[Show abstract][Hide abstract] ABSTRACT: Early life stress can alter hypothalamic pituitary adrenal (HPA) axis function. Differences in cortisol levels have been found in preterm infants exposed to substantial procedural stress during neonatal intensive care, compared to infants born full-term, but only a few studies investigated whether altered programming of the HPA axis persists past toddler age. Further, there is a dearth of knowledge of what may contribute to these changes in cortisol. This prospective cohort study examined the cortisol profiles in response to the stress of cognitive assessment, as well as the diurnal rhythm of cortisol, in children (n = 129) born at varying levels of prematurity (24–32 weeks gestation) and at full-term (38–41 weeks gestation), at age 7 years. Further, we investigated the relationships among cortisol levels and neonatal procedural pain-related stress (controlling for multiple medical confounders), concurrent maternal factors (parenting stress, depressive and anxiety symptoms) and children's behavioral problems. For each aim we investigate acute cortisol response profiles to a cognitive challenge as well as diurnal cortisol patterns at home. We hypothesized that children born very preterm will differ in their pattern of cortisol secretion from children born full-term, possibly depended on concurrent child and maternal factors, and that exposure to neonatal pain-related stress would be associated with altered cortisol secretion in children born very preterm, possibly in a sex-dependent way. Saliva samples were collected from 7-year old children three times during a laboratory visit for assessment of cognitive and executive functions (pretest, mid-test, end—study day acute stress profile) and at four times over two consecutive non-school days at home (i.e. morning, mid-morning, afternoon and bedtime—diurnal rhythm profile). We found that cortisol profiles were similar in preterm and full-term children, albeit preterms had slightly higher cortisol at bedtime compared to full-term children. Importantly, in the preterm group, greater neonatal procedural pain-related stress (adjusted for morphine) was associated with lower cortisol levels on the study day (p = .044) and lower diurnal cortisol at home (p = .023), with effects found primarily in boys. In addition, child attention problems were negatively, and thought problems were positively, associated with the cortisol response during cognitive assessment on the study day in preterm children. Our findings suggest that neonatal pain/stress contributes to altered HPA axis function up to school-age in children born very preterm, and that sex may be an important factor.
[Show abstract][Hide abstract] ABSTRACT: Individuals with fetal alcohol spectrum disorder (FASD) are at increased risk for substance use disorders (SUD). In typically developing individuals, susceptibility to SUD is associated with alterations in dopamine and hypothalamic-pituitary-adrenal (HPA) systems, and their interactions. Prenatal alcohol exposure (PAE) alters dopamine and HPA systems, yet effects of PAE on dopamine-HPA interactions are unknown. Amphetamine-stress cross-sensitization paradigms were utilized to investigate sensitivity of dopamine and stress (HPA) systems, and their interactions following PAE.
Adult Sprague-Dawley offspring from PAE, pair-fed, and ad libitum-fed control groups were assigned to amphetamine-(1-2 mg/kg) or saline-treated conditions, with injections every other day for 15 days. Fourteen days later, all animals received an amphetamine challenge (1 mg/kg) and 5 days later, hormones were measured under basal or acute stress conditions. Amphetamine sensitization (augmented locomotion, days 1-29) and cross-sensitization with acute restraint stress (increased stress hormones, day 34) were assessed.
PAE rats exhibited a lower threshold for amphetamine sensitization compared to controls, suggesting enhanced sensitivity of dopaminergic systems to stimulant-induced changes. Cross-sensitization between amphetamine (dopamine) and stress (HPA hormone) systems was evident in PAE, but not in control rats. PAE males exhibited increased dopamine receptor expression (medial prefrontal cortex (mPFC)) compared to controls.
PAE alters induction and expression of sensitization/cross-sensitization, as reflected in locomotor, neural, and endocrine changes, in a manner consistent with increased sensitivity of dopamine and stress systems. These results provide insight into possible mechanisms that could underlie increased prevalence of SUD, as well as the impact of widely prescribed stimulant medications among adolescents with FASD.
