELS) on brain and cognitive development has been widely acknowledged, yet the precise mechanisms underlying this association remain elusive. We hypothesize that ELS might disrupt the genome-wide influence on brain morphology and connectivity development, consequently exerting a detrimental impact on children's cognitive ability. We analyzed the multimodal data of DNA genotypes, brain imaging (structural and diffusion MRI), and neurocognitive battery (NIH Toolbox) of 4276 children (ages 9–10 years, European ancestry) from the Adolescent Brain Cognitive Development (ABCD) study. The genome-wide influence on cognitive function was estimated using the polygenic score (GPS). By using brain morphometry and tractography, we identified the brain correlates of the cognition GPSs. Statistical analyses revealed relationships for the gene-brain-cognition pathway. The brain structural variance significantly mediated the genetic influence on cognition (indirect effect = 0.016, PFDR < 0.001). Of note, this gene-brain relationship was significantly modulated by abuse, resulting in diminished cognitive capacity (Index of Moderated Mediation = −0.007; 95 % CI = −0.012 ∼ −0.002). Our results support a novel gene-brain-cognition model likely elucidating the long-lasting negative impact of ELS on children's cognitive development.

Differential Diagnosis of Major Depressive Disorder and Bipolar Disorder: Genetic and Hormonal Assessment and the Influence of Early-Life Stress.

Few studies have assessed biomarkers for the differentiation of major depressive disorder (MDD) and bipolar disorder (BD). However, some elements of depression such as hormones and receptors of the renin-angiotensin-adrenal system (RAAS), the hypothalamus-pituitary-adrenal (HPA) axis, and history of early-life stress (ELS) could be considered for differential diagnosis. Therefore, this study aimed to assess aldosterone and cortisol levels, MR and GR gene polymorphisms, and ELS as potential biomarkers for differentiating MDD and BD. This study presents a case-control design. Groups comprised samples for genetic, cortisol, and aldosterone analysis: healthy control (HC; n = 113/97/103), MDD (n = 78/69/67) and BD (n = 82/68/65) subjects. Furthermore, all subjects were assessed for diagnostic screening, the severity of depression, and history of ELS by applying MINI-PLUS, GRID-HDRS, and CTQ, respectively. In addition, genotype and allelic frequencies of GR (N363S, R22/23K and BclI) and MR (MI180V and -2G/C) polymorphisms were evaluated via PCR. Our findings demonstrate that basal aldosterone levels may be a biomarker for differentiating BD and MDD. Furthermore, ELS affects the HPA axis in BD, cortisol may be considered a biomarker for distinguishing BD and MDD, but only in the absence of ELS, and, finally, history of ELS and MR-2G/C variant alleles are factors that contribute to the severity of depressive symptoms in MDD and BD.

Age-related no-go P300 amplitudes are moderated by exposure to early-life stress

Deficits in inhibitory control are common with advancing age and may underlie declines in other complex cognitive functions. The inhibitory P300 event-related potential (ERP) generally decreases in amplitude with age, reflecting deficits in inhibitory performance evaluation and adaptation, with possible generators including precentral and inferior frontal gyri and midcingulate and parietal cortex. Exposure to early-life stress (ELS) is also associated with deficits in inhibitory control, smaller P300 amplitudes, and dysfunction in regions associated with P300 generation. Although biopsychosocial effects of ELS are evident in older adulthood, the influence of ELS on neural processes in later life is unknown. In the current study, 13 young adults and 21 healthy older adults completed a high-accuracy go/no-go task and the Juvenile Victimization Questionnaire (JVQ), an indicator of ELS. Regression analyses revealed significant central-parietal models, with smaller P300 amplitudes predicted by both older age and greater exposure to ELS. Age group*ELS interactions moderated P300 prediction at central and centro-parietal electrodes, such that older age predicted smaller P300 amplitudes only in those with lower to moderate ELS. Amplitudes did not significantly differ by age in those with higher ELS. Post-hoc within-age group correlations showed that greater ELS was associated with smaller P300 amplitudes in young adults. However, greater ELS was modestly associated with larger central amplitudes in older adults, potentially suggestive of anterior age-related compensatory recruitment to maintain high task performance. These findings suggest long-lasting neural implications of ELS that interact with normative neuro-cognitive aging processes, such that ELS may be an important risk factor for age-related cognitive decline.

