Infant-caregiver experiences are major contributing factors to neural and behavioral development. Research continues to indicate that epigenetic mechanisms provide a way in which infant-caregiver experiences affect gene activity and other downstream processes in the brain that influence behavioral development. Our laboratory previously demonstrated in a rodent model that exposure to maltreatment alters methylation of DNA associated with thebrain derived neurotrophic factor(bdnf)andreelingenes as well as mRNA of key epigenetic regulatory genes in the medial prefrontal cortex (mPFC). In the current study we characterized patterns of histone acetylation atbdnfandreelingene loci after our caregiver manipulations. Using a within-litter design (n=8–10/group from 8 litters), pups were exposed to adverse (maltreatment condition: exposure to a stressed caregiver) or nurturing (cross-foster condition: exposure to a nurturing caregiver) caregiving environments outside the home cage for 30 minutes each day during the first postnatal week. Remaining pups in a litter were left with the biological mother during each session (providing normal care controls). We then used chromatin immunoprecipitation (ChIP) and quantitative RT-PCR to measure histone 3 lysine 9/14 acetylation atbdnfexons I and IV and thereelinpromoter in the adult mPFC. Maltreated females had decreased acetylation atbdnf IV,while neither males nor females exhibited histone acetylation alterations atbdnf Ior thereelinpromoter. These data demonstrate the ability of maltreatment to have long-term consequences on histone acetylation in the mPFC, and provide further evidence of the epigenetic susceptibility ofbdnf IVto the quality of infant-caregiver experiences.
Exogenous cortisol administration has been used to test the influence ofglucocorticoids on a variety of outcomes, including memory and affect. Carefulcontrol of factors known to influence cortisol and other endogenous hormonelevels is central to the success of this research. While use of hormonal birthcontrol (HBC) is known to exert many physiological effects, including decreasingthe salivary cortisol response to stress, it is unknown how HBC influencescirculating cortisol levels after exogenous cortisol administration. Todetermine those effects, we examined the role of HBC on participants’cortisol levels after receiving synthetic cortisol (hydrocortisone) in twoseparate studies. In Study 1, 24 healthy women taking HBC and 26 healthy menwere administered a 0.1 mg/kg body weight intravenous dose of hydrocortisone,and plasma cortisol levels were measured over 3 hours. In Study 2, 61participants (34 women; 16 were on HBC) received a 15 mg hydrocortisone pill,and salivary cortisol levels were measured over 6 hours. Taken together, resultsfrom these studies suggest that HBC use is associated with a greater cortisolincrease following cortisol administration. These data have importantmethodological implications: (1) when given a controlled dose of hydrocortisone,cortisol levels may increase more dramatically in women taking HBC vs. women noton HBC or men; and (2) in studies manipulating cortisol levels, women onhormonal contraceptives should be investigated as a separate group.
Chronic stress causes hypothalamo-pituitary-adrenal (HPA) axis hyperactivity and cardiovascular dyshomeostasis. Noradrenergic neurons in the nucleus of the solitary tract (NTS) are considered to play a role in these changes. Here, we tested the hypothesis that NTS noradrenergic A2 neurons are required for cardiovascular and HPA axis responses to both acute and chronic stress. Adult male rats received bilateral microinjection into the NTS of 6-hydroxydopamine (6-OHDA) to lesion A2 neurons cardiovascular study, n= 5; HPA study, n= 5], or vehicle cardiovascular study, n= 6; HPA study, n= 4]. Rats were exposed to acute restraint stress followed by 14 days of chronic variable stress (CVS). On the last day of testing, rats were placed in a novel elevated plus maze (EPM) to test post-CVS stress responses. Lesions of NTS A2 neurons reduced the tachycardic response to acute restraint, confirming that A2 neurons promote sympathetic activation following acute stress. In addition, CVS increased the ratio of low frequency to high frequency power for heart rate variability, indicative of sympathovagal imbalance, and this effect was significantly attenuated by 6-OHDA lesion. Lesions of NTS A2 neurons reduced acute restraint-induced corticosterone secretion, but did not affect the corticosterone response to the EPM, indicating that A2 neurons promote acute HPA axis responses, but are not involved in CVS-mediated HPA axis sensitization. Collectively, these data indicate that A2 neurons promote both cardiovascular and HPA axis responses to acute stress. Moreover, A2 catecholaminergic neurons may contribute to the potentially deleterious enhancement of sympathetic drive following chronic stress.