[Show abstract][Hide abstract] ABSTRACT: Background
Prenatal alcohol exposure (PAE) has adverse effects on reproductive function and hypothalamic–pituitary–gonadal (HPG) activity. Kisspeptin neurons play a role in mediating feedback effects of estradiol (E2) and progesterone (P4) on the HPG axis. We hypothesized that PAE will have long-term effects on the response of kisspeptin neurons to E2 and P4.Methods
Adult female rats (53 to 58 days) from prenatal ad libitum-fed control (C), pair-fed (PF), and alcohol-exposed (PAE) groups were subjected to Sham ovariectomy (OVX) or OVX without or with replacement with low or high physiological levels of E2 and P4, and terminated under basal conditions. E2 and P4 levels, and the response of kisspeptin-ir neurons in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei to these hormones, were measured. As the E2 signal is conveyed to kisspeptin neurons via estrogen receptor-α (ER-α), we investigated PAE effects on the number of kisspeptin-ir/ER-α-ir neurons. To determine whether PAE alters interactions between kisspeptin and gonadotropin-releasing hormone (GnRH) neurons, close contacts between kisspeptin-ir fibers and GnRH-ir cell bodies were examined.ResultsOur data present the novel finding that kisspeptin-ir neurons in the ARC of PAE females show differential responses to E2 and to the combined treatment with E2 and P4 compared with controls: (i) OVX increased the number of kisspeptin-ir neurons in C and PF, but not PAE females compared with their Sham counterparts; (ii) E2 replacement restored kisspeptin-ir cell numbers to Sham levels in C and PF females but caused a robust down-regulation of kisspeptin-ir neurons below Sham levels in PAE females; (iii) OVX and replacement with high physiological concentrations of E2 resulted in fewer kisspeptin-ir cells in PAE than C females; (iv) OVX and replacement with high levels of both E2 and P4 markedly decreased the number of kisspeptin-ir neurons, below levels observed following E2 alone, in PF and C females, but had no significant effect in PAE females.Conclusions
These data suggest that a possible mechanism underlying adverse effects of PAE on HPG function involves actions of alcohol on the kisspeptin system.
Alcoholism Clinical and Experimental Research 11/2014; 38(11). · 3.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prenatal alcohol exposure (PAE) can produce a myriad of deficits. Unfortunately, affected individuals may also be exposed to the stress of an adverse home environment, contributing to deficits of attentional processes that are the hallmark of optimal executive function. Male offspring of ad-libitum-fed Control (Con), Pairfed (PF), and PAE dams were randomly assigned to either a 5-day period of variable chronic mild stress (CMS) or no CMS in adolescence. In adulthood, rats were trained in a non-match to sample task (T-maze), followed by extensive assessment in the five-choice serial reaction time task. Once rats acquired the five-choice serial reaction time task (stable accuracy), they were tested in three challenge conditions: (i) increased sustained attention, (ii) selective attention and, (iii) varying doses of d-amphetamine, an indirect dopamine and norepinephrine agonist. At birth and throughout the study, PAE offspring showed reduced body weight. Moreover, although PAE animals were similar to Con animals in task acquisition, they were progressively less proficient with transitions to shorter stimulus durations (decreased accuracy and increased omissions). Five days of adolescent CMS increased basal corticosterone levels in adolescence and disrupted cognitive performance in adulthood. Further, CMS augmented PAE-related disturbances in acquisition and, to a lesser extent, also disrupted attentional processes in Con and PF animals. Following task acquisition, challenges unmasked persistent attentional difficulties resulting from both PAE and adolescent CMS. In conclusion, PAE, adolescent CMS, and their interaction produced unique behavioural profiles that suggest vulnerability in select neurobiological processes at different stages of development.