Early Life Stress and Heart Function in the Pristane‐Induced Model of Systemic Lupus Erythematosus (SLE) in Mice

Early life stress (ELS) is defined as childhood adversity such as maltreatment (e.g., verbal and physical abuse), sexual abuse, and household dysfunction occurring prior to age 18. ELS is associated with increased risk of chronic disease and poorer health outcomes earlier in adulthood compared to those without exposure to ELS. SLE is an autoimmune disease most prevalent in women with high mortality from cardiovascular disease and influenced by environmental factors including psychosocial stress such as ELS. SLE affects multiple organs including the heart. Pericarditis and heart failure are known pathologies affecting SLE patients at a higher rate than patients without SLE, however the influence of ELS on heart disease development is unknown. We hypothesized that a mouse model of ELS, maternal separation with early weaning, MSEW, have increased risk of heart disease particularly in response to the development of SLE in adulthood. MSEW entails separating pups from the dam 4h/day (postnatal, PD 2 to 5) and 8h/day (PD 6 to 16) followed by weaning at PD17. Normally reared (NR) litters remain with the dam and are weaned at PD21. The pristane‐induced model of SLE uses a single intraperitoneal (i.p.) injection to induce SLE‐like symptoms in female mice. Previous data have shown that Anti‐Smith autoantibody is not elevated in the SLE animals at 5 months after the i.p. injection compared to the NR and MSEW controls (P=0.0514). However, there is an increase in the presence of Anti‐Smith autoantibody in the SLE animals at 6 months after the i.p. injection (P=0.0007). Therefore, our objective was to determine parameters of systolic and diastolic heart function in NR control mice (NR+CON), NR+SLE, MSEW, and MSEW+SLE at time points early in the development of SLE at 4 months post‐injection with a VEVO 3100 high resolution echocardiography. Systolic function assessed by Ejection Fraction (P=0.3535), Fractional Shortening (P=0.3301), Left ventricular Mass (P=0.9216), Left Ventricular Diastolic Volume (P=0.4767), and Left Ventricular Systolic Volume (P=0.9568) showed no significant differences. Similarly, diastolic function assessed by E/e’ ratio (P=0.9159), Myocardial Performance Index (P=0.2867), MV E/A ratio (P=0.9231), and e’/a’ ratio (P=0.1104) showed no significant differences. These results suggest that the pristane‐induced model of SLE or ELS did not induce systolic or diastolic dysfunction early in the development of SLE. Future work will focus on a longitudinal strategy for the identification of heart dysfunction in mice with SLE.

Macrophage inflammatory response increases in adult female exposed to neonate stress

Abstract Impacts of stress on the immune system vary depending on the nature, intensity, and time during which stress is experienced (eg, acute stress is pro-inflammatory vs chronic stress is anti-inflammatory). However, there is limited knowledge on the long-term impact of early life stress on immune responses. Given that immune programming occurs early in life and that immunity and stress both involve sexual dimorphisms, our hypothesis is that neonatal maternal separation (NMS) induces sex-specific immune alterations. Objective Our objective is to evaluate the influence of early life stress on immune response in adult and its dimorphism related to biological sex. Methods We used a well-established rat model of early life stress, NMS, in which we observed sex-specific modulations of the myeloid compartment. Thus, we evaluated the impact of NMS on macrophage activation using LPS stimulation of bone-marrow derived macrophages (BMDM) in vitro. Expression of activation (MHCII, CD40, CD86 and CD80) and maturation markers (SIRPα, CD11b, CD200 and CD200R) were analyzed by flow cytometry. TNF levels were measured by ELISA. Results LPS stimulation of female NMS BMDM had higher expression of activation markers compared to controls. Inflammatory cytokine levels, TNF, increased after LPS stimulation and further increased in female NMS, whereas male NMS level was lower than control male. Futhermore, LPS stimulation lowered CD200 receptor (CD200R) to a greater extent in male NMS than in female NMS. Conclusion These results suggest that NMS accentuates the pro-inflammatory response in adult female (but not in male) and will provide a strong base for improving sex-specific interventions in the context of diseases involving stress and the immune system. Supported by grants from CIHR, QRHN and CRIUCPQ