Perceived stress is associated with poor health outcomes including negative affect, increased susceptibility to the common cold, and cardiovascular disease; the consequences of perceived stress for mortality, however, have received less attention. This study characterizes the relationship between perceived stress and 11-year mortality in a population of Taiwanese adults aged 53+. Using the Survey of Health and Living Status of the Near Elderly and Elderly of Taiwan, we calculated a composite measure of perceived stress based on six items pertaining to the health, financial situation, and occupation of the respondents and their families. Proportional hazard models were used to determine whether perceived stress predicted mortality. After adjusting for sociodemographic factors only, we found that a one standard deviation increase in perceived stress was associated with a 19% increase in all-cause mortality risk during the 11-year follow-up period (HR=1.19, 95% CI 1.13–1.26). The relationship was greatly attenuated when perceptions of stress regarding health were excluded, and was not significant after adjusting for medical conditions, mobility limitations, and depressive symptoms. We conclude that the association between perceived stress and mortality is explained by an individual's current health; however, our data do not allow us to distinguish between two possible interpretations of this conclusion: a) the relationship between perceived stress and mortality is spurious, or b) poor health acts as the mediator.
Previous studies suggest that multiple corticolimbic and hypothalamic structures are involved in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, including the dorsomedial hypothalamus (DMH), but a potential role of the DMH has not been directly tested. To investigate the role of the DMH in glucocorticoid-mediated negative feedback, adult male Sprague Dawley rats were implanted with jugular cannulae and bilateral guide cannulae directed at the DMH, and finally were either adrenalectomized (ADX) or were subjected to sham-ADX. Adrenalectomized rats received CORT replacement in the drinking water (25 μg/ml), which, based on initial studies, restored a rhythm of plasma CORT concentrations in ADX rats that was similar in period and amplitude to the diurnal rhythm of plasma CORT concentrations in sham-ADX rats, but with a significant phase delay. Following recovery from surgery, rats received microinjections of either CORT (10 ng, 0.5 μL, 0.25 μL/min, per side) or vehicle (aCSF containing 0.2% EtOH), bilaterally, directly into the DMH, prior to a 40 min period of restraint stress. In sham-ADX rats, bilateral intra-DMH microinjections of CORT, relative to bilateral intra-DMH microinjections of vehicle, decreased restraint stress-induced elevation of endogenous plasma CORT concentrations 60 minutes after the onset of intra-DMH injections. Intra-DMH CORT decreased the overall area under the curve for plasma CORT concentrations during the intermediate time frame of glucocorticoid negative feedback, from 0.5–2 h following injection. These data are consistent with the hypothesis that the DMH is involved in feedback inhibition of HPA axis activity at the intermediate time frame.
Adolescence represents a uniquely sensitive developmental stage in the transition from childhood to adulthood. During this transition, neuronal circuits are particularly susceptible to modification by experience. In addition, adolescence is a stage in which the incidence of anxiety disorders peaks in humans and over 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents. While postnatal critical periods of plasticity for primary sensory processes, such as in the visual system are well established, less is known about potential critical or sensitive periods for fear learning and memory. Here, we review the nonlinear developmental aspects of fear learning and memory during a transition period into and out of adolescence. We also review the literature on the non-linear development of GABAergic neurotransmission, a key regulator of critical period plasticity. We provide a model that may inform improved treatment strategies for children and adolescents with fear-related disorders.
Extensive research among adults supports the biopsychosocial (BPS) model of challenge and threat, which describes relationships among stress appraisals, physiological stress reactivity, and performance; however, no previous studies have examined these relationships in adolescents. Perceptions of stressors as well as physiological reactivity to stress increase during adolescence, highlighting the importance of understanding the relationships among stress appraisals, physiological reactivity, and performance during this developmental period. In this study, 79 adolescent participants reported on stress appraisals before and after a Trier Social Stress Test in which they performed a speech task. Physiological stress reactivity was defined by changes in cardiac output and total peripheral resistance from a baseline rest period to the speech task, and performance on the speech was coded using an objective rating system. We observed in adolescents only two relationships found in past adult research on the BPS model variables: (1) pre-task stress appraisal predicted post-task stress appraisal and (2) performance predicted post-task stress appraisal. Physiological reactivity during the speech was unrelated to pre- and post-task stress appraisals and to performance. We conclude that the lack of association between post-task stress appraisal and physiological stress reactivity suggests that adolescents might have low self-awareness of physiological emotional arousal. Our findings further suggest that adolescent stress appraisals are based largely on their performance during stressful situations. Developmental implications of this potential lack of awareness of one’s physiological and emotional state during adolescence are discussed.