European Journal of Neuroscience 10/2014; · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Individuals exposed to alcohol during gestation show higher rates of psychopathologies. The hyperresponsivity to stress induced by prenatal alcohol exposure (PAE) may be related to this increased rate of psychopathologies, especially because this population is more likely to be exposed to stressful environments throughout life. However, alcohol-induced changes in the overlapping neurocircuitries that underlie stress and the expression of psychopathologies are not fully understood. Here, we performed a comprehensive analysis of the neural activity within central areas known to play key roles in both emotional and stress regulation. Adult male and female offspring from PAE, pair-fed, and ad libitum-fed control conditions were exposed to chronic mild stress (CMS). Following CMS, the neural activity (c-fos mRNA) of the amygdala, ventral hippocampal formation, medial prefrontal cortex (mPFC), and paraventricular nucleus of hypothalamus (PVN) was assessed in response to an acute stress (elevated plus maze). Our results demonstrate that, overall, PAE decreased neural activity within the amygdala and hippocampal formation in males and increased neural activity within the amygdala and mPFC in females. CMS reduced neural activity within the mPFC and PVN in PAE males, but reduced activity in all areas analyzed in control males. By contrast, CMS reduced neural activity in the mPFC in PAE females and had no effects in control females. Furthermore, the constrained principal component analysis revealed that these patterns of neural activity resulted in differential activation of the functional neural networks in males compared to females, indicating sexually dimorphic effects of PAE and CMS. Importantly, the altered networks of brain activation in PAE animals may underlie the hyperresponsivity to stress and increased psychopathologies observed among individuals prenatally exposed to alcohol.
[Show abstract][Hide abstract] ABSTRACT: Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm ≤32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-κB, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm.
PLoS ONE 09/2013; 8(9):e73926. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies on male rodents found that prenatal alcohol exposure (PAE) decreases the number of serotonin immunoreactive (5-HT-ir) neurons in the brainstem. However, data on the effects of PAE in females are lacking. In light of known sex differences in responsiveness of the 5-HT system and known effects of estrogen (E2 ) and progesterone (P4 ) in the brain, we hypothesized that sex steroids will modulate the adverse effects of PAE on 5-HT neurons in adult females.
Adult females from 3 prenatal groups (Prenatal alcohol-exposed [PAE], Pair-fed [PF], and ad libitum-fed Controls [C]) were ovariectomized (OVX), with or without hormone replacement, or underwent Sham OVX. 5-HT-ir cells were examined in key brainstem areas.
Our data support the hypothesis that PAE has long-term effects on the 5-HT system of females and that ovarian steroids have a modulatory role in these effects. Intact (Sham OVX) PAE females had marginally lower numbers of 5-HT-ir neurons in the dorsal raphe nucleus of the brainstem compared with PF and C females. This marginal difference became significant following removal of hormones by OVX. Replacement with E2 restored the number of 5-HT-ir neurons in PAE females to control levels, while P4 reversed the effects of E2 . Importantly, despite these differential responses of the 5-HT system to ovarian steroids, there were no differences in E2 and P4 levels among prenatal treatment groups.
These data demonstrate long-term, adverse effects of PAE on the 5-HT system of females, as well as differential sensitivity of PAE compared with control females to the modulatory effects of ovarian steroids on 5-HT neurons. Our findings have important implications for understanding sex differences in 5-HT dysfunction in depression/anxiety disorders and the higher rates of these mental health problems in individuals with fetal alcohol spectrum disorder.