P456. The Effects of Early Life Stress on Tourette Syndrome-Relevant Pathology

Tourette syndrome (TS) has a marked male preponderance, its symptoms peak in adolescence, and typically improve with age. Stress is a critical environmental factor for TS. Acute stress exacerbates tics, and chronic psychosocial stress exposure in children and adolescents predicts TS symptom severity in the future. Here, we characterize the influence of early life stress (ELS) on the behavioral and cellular pathology relevant to TS.

Influence of early life stress on depression: from the perspective of neuroendocrine to the participation of gut microbiota.

Depression is the most common mental disorder and has become a heavy burden in modern society. Clinical studies have identified early life stress as one of the high-risk factors for increased susceptibility to depression. Alteration of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress is one of the key risk factors for depression susceptibility related to early life stress. Laboratory animal studies have demonstrated that maternal separation (MS) for extended periods elicits HPA axis changes. These changes persist into adulthood and resemble those present in depressed adult individuals, including hyperactivity of the HPA axis. In addition, there is growing evidence that inflammation plays an important role in depression susceptibility concerned with early life stress. Individuals that have experienced MS have higher levels of pro-inflammatory cytokines and are susceptible to depression. Recently, it has been found that the gut microbiota plays an important role in regulating behavior and is also associated with depression. The translocation of gut microbiota and the change of gut microbiota composition caused by early stress may be a reason. In this review, we discussed the mechanisms by which early life stress contributes to the development of depression in terms of these factors. These studies have facilitated a systematic understanding of the pathogenesis of depression related to early life stress and will provide new ideas for the prevention and treatment of depression.

Test of the Serotonin Transporter Gene × Early Life Stress Interaction Effect on Subjective Well‐Being and Loneliness Among Japanese Young Adults

AbstractThis study investigated whether aspects of early life environment (quality of parental relationship, frequency of parental violence including disciplinary violence, amount of parental attention, and family income during childhood) would affect one's subjective well‐being and loneliness later in life (i.e., during young adulthood). This study also investigated whether the negative influence of early life stress is greater among individuals with the SS genotype of the serotonin transporter‐linked polymorphic region (5‐HTTLPR) in the serotonin transporter gene. Participants were 568 university students whose genotypes were identified using nail samples. They reported their current levels of subjective well‐being and loneliness as well as their recollections of their early family environments. The results showed that less stressful early life environments, such as high levels of parents' relationship quality and parental attention, were positively (negatively) associated with subjective well‐being (loneliness), while frequent parental violence was negatively (positively) associated with subjective well‐being (loneliness). Nevertheless, the gene × environment interaction effects were consistently non‐significant—the SS genotype did not accentuate the effects of early life stress.