Stressors are typically multidimensional, comprised of multiple physical and sensory components that rarely occur as single isolated events. In this study, the functional activation patterns of key corticolimbic structures in response to context exposure alone, its combination with restraint, and how prior experience with either of these modulates subsequent activation was measured using Fos expression. On day 1, rats were transported to a novel context and either restrained for 6 hours or left undisturbed. On day 2, these two groups were either restrained or not in the same context, then processed for Fos immunohistochemistry. Regardless of previous experience, rats in context and not restrained expressed more Fos-like immunoreactive (IR) labeling in CA1 and CA3 of dorsal hippocampus, and basolateral and central amygdala, while this pattern was reversed in the dentate gyrus infrapyramidal blade. Conversely for the infralimbic region of the medial prefrontal cortex (mPFC), the previous day's experience with restraint or immediate experience with restraint elevated Fos-like IR compared to rats placed in context on both days. These data show that exposure to context produces robust Fos induction in the hippocampus and amygdala, regardless of prior experience with restraint and compared to the immediate experience to restraint, with prior experience modulating Fos expression within the mPFC.
Corticotropin-releasing hormone (CRH) contributes crucially to the regulation of central and peripheral responses to stress. Because of the importance of a finely tuned stress system, CRH expression is tightly regulated in an organ- and brain region-specific manner. Thus, in the hypothalamus, CRH is constitutively expressed and this expression is further enhanced by stress; however, the underlying regulatory mechanisms are not fully understood. The regulatory region of thecrhgene contains several elements, including the cyclic-AMP response element (CRE), and the role of the CRE interaction with the cyclic-AMP response element binding protein (CREB) in CRH expression has been a focus of intensive research. Notably, whereas thousands of genes contain a CRE, the functional regulation of gene expression by the CRE:CREB system is limited to ~100 genes, and likely requires additional proteins. Here, we investigated the role of a member of the CREB complex, CREB binding protein (CBP), in basal and stress-induced CRH expression during development and in the adult. Using mice with a deficient CREB-binding site on CBP, we found that CBP:CREB interaction is necessary for normal basal CRH expression at the mRNA and protein level in the nine-day-old mouse, prior to onset of functional regulation of hypothalamic CRH expression by glucocorticoids. This interaction, which functions directly oncrhor indirectly via regulation of other genes, was no longer required for maintenance of basal CRH expression levels in the adult. However, CBP:CREB binding contributed to stress-induced CRH expression in the adult, enabling rapid CRH synthesis in hypothalamus. CBP:CREB binding deficiency did not disrupt basal corticosterone plasma levels or acute stress-evoked corticosterone release. Because dysregulation of CRH expression occurs in stress-related disorders including depression, a full understanding of the complex regulation of this gene is important in both health and disease.
Developmental plasticity models hypothesize the role of genetic and prenatal environmental influences on the development of the hypothalamic–pituitary–adrenal (HPA) axis and highlight that genes and the prenatal environment may moderate early postnatal environmental influences on HPA functioning. This article examines the interplay of genetic, prenatal and parenting influences across the first 4.5 years of life on a novel index of children’s cortisol variability. Repeated measures data were obtained from 134 adoption-linked families, adopted children and both their adoptive parents and birth mothers, who participated in a longitudinal, prospective US domestic adoption study. Genetic and prenatal influences moderated associations between inconsistency in overreactive parenting from child age 9 months to 4.5 years and children’s cortisol variability at 4.5 years differently for mothers and fathers. Among children whose birth mothers had high morning cortisol, adoptive fathers’ inconsistent overreactive parenting predicted higher cortisol variability, whereas among children with low birth mother morning cortisol adoptive fathers’ inconsistent overreactive parenting predicted lower cortisol variability. Among children who experienced high levels of prenatal risk, adoptive mothers’ inconsistent overreactive parenting predicted lower cortisol variability and adoptive fathers’ inconsistent overreactive parenting predicted higher cortisol variability, whereas among children who experienced low levels of prenatal risk there were no associations between inconsistent overreactive parenting and children’s cortisol variability. Findings supported developmental plasticity models and uncovered novel developmental, gene × environment and prenatal × environment influences on children’s cortisol functioning.