Alcoholism Clinical and Experimental Research 08/2013; · 3.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Effects of prenatal alcohol exposure (PAE) on central nervous system function include an increased prevalence of mental health problems, including substance use disorders (SUD). The hypothalamic-pituitary-adrenal (HPA) and dopamine (DA) systems have overlapping neurocircuitries and are both implicated in SUD. PAE alters both HPA and dopaminergic activity and regulation, resulting in increased HPA tone and an overall reduction in tonic DA activity. However, effects of PAE on the interaction between HPA and DA systems have not been investigated. The present study examined PAE effects on basal regulation of central stress and DA systems in key brain regions where these systems intersect. Adult Sprague-Dawley male and female offspring from prenatal alcohol-exposed (PAE), pairfed (PF), and ad libitum-fed control (C) groups were subjected to chronic variable stress (CVS) or remained as a no stress (non-CVS) control group. Corticotropin releasing hormone (CRH) mRNA, as well as glucocorticoid and DA receptor (DA-R) expression were measured under basal conditions 24h following the end of CVS. We show, for the first time, that regulation of basal HPA and DA systems, and likely, HPA-DA interactions, are altered differentially in males and females by PAE and CVS. PAE augmented the typical attenuation in weight gain during CVS in males and caused increased weight loss in females. Increased basal corticosterone levels in control, but not PAE, females suggest that PAE alters the profile of basal hormone secretion throughout CVS. CVS downregulated basal CRH mRNA in the prefrontal cortex and throughout the bed nucleus of the stria terminalis (BNST) in PAE females but only in the posterior BNST of control females. PAE males and females exposed to CVS exhibited more widespread upregulation of basal mineralocorticoid receptor mRNA throughout the hippocampus, and an attenuated decrease in DA-R expression throughout the nucleus accumbens and striatum compared to CVS-exposed control males and females. Overall, these findings enhance our understanding of PAE effects on the cross-talk between HPA and DA systems, and provide insight into possible mechanisms underlying mental health problems that are related to stress and DA signaling, including SUD, which have a high prevalence among individuals with FASD.
[Show abstract][Hide abstract] ABSTRACT: Objective:To examine whether early inflammation is related to cortisol levels at 18 months corrected age (CA) in children born very preterm.Study Design:Infants born 32 weeks of gestational age were recruited in the neonatal intensive care unit (NICU), and placental histopathology, magnetic resonance imaging (MRI) and chart review were obtained. At 18 months CA, developmental assessment and collection of three salivary cortisol samples were carried out. Generalized least squares was used to analyze data from 85 infants providing 222 cortisol samples.Results:Infants exposed to chorioamnionitis with funisitis had a significantly different pattern of cortisol across the samples compared with infants with chorioamnionitis alone or no prenatal inflammation (F(4, 139)=7.3996, P<0.0001). Postnatal infections, necrotizing enterocolitis and chronic lung disease were not significantly associated with the cortisol pattern at 18 months CA.Conclusion:In children born very preterm, prenatal inflammatory stress may contribute to altered programming of the hypothalamic-pituitary-adrenal (HPA) axis.Journal of Perinatology advance online publication, 4 April 2013; doi:10.1038/jp.2013.24.
Journal of perinatology: official journal of the California Perinatal Association 04/2013; 33(8). · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: During late prenatal and early postnatal life, the reproductive system in males undergoes an extensive series of physiological and morphological changes. Prenatal ethanol (EtOH) exposure has marked effects on the development of the reproductive system, with long-term effects on function in adulthood. The present study tested the hypothesis that prenatal EtOH exposure will delay the onset of spermatogenesis. METHODS: Development of the seminiferous tubules and the onset of spermatogenesis were examined utilizing a rat model of fetal alcohol spectrum disorder (FASD). Male offspring from ad libitum-fed control (C), pair-fed (PF), and EtOH-fed (prenatal alcohol exposure [PAE]) dams were terminated on postnatal (PN) days 5, 15, 18, 20, 25, 35, 45, and 55, to investigate morphological changes through morphometric analysis of the testes from early neonatal life through young adulthood. RESULTS: PAE males had lower relative (adjusted for body weight) testis weights compared with PF and/or C males from PN15 through puberty (PN45). In addition, fewer gonocytes (primordial germ cells) were located on the basal lamina on PN5, while more of those touching the basal lamina were dividing in PAE compared with PF and C males, suggesting delayed cell division and migration processes. As well, the percentage of tubules with open lumena was lower in PAE compared with PF and C males on PN18 and 20, and PAE males had fewer primary spermatocytes per tubule on PN18 and round spermatids per tubule on PN25 compared with C males. Finally, the percentage of tubules at stages VII and VIII, when mature spermatids move to the apex of the epithelium and are released, was lower in PAE compared with PF and/or C males in young adulthood (PN55). CONCLUSIONS: Maternal EtOH consumption appears to delay both reproductive development and the onset of spermatogenesis in male offspring, with effects persisting at least until young adulthood.