Influences of the menopause transition and adverse childhood experiences on peripheral basal inflammatory markers

ObjectiveTo characterize the influence of early life stress on peripheral basal inflammatory markers across the menopause transition. MethodsParticipants from the longitudinal Penn Ovarian Aging study were assessed for childhood adversity at study end (14 years) using the Adverse Childhood Experiences (ACE) questionnaire. Responses were categorized as low (0–1) or high (≥2) ACE exposure. The stored blood sample catalogue was reviewed to exclude those samples collected during use of medications that could impact immune status or medications suggestive of infection or allergies. Remaining blood samples (n ​= ​640) from 167 participants were assayed for interleukin-6 (IL-6), interleukin 1-beta (IL-1β), high sensitivity C-reactive protein (hsCRP), and tumor necrosis factor alpha (TNF-α). Menopause staging (premenopause, early transition, late transition, and postmenopause) was determined by questionnaire and menstrual diaries at yearly assessments. Generalized linear models for repeated measures were used to quantify the association between outcomes of interest (i.e., IL-6, IL-1β, hsCRP, and TNF-α) and exposures (i.e., menopause stage, ACE status, their interaction) while controlling for relevant covariates (i.e., BMI, smoking, age at first blood sample, and race). Inflammatory marker levels were log-transformed for modeling. ResultsLog IL-6 levels were higher in the late perimenopause versus premenopause (p ​= ​0.035). Menopause stage ​× ​ACE interaction was observed for log IL-6, IL-1β, and TNF-α (p ​= ​0.042, p ​= ​0.054, p ​= ​0.053, respectively); for individuals with high (≥2) ACE exposure, IL-6 was higher in the late perimenopause (p ​= ​0.015) while IL-1β and TNF-α were lower in the postmenopause versus premenopause (p ​= ​0.019 and p ​= ​0.020). ConclusionsResults from this investigation indicate that the late perimenopause stage may be a window of risk for inflammation, particularly for individuals with greater childhood adversity. Prospective studies designed to address childhood stress and inflammation across the menopause transition are needed to confirm these findings. Heightened inflammation, even if transitory, may have negative impact on healthy aging.

Clinical Outcomes of Severe Forms of Early Social Stress.

Early social stress, particularly severe but nevertheless frequent forms such as abuse and neglect, are among the major risk factors for the development of mental disorders. However, we only have very limited knowledge of the psychobiological disease mechanisms underlying the influence of early life stress and stress-related disorders during this vulnerable phase of life. Early stress can have long-lasting adverse effects on the brain and other somatic systems, e.g. through influences on brain development. In adulthood, the prior experience of abuse or neglect can result in complex clinical profiles. Besides conditions such as mood and anxiety disorders as well as posttraumatic stress disorder, substance use disorders (SUD) are among the most prevalent sequelae of early social stress. Current social stress further influences the development and maintenance of these disorders, e.g., by increasing the risk of relapses. In this chapter, we will first give an overview of currently used methods to assess the phenomenology and pathophysiology of stress-related disorders and then focus on the phenomenological and neurobiological background of the interaction between early social stress and SUD. We will give an overview of important insights from neuroimaging studies and will also highlight recent findings from studies using digital tools such as ecological momentary assessment or virtual reality to capture the influence of early social stress as well as current social stress in everyday life of persons with SUD.

Early Life Stress and the Onset of Obesity: Proof of MicroRNAs' Involvement Through Modulation of Serotonin and Dopamine Systems' Homeostasis.

Healthy persons hold a very complex system for controlling energy homeostasis. The system functions on the interconnected way between the nutritional, endocrine, neural, and epigenetic regulation, which includes the microRNAs (miRNAs). Currently, it is well accepted that experiences of early life stress (ELS) carry modification of the central control of feeding behavior, one of the factors controlling energy homeostasis. Recently, studies give us a clue on the modulation of eating behavior, which is one of the main factors associated with the development of obesity. This clue connected the neural control through the serotonin (5HT) and dopamine (DA) systems with the fine regulation of miRNAs. The first pieces of evidence highlight the presence of the miR-16 in the regulation of the serotonin transporter (SERT) as well as the receptors 1a (5HT1A) and 2a (5HT2A). On the other hand, miR-504 is related to the dopamine receptor D2 (DRD2). As our knowledge advance, we expected to discover other important pathways for the regulation of the energy homeostasis. As both neurotransmission systems and miRNAs seem to be sensible to ELS, the aim of this review is to bring new insight about the involvement of miRNAs with a central role in the control of eating behavior focusing on the influences of ELS and regulation of neurotransmission systems.