Exposure to early life stress dramatically impacts adult behavior, physiology, and neuroendocrine function. Using rats bred for novelty-seeking differences and known to display divergent anxiety, depression, and stress vulnerability, we examined the interaction between early life adversity and genetic predisposition for high- versus low-emotional reactivity. Thus, bred Low Novelty Responder (bLR) rats, which naturally exhibit high anxiety- and depression-like behavior, and bred High Novelty Responder (bHR) rats, which show low anxiety/depression together with elevated aggression, impulsivity, and addictive behavior, were subjected to daily 3 h maternal separation (MS) stress postnatal days 1–14. We hypothesized that MS stress would differentially impact adult bHR/bLR behavior, physiology (stress-induced defecation), and neuroendocrine reactivity. While MS stress did not impact bHR and bLR anxiety-like behavior in the open field test and elevated plus maze, it exacerbated bLRs’ already high physiological response to stress – stress-induced defecation. In both tests, MS bLR adult offspring showed exaggerated stress-induced defecation compared to bLR controls while bHR offspring were unaffected. MS also selectively impacted bLRs’ (but not bHRs’) neuroendocrine stress reactivity, producing an exaggerated corticosterone acute stress response in MS bLR versus control bLR rats. These findings highlight how genetic predisposition shapes individuals’ response to early life stress. Future work will explore neural mechanisms underlying the distinct behavioral and neuroendocrine consequences of MS in bHR/bLR animals.
Past studies have demonstrated that increases in cortisol secretion are associated with either enhancements or impairments of long-term memory, depending on the subprocess involved. However, working memory is generally studied as a unified system within the cortisol literature. The present study sought to determine if cortisol increases are positively associated with increases in performance in the encoding subprocess of working memory, and whether increases are positively or negatively associated with performance changes in the maintenance subprocess. Thirty-three young men (M= 19.4 years,SD= 0.89) participated in a change detection task, consisting of a condition requiring encoding only and a condition requiring both encoding and maintenance. To elicit a cortisol response, participants completed the Trier Social Stress Test (TSST) between two administrations of the task. Cardiovascular measurements and saliva samples were obtained before the TSST (T1), and mid-way between blocks of the second administration of the change detection task (T2), to measure autonomic and cortisol responses to the TSST evident during the second change detection task. Cortisol increases between T1 and T2 were positively correlated with both encoding (r(32) = 0.503,p= 0.003) and maintenance (r(32) = 0.463,p= 0.007) performance. This is a novel finding as previous studies have shown an impairing effect of cortisol on working memory. The positive relation between cortisol and working memory has likely been obscured in previous tasks, which did not examine these specific subprocesses in isolation from each other. The beneficial role of cortisol in the stress response is discussed.
Allostatic load theory implies a relationship between exposure to psychological stress and multi-system physiological dysregulation. We used data from population-based samples in Russia (Moscow), Taiwan, and the United States (US)—which are likely to vary widely with respect to levels of stress exposure and biological markers—to determine the magnitude of the association between perceived stress and physiological dysregulation. The measure of overall dysregulation is based on 15 markers including standard cardiovascular/metabolic risk factors as well as markers of inflammation and neuroendocrine activity. Subjective psychological stress was measured by the perceived stress scale. Only the Moscow sample demonstrated a positive association with overall dysregulation in both sexes. In the US, we found an association among women but not men. Among the Taiwanese, who report the lowest perceived stress, there was no association in women but an unexpectedinverserelationship in men. The effects also varied across system-level subscores: the association with perceived stress was most consistent for standard cardiovascular/metabolic factors. Perceived stress was associated with inflammation and neuroendocrine activity in some samples. Although the evidence that exposure to stressors or perceived stress is the primary source of physiological dysregulation is generally modest, it is stronger in Russia where the level of perceived stress is particularly high. For Russia only, we also have information about heart function based on a 24h ambulatory electrocardiogram; perceived stress was consistently associated with heart rate dysregulation in Russian men and women.
This study compared cortisol responses to a standardized psychosocial stressor during a major depressive episode (MDE) and again during remission in adolescents and young adults. Participants were 26 individuals with no personal or family history of a major psychiatric disorder (NC) and 24 individuals with a diagnosis of major depressive disorder (MDD) at Time 1. The MDD group showed robust cortisol responses during their index episode and after recovery. In contrast, the NC group showed habituation to the repeated psychosocial stressor, as evident in a flatter cortisol response profile at Time 2. Within the MDD group, net peak cortisol during the first stress test was positively associated with the duration of the index MDE and negatively associated with the total duration of all MDEs. Whereas summary indices of cortisol responses were relatively stable across repeated stress tasks within the MDD group, this was not the case for NC. Results demonstrate that cortisol responses fail to habituate to repeated psychosocial stress during recovery from an MDE and could reflect a trait-like marker of risk for recurrence.
Prior studies have indicated that post-encoding stress can protect memories from the effects of forgetting, and this has been taken as evidence that stress facilitates memory consolidation. However, it is not known whether stress acts by directly influencing the strength of the underlying memories or whether it influences the generation process that plays a critical role in tests such as free recall. To address this issue, we examined the effects of stress produced by skydiving on recognition memory for negative and neutral pictures. Relative to a non-stress control condition, post-encoding stress in males was found to increase recognition memory for neutral pictures. However, stress was not found to improve recognition for emotional pictures, nor was it found to influence recognition memory in female participants. Additional analysis of recognition performance suggested that stress increased familiarity-based recognition rather than recollection. The current study indicates that stress can improve familiarity-based recognition, thus showing that that stress directly increases the strength of the underlying memories.