Alcoholism Clinical and Experimental Research 03/2013; · 3.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study examined the relationship between children's hair cortisol and socioeconomic status of the family, as measured by parental education and income. Low family socioeconomic status has traditionally been considered a long-term environmental stressor. Measurement of hair cortisol provides an integrated index of cumulative stress exposure across an extended period of time. The present study is the first to examine the relationship between hair cortisol and parental education as well as parental income in a representative sample of preschoolers. Data on hair cortisol, family income, and parental education were collected for a representative sample of 339 children (Mean age=4.6 years; SD=.5 years) from across 23 neighbourhoods of the city of Vancouver, Canada. As maternal education was shown previously to be associated with hair zinc level, hair zinc measurements were included as well in order to explore potential relationships between hair zinc and hair cortisol. The relationship between hair cortisol and parental education was examined using hierarchical regression, with hair zinc, gender, age, and single parenthood included as covariates. Maternal and paternal education both were correlated significantly with hair cortisol (r=-0.18; p=.001). The relationship remained statistically significant even after controlling for all demographic covariates as well as for hair zinc and after taking the neighbourhood-level clustering of the data into account. Parental income, on the other hand, was not related significantly to children's hair cortisol. This study provides evidence that lower maternal and paternal education are associated with higher hair cortisol levels. As hair cortisol provides an integrated index of cortisol exposure over an extended time period, these findings suggest a possibly stable influence of SES on the function of the hypothalamic-pituitary-adrenal (HPA) axis. Cumulative exposure to cortisol during early childhood may be greater in children from low socio-economic backgrounds, possibly through increased exposure to environmental stressors.
[Show abstract][Hide abstract] ABSTRACT: The chronic mild (or unpredictable/variable) stress (CMS) model was developed as an animal model of depression more than 20 years ago. The foundation of this model was that following long-term exposure to a series of mild, but unpredictable stressors, animals would develop a state of impaired reward salience that was akin to the anhedonia observed in major depressive disorder. In the time since its inception, this model has also been used for a variety of studies examining neurobiological variables that are associated with depression, despite the fact that this model has never been critically examined to validate that the neurobiological changes induced by CMS are parallel to those documented in depressive disorder. The aim of the current review is to summarize the current state of knowledge regarding the effects of chronic mild stress on neurobiological variables, such as neurochemistry, neurochemical receptor expression and functionality, neurotrophin expression and cellular plasticity. These findings are then compared to those of clinical research examining common variables in populations with depressive disorders to determine if the changes observed following chronic mild stress are in fact consistent with those observed in major depression. We conclude that the chronic mild stress paradigm: (1) evokes an array of neurobiological changes that mirror those seen in depressive disorders and (2) may be a suitable tool to investigate novel systems that could be disturbed in depression, and thus aid in the development of novel targets for the treatment of depression.
[Show abstract][Hide abstract] ABSTRACT: To determine whether a single course of antenatal dexamethasone alters resting cortisol at 3, 8 and 18 months corrected age in preterm infants.
Preterm infants born ≤32 weeks gestational age were recruited during 2001-2004 from a single neonatal intensive care unit. Resting salivary cortisol was collected at least once at 3, 8 and 18 months corrected age in a longitudinal cohort. A mixed-effects repeated measures analysis was used to accommodate cases with less than complete follow-up.
One hundred and thirty three infants were included in the present study, contributing 266 cortisol samples. Of these, 107 infants had been exposed to a single course of antenatal dexamethasone and 26 not exposed to antenatal steroids. There was no significant main effect of antenatal steroids on resting cortisol at any age. This result was not altered after adjusting for gestational age at birth, neonatal cumulative pain, morphine exposure, mechanical ventilation days and post-natal steroid exposure.
No effect of a single course of dexamethasone on resting salivary cortisol, an indicator of hypothalamic-pituitary-adrenal axis function, was found in infancy up to 18 months corrected age in infants born very preterm.