Influence of Early Life Stress on Alcohol and Crack Dependents

Background: Early life stress is a significant public health problem associated with increased rates of psychiatric disorders, especially those related to drug abuse. Objective: To identify the prevalence of early life stress in drug users, to compare the intensity of trauma in alcohol and crack users, and to relate the power of injury to the severity of drug dependence. Method: Cross-sectional analytical study with a sample of 105 alcohol and crack users treated by an outpatient service. The instruments for data collection were sociodemographic data questionnaire, the Mini-International Neuropsychiatric Interview, and the Severity of Dependence Scale. The categorical variables association was analyzed using the Chi-squared test, considering p < 0.05 significance. ANOVA was used to verify the variance. To assess the difference between sociographic and dependent variables, we used the Mann-Whitney and Kruskal-Wallis tests. Results: High prevalence of early stress and severity of dependence were identified, with higher rates among crack users. The early stress revealed in the Alcohol group high rates of emotional (88.7%) and physical (94.3%) neglect and in the Crack group significant frequency of physical (61.5%) emotional abuse (51.9%), sexual (46.2%), and emotional (78.8%) and physical (90.4%) neglect. Crack users are 2.6 times more likely to have been emotionally abused, and 2.1 times more likely to have been sexually abused during childhood when compared to the alcohol group. Conclusion: Early stress was prevalent with significant intensity in drug users, and evaluation of this problem is essential for a better understanding of these disorders.

Examining the Influence of Early Life Stress on Serum Lipid Profiles and Cognitive Functioning in Depressed Patients.

BackgroundEarly childhood adversity is a strong predictor of the development of major depressive disorder (MDD), but not all depressed patients experience early life stress (ELS). Cardio-metabolic diseases and cognitive deficits often coincide in MDD and worsen its course and outcome. Adverse childhood experiences have been associated with elevated risk for cardiovascular disease (CVD), but little is known on the impact of ELS on cardiovascular risk factors in MDD. Here, we examined MDD patients with and without ELS to explore the effects of ELS on serum lipid and lipoprotein levels and on cognitive performances of the patients.MethodsParticipants with a mean age of 35 years (18–55 years) were recruited from the university mental health clinic and general community. Three groups, matched in age, gender and lifestyle were examined: MDD patients with ELS (n = 21), MDD patients without ELS (n = 21), and healthy controls (n = 20). The following CVD risk factors were assessed: serum lipids (total cholesterol, triglycerides, high- and low-density lipoproteins), body mass index and exercise in a typical week. MDD severity was measured by the Beck Depression Inventory. Childhood Trauma Questionnaire was used to assess early life adversities. Executive functions and attentional processes were assessed by the Wisconsin Card Sorting and Conners’ Continuous Performance tests.ResultsMajor depressive disorder patients with ELS had higher serum triglyceride and lower HDL-cholesterol concentrations compared to MDD patients without ELS. Linear regression analysis revealed that the severity of ELS had a significant negative association with HDL-cholesterol levels and significant positive associations with the serum levels of TG and TC/HDL-cholesterol index. We also found significant associations between some specific trauma types and lipid profiles. Finally, we could detect significant associations between depression severity and specific domains of the cognitive tests as well as between lipid profiles and certain domains of the Wisconsin Card Sorting Test. However, we could not detect any association between the severity of ELS and cognitive performance.ConclusionAfter controlling for depressive symptom severity and lifestyle variables, ELS was found to be a strong predictor of serum lipid alterations. Several, inter-correlated pathways may mediate the undesirable effects of ELS on the course and outcome of MDD.