Previous research on the association between maternal daily stress and cortisol in pregnancy has yielded inconsistent findings. However, past studies have not considered whether stressful experiences in childhood impact maternal cortisol regulation in pregnancy. In this pilot study we aimed to examine whether the association between maternal daily stress and cortisol differed according to maternal history of child abuse. Forty-one women provided salivary cortisol samples at wake-up, 30 minutes after wake-up, and bedtime for 3 days at 3 times over second and third trimesters of pregnancy. On each day of cortisol collection women reported their daily stress. Women reported child abuse experiences prior to age 18 by completing 15 items from the Adverse Childhood Experiences scale. Twenty-one percent (N=9) of women reported a history of child sexual abuse (CSA), 44% (N=18) reported a history of non-sexual child abuse, and 34% (N=14) reported no history of child abuse. Hierarchical Linear Modeling (HLM) analyses revealed that stress in the day prior was associated with increases in morning cortisol in women with CSA histories compared to women with non-sexual abuse histories or no history of child abuse. Increases in evening cortisol were associated with increases in daily stress in women with CSA histories compared to women with non-sexual abuse histories or no history of child abuse. Results reveal a dynamic association between daily stress and cortisol in pregnancy and suggest that patterns differ according to maternal child abuse history.
Restraint and immobilization have been extensively used to study habituation of the neuroendocrine response to a repeated stressor, but behavioral consequences of this stress regimen remain largely uncharacterized. In this study, we used sucrose preference and the elevated-plus maze to probe behavioral alterations resulting from 14 days of restraint in rats. We observed a decrease in sucrose preference in stressed animals, particularly in a subgroup of individuals, but no alteration in anxiety behaviors (as measured in the elevated-plus maze) four days following the last restraint. In these low-sucrose preference animals, we observed a downregulation of the expression of preproenkephalin mRNA in the nucleus accumbens. Furthermore, we observed a strong correlation between enkephalin expression and sucrose preference in the shell part of the nucleus accumbens, with a lower level of enkephalin expression being associated with lower sucrose preference. Interestingly, quantification of the corticosterone response revealed a delayed habituation to restraint in the low-sucrose preference population, which suggests that vulnerability to stress-induced deficits might be associated with prolonged exposure to glucocorticoids. The induction of ΔFosB is also reduced in the nucleus accumbens shell of the low-sucrose preference population and this transcription factor is expressed in enkephalin neurons. Taken together, these results suggest that a ΔFosB-mediated downregulation of enkephalin in the nucleus accumbens might underlie the susceptibility to chronic stress. Further experiments will be needed to determine causality between these two phenomena.
Stress often negatively impacts physical and mental health but it has been suggested that voluntary physical activity may benefit health by reducing some of the effects of stress. The present experiments tested whether voluntary exercise can reduce heart rate, core body temperature and locomotor activity responses to acute (novelty or loud noise) or repeated stress (loud noise). After 6 weeks of running-wheel access, rats exposed to a novel environment had reduced heart rate, core body temperature, and locomotor activity responses compared to rats housed under sedentary conditions. In contrast, none of these measures were different between exercised and sedentary rats following acute 30-min noise exposures, at either 85 or 98 dB. Following 10 weeks of running-wheel access, both groups displayed significant habituation of all these responses to 10 consecutive daily 30-min presentations of 98 dB noise stress. However, the extent of habituation of all three responses was significantly enhanced in exercised compared to sedentary animals on the last exposure to noise. These results suggest that in physically active animals, under some conditions, acute responses to stress exposure may be reduced, and response habituation to repeated stress may be enhanced, which ultimately may reduce the negative and cumulative impact of stress.
This experiment examined whether chronic stress disrupts novelty-seeking behavior under conditions that impair spatial memory. Rats were restrained for 6 h per day for 21 days, then tested in either a traditional spatial recognition Y-maze that requires extra-maze spatial cues to navigate or a version with salient intra-maze cues in addition to the extra-maze spatial cues. As previously shown, chronic restraint stress impaired performance on the spatial version of the Y-maze. However, chronically stressed rats performed well in the intra-maze cue version. The results indicate that the deficits in Y-maze performance following chronic stress are not attributed to neophobia, but likely reflect neurochemical and/or neurobiological changes underlying spatial memory ability.