[Show abstract][Hide abstract] ABSTRACT: Event-related potentials (ERPs) and other electroencephalographic (EEG) evidence show that frontal brain areas of higher and lower socioeconomic status (SES) children are recruited differently during selective attention tasks. We assessed whether multiple variables related to self-regulation (perceived mental effort) emotional states (e.g., anxiety, stress, etc.) and motivational states (e.g., boredom, engagement, etc.) may co-occur or interact with frontal attentional processing probed in two matched-samples of fourteen lower-SES and higher-SES adolescents. ERP and EEG activation were measured during a task probing selective attention to sequences of tones. Pre- and post-task salivary cortisol and self-reported emotional states were also measured. At similar behavioural performance level, the higher-SES group showed a greater ERP differentiation between attended (relevant) and unattended (irrelevant) tones than the lower-SES group. EEG power analysis revealed a cross-over interaction, specifically, lower-SES adolescents showed significantly higher theta power when ignoring rather than attending to tones, whereas, higher-SES adolescents showed the opposite pattern. Significant theta asymmetry differences were also found at midfrontal electrodes indicating left hypo-activity in lower-SES adolescents. The attended vs. unattended difference in right midfrontal theta increased with individual SES rank, and (independently from SES) with lower cortisol task reactivity and higher boredom. Results suggest lower-SES children used additional compensatory resources to monitor/control response inhibition to distracters, perceiving also more mental effort, as compared to higher-SES counterparts. Nevertheless, stress, boredom and other task-related perceived states were unrelated to SES. Ruling out presumed confounds, this study confirms the midfrontal mechanisms responsible for the SES effects on selective attention reported previously and here reflect genuine cognitive differences.
Frontiers in Human Neuroscience 01/2012; 6:306. · 2.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prenatal alcohol exposure (PAE) has adverse effects on the development of numerous physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis and the immune system. HPA hyper-responsiveness and impairments in immune competence have been demonstrated. The present study investigated immune function in PAE females utilizing an adjuvant-induced arthritis (AA) model, widely used as a model of human rheumatoid arthritis. Given the effects of PAE on HPA and immune function, and the known interaction between HPA and immune systems in arthritis, we hypothesized that PAE females would have heightened autoimmune responses, resulting in increased severity of arthritis, compared to controls, and that altered HPA activity might play a role in the immune system changes observed. The data demonstrate, for the first time, an adverse effect of PAE on the course and severity of AA in adulthood, indicating an important long-term alteration in functional immune status. Although overall, across prenatal treatments, adjuvant-injected animals gained less weight, and exhibited decreased thymus and increased adrenal weights, and increased basal levels of corticosterone and adrenocorticotropin, PAE females had a more prolonged course of disease and greater severity of inflammation compared to controls. In addition, PAE females exhibited blunted lymphocyte proliferative responses to concanavalin A and a greater increase in basal ACTH levels compared to controls during the induction phase, before any clinical signs of disease were apparent. These data suggest that prenatal alcohol exposure has both direct and indirect effects on inflammatory processes, altering both immune and HPA function, and likely, the normal interactions between these systems.
Brain Behavior and Immunity 12/2011; 26(3):439-50. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Enhanced dopamine efflux in the prefrontal cortex is a well-documented response to acute stress. However, the underlying mechanism(s) for this response is unknown. Using in vivo microdialysis, we demonstrate that blocking glucocorticoid receptors locally within the rat prefrontal cortex results in a reduction in stress-evoked dopamine efflux. In contrast, blocking glucocorticoid receptors in the ventral tegmental area did not affect stress-evoked dopamine efflux in the prefrontal cortex. Additionally, local administration of corticosterone into the prefrontal cortex increased prefrontal dopamine efflux. The functional impact of enhanced dopamine efflux evoked by acute stress was demonstrated using a cognitive task dependent on the prefrontal cortex and sensitive to impairment in working memory. Notably, stress-induced impairments in cognition were attenuated by blockade of glucocorticoid receptors in the prefrontal cortex. Taken together, these data demonstrate that glucocorticoids act locally within the prefrontal cortex to modulate mesocortical dopamine efflux leading to the cognitive impairments observed during acute stress.