Dual influences of early life stress induced by limited bedding on walking adaptability and Bdnf/TrkB and Drd1/Drd2 gene expression in different mouse brain regions

Introduction Evidence suggests early life stress impairs development, quality of life and increases vulnerability to disease. One important aspect of the stress experience is its impact on cognitive-motor performance, which includes the ability to adapt walking according to the environmental conditions. This study aimed to investigate how early-life stress affects walking adaptability of mice, while investigating BDNF/TrkB and Drd1/Drd2 expression in different brain regions.Methods Briefly, we exposed male C56BL/6 to the limited bedding protocol (LB) from post-natal day (PND) 2 to PND9 and then tested animals in the ladder walking task at PND60. RT-qPCR was used to investigate gene expression in the mPFC, hippocampus, motor cortex and cerebellum 2 h after the taskResults LB induced a wide range of variability and therefore two distinct subgroups of animals within the LB group were established: a) superior performance (LB-SP); and b) inferior performance (LB-IP), compared to controls. Additionally, Drd1 gene expression was increased in the mPFC of LB-IP animals and in the cerebellum of LB-SP animals, while Drd2 expression was reduced in the hippocampus of the LB-IP group. BDNF exon IV gene expression in the mPFC and motor cortex was increased in both the LB-IP and LB-SP subgroups. TrkB gene expression in the hippocampus was reduced in the LB-IP group. A strong negative correlation was found between walking adaptability performance and BDNF exon IV gene expression in the motor cortex. Conversely, a positive correlation was found between walking adaptability performance and TrkB expression in the mPFC and a negative correlation in the hippocampus. Both Drd1 and Drd2 gene expression were negatively correlated with the ability to adapt walking.Conclusions Overall, our findings suggest exposure to early life stress leads to distinct walking adaptability phenotypes, which may be related to Drd1, Drd2, Bdnf exon IV and TrkB gene expression in brain regions that influence walking adaptability.

Early maternal separation promotes alterations in the thermoregulatory profile of adult Wistar rats

Stressful lifelong events may influence psychiatric diseases, like depression and anxiety. Interestingly, depressed patients have dysfunction of thermoregulatory cooling mechanisms. Thus, understanding the mechanisms related to the thermoregulatory changes in stress-related pathologies is important to better understand the symptoms and treatments for those diseases. However, the influence of early-life stress on the thermoregulatory profile of adults is unknown. In this study, we aimed to evaluate the thermoregulatory profile of adult male Wistar rats submitted to early-life stress by maternal separation (MS). On postnatal days 2–14, rats were submitted daily to MS for 3 h per day. At 3–4 months of age, anxiety-like behavior was evaluated using the open field test and elevated plus maze, depression-like behavior was evaluated using the forced swim test and thermoregulatory profile were also evaluated. In the behavioral tests, MS animals exhibited anxiety- and depression-like behaviors, and had higher core body temperatures during dark period of the circadian cycle, when compared to controls. In addition, MS animals presented higher hyperthermic and vasoconstriction responses than control animals when exposed to the warmth environment, and engaged in cold-seeking behavior whenever possible to select their preferred ambient temperature. The results suggest that, besides emotional alterations, MS induces a change in the thermoregulatory profile of rats that persists into adulthood.

The influence of early life stress on the integration of emotion and working memory

IntroductionEarly life stress (ELS) impacts emotional and cognitive competences. We aimed to investigate whether the effects of ELS on working memory (WM) performance depend on the valence of the stimuli. MethodsBetween January and October 2015, we recruited (N=31) healthy subjects with (N=15) and without (N=16) ELS experiences. Participants performed a WM-task with emotional stimuli. ResultsResults show a trend towards decreased WM accuracy in subjects with ELS experiences (p=.06) with increased WM accuracy (p=.08) and an altered pattern of BOLD responses in the left posterior cingulate cortex (PCC)/precuneus (p<.001) and the rostral anterior cingulate cortex (rACC) (p<.01) in response to negative stimuli. LimitationsThe small sample size and potential confounding factors should be considered when interpreting the results. ConclusionOur data suggests that negative valence influences cognitive performance and brain activity in subjects with ELS experiences.

Catechol-O-Methyltransferase gene (val158met) polymorphisms and anxious symptoms in early childhood: The roles of hypothalamus-pituitary-adrenal axis reactivity and life stress.

Individual differences in hypothalamus-pituitary-adrenal (HPA) axis reactivity to stress (measured via salivary cortisol) have been widely implicated in the etiology of internalizing problems such as depression and anxiety. Literature suggests that stress during early childhood is an important source of contextual risk although its effects may be moderated by polymorphisms of neurotransmitter genes. The COMT val158met is one such polymorphism, and literature documents its link to internalizing problems. To extend these findings, and to better understand the role of this polymorphism in developmental risk, we investigated links between the val158met polymorphism and early-age cortisol response. Additionally, we investigated whether cortisol reactivity mediated the link between COMT and emerging internalizing symptoms. The study was conducted in a community sample of 409 preschoolers. Saliva samples were collected pre-stress task (baseline) and every 10min post-stress task for one-hour to asses cortisol response. Child anxious and depressive symptoms were tabulated based on parent-reports. Markers of early childhood stress included marital discord, socio-economic status and the UCLA Life Stress Interview. Findings indicated that the val158met polymorphism is associated with childhood cortisol response (p<0.05). A gene-environment interaction between val158met and life stress also predicted child anxiety symptoms (p<0.01). Finally, cortisol response mediated the main-effect of val158met on child anxiety symptoms (pathway ps<0.05). Analyses suggest that COMT val158met moderates the influence of early life stress on preschool-age symptoms of anxiety. Additionally, cortisol reactivity acts as a mechanistic mediator of the main-effect of COMT genotype on child anxious symptoms.

The interplay of genetic and environmental factors in shaping well-being across the lifespan: Evidence from the serotonin transporter gene

ABSTRACTBackground: Converging evidence suggests that well-being plays an important role in promoting and maintaining mental health across the life span. It has been shown that well-being has a considerable heritable component, but little is known about the specific genes involved.Methods: In this study, we investigated a healthy sample (N = 298) that was genotyped for the serotonin transporter-linked polymorphic region (5-HTTLPR). We hypothesized that 5-HTTLPR gene variation would influence well-being, and additionally investigated interaction effects with age and the environmental influence of early life stress (ELS).Results: Using multiple regression, our results showed a significant three-way interaction between genotype, ELS, and age. Exploration of this interaction showed that young subjects had decreased levels of well-being if they were exposed to ELS and homozygous for the short variant of 5-HTTLPR. This relationship was reversed in old age: subjects that were exposed to ELS and carried the long variant of 5-HTTLPR had decreased levels of well-being.Conclusion: Our results indicate that genetic and environmental factors have joint effects on well-being that are susceptible to profound changes across the life span.

Stressing out in medieval Denmark: An investigation of dental enamel defects and age at death in two medieval Danish cemeteries

The influence of early life stress on later life experiences has become a major focus of research in medicine and more recently in bioarchaeology. Dental enamel, which preserves a record of childhood stress events, represents an important resource for this investigation when paired with the information from adult skeletal remains, such as age at death. The purpose of this research was to use a life history approach to the exploration of sex differences in the relationship between childhood stress and adult longevity by examining accentuated striae of Retzius (AS). A medieval Danish sample (n=70) drawn from the rural cemetery of Sejet and the urban cemetery of Ole Wormsgade was considered for AS and age at death. The results suggest sex differences in survivorship, with more stress being associated with reduced survivorship in males and increased survivorship in females. A consideration of AS formation time also suggests a difference in the impact of developmental timing between males and females. These results are interpreted in terms of differential frailty and selective mortality, drawing in both biomedical and cultural perspectives.