Proceedings of the National Academy of Sciences 11/2011; 108(45):18459-64. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cortisol levels were compared in children born preterm at extremely low gestational age (ELGA; 24-28 weeks), very low gestational age (VGLA; 29-32 weeks), and full-term in response to cognitive assessment at 18 months corrected age (CA). Further, we investigated the relationship between maternal interactive behaviors and child internalizing behaviors (rated by the mother) in relation to child cortisol levels. EGLA children had higher "pretest" cortisol levels and a different pattern of cortisol response to cognitive assessment compared to VGLA and full-terms. Higher cortisol levels in ELGA, but not full-term, children were associated with less optimal mother interactive behavior. Moreover, the pattern of cortisol change was related to internalizing behaviors among ELGA, and to a lesser degree VLGA children. In conclusion, our findings suggest altered programming of the hypothalamic-pituitary-adrenal (HPA) axis in preterm children, as well as their greater sensitivity to environmental context such as maternal interactive behavior.
[Show abstract][Hide abstract] ABSTRACT: Prenatal alcohol exposure (PAE) alters adult neurogenesis and the neurogenic response to stress in male rats. As the effects of stress on neurogenesis are sexually dimorphic, the present study investigated the effects of PAE on adult hippocampal neurogenesis under both nonstressed and stressed conditions in female rats. Pregnant females were assigned to one of three prenatal treatments: (1) alcohol (PAE)-liquid alcohol (ethanol) diet ad libitum (36% ethanol-derived calories); (2) pair-fed-isocaloric liquid diet, with maltose-dextrin substituted for ethanol, in the amount consumed by a PAE partner (g/kg body wt/day of gestation); and (3) control-lab chow ad libitum. Female offspring were assigned to either nonstressed (undisturbed) or stressed (repeated restraint stress for 9 days) conditions. On day 10, all rats were injected with bromodeoxyuridine (BrdU) and perfused either 24 hours (cell proliferation) or 3 weeks (cell survival) later. We found that PAE did not significantly alter cell proliferation or survival, whereas females from the pair-fed condition exhibited elevated levels of cell survival compared to control females. Importantly, however, the proportion of both new neurons and new glial cells in the hippocampal dentate gyrus was reduced in PAE compared to control females. Exposure to stress did not alter neurogenesis in any of the prenatal treatment groups. In summary, compared to females from the control condition, prenatal dietary restriction enhanced the survival of new neurons, whereas PAE altered the differentiation of newly produced cells in the adult dentate gyrus. Alterations in hippocampal neurogenesis following PAE may contribute to learning and memory deficits seen in individuals with fetal alcohol spectrum disorders.
Hormones and Behavior 11/2010; 58(5):835-43. · 4.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pain response may be altered in infants born very preterm owing to repeated exposure to procedures in the neonatal intensive care unit. Findings have been inconsistent in studies of behavioral and cardiac responses to brief pain in preterm versus full-term infants following neonatal intensive care unit discharge. To our knowledge, cortisol reactivity to pain has not been compared in preterm and full-term infants. We examined pain reactivity to immunization in preterm and full-term infants.
Cortisol, facial behavior, and heart rate reactivity before, during, and after immunization were examined in infants born preterm at extremely low gestational age (ELGA 24 to 28 wk), very low gestational age (VLGA 29 to 32 wk), and full-term, at corrected age 4 months.
In all groups, cortisol, behavior, and heart rate increased during immunizations. Cortisol concentrations were lower in preterm ELGA and VLGA boys, compared with full-term boys. In contrast, facial and heart rate responses to immunization did not differ between preterm and full-term infants.
Although earlier reports found differences in pain processing in preterm infants earlier and later in development, the present findings indicate that pain responses, indexed by behavior and heart-rate, do not seem to differ in preterm compared with full-term infants at 4 months corrected age. Importantly, however, stress regulation seems altered in preterm male infants. As cortisol impacts development and functioning of the brain, altered stress regulation has important implications beyond pain systems.
The Clinical journal of pain 10/2010; 26(8):698-704. · 2.70 Impact Factor