Susanne Brummelte

Procedural pain and brain development in premature newborns.

Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants.

Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging.

Adult neurogenesis exists in most mammalian species, including humans, in two main areas: the subventricular zone (new cells migrate to the olfactory bulbs) and the dentate gyrus of the hippocampus. Many factors affect neurogenesis in the hippocampus and the subventricular zone, however the focus of this review will be on factors that affect hippocampal neurogenesis, particularly in females. Sex differences are often seen in levels of hippocampal neurogenesis, and these effects are due in part to differences in circulating levels of steroid hormones such as estradiol, progesterone, and corticosterone during the estrous cycle, in response to stress, with reproduction (including pregnancy and lactation), and aging. Depletion and administration of these same steroid hormones also has marked effects on hippocampal neurogenesis in the adult female, and these effects are dependent upon reproductive status and age. The present review will focus on current research investigating how hippocampal neurogenesis is altered in the adult female rodent across the lifespan.

Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats.

Adult neurogenesis in the dentate gyrus of the hippocampus is altered with stress exposure and has been implicated in depression. High levels of corticosterone (CORT) suppress neurogenesis in the dentate gyrus of male rats. However both acute and chronic stress do not consistently reduce adult hippocampal neurogenesis in female rats. Therefore, this study was conducted to investigate the effect of different doses of corticosterone on hippocampal neurogenesis in male and female rats. Rats received 21 days of s.c. injections of either oil, 10 or 40 mg/kg CORT. Subjects were perfused 24 h after the last CORT injection and brains were analyzed for cell proliferation (Ki67-labeling) or immature neurons (doublecortin-labeling). Results show that in both males and females high CORT, but not low CORT, reduced both cell proliferation and the density of immature neurons in the dentate gyrus. Furthermore, high CORT males had reduced density in immature neurons in both the ventral and dorsal regions while high CORT females only showed the reduced density of immature neurons in the ventral hippocampus. The high dose of CORT disrupted the estrous cycle of females. Further, the low dose of CORT significantly reduced weight gain and increased basal CORT levels in males but not females, suggesting a greater vulnerability in males with the lower dose of CORT. Thus we find subtle sex differences in the response to chronic CORT on both body weight and on neurogenesis in the dorsal dentate gyrus that may play a role in understanding different vulnerabilities to stress-related neuropsychiatric disorders between the sexes.

Depression during pregnancy and postpartum: contribution of stress and ovarian hormones.

Depression is the most common psychiatric disease among women, exhibiting a prevalence which is 2-3x higher than in men. The postpartum period is considered the time of greatest risk for women to develop major depression and postpartum depression affects approximately 15% of women. A dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is the most prominent endocrine change seen in depression and normalization of the HPA axis is a major target of recent therapies. Females exhibit different stress sensitivities than males which might contribute to their increased vulnerability for depression. Maternal stress or depression during pregnancy and/or postpartum is particularly concerning as early developmental influences can affect the maturation of the offspring as well as the mental health of the mother. Despite the urgent need for more information on depression in females, especially during pregnancy and postpartum, most animal models of depression have utilized only males. Given the sex differences in incidence of depression and treatment, it is vitally important to create or validate animal models of depression in females. This review will focus on the association between stress, glucocorticoids and depression in humans, with a special focus on depression in women during pregnancy and postpartum and on animal models of postpartum depression and the consequences for the offspring.

Chronic corticosterone during pregnancy and postpartum affects maternal care, cell proliferation and depressive-like behavior in the dam

Stress during pregnancy and the postpartum can influence the well-being of both the mother and her offspring. Prolonged elevated levels of glucocorticoids are associated with depression and we developed an animal model of postpartum depression/stress based on high levels of corticosterone (CORT) during the postpartum. Gestational stress is a risk factor for postpartum depression and prenatal and/or postnatal high levels of CORT may have differential effects on the mother. Thus the present study was conducted to investigate the effects of low (10mg/kg) or high levels of CORT (40mg/kg) given to dams either during gestation, postpartum or across both gestation and postpartum on maternal care, depressive-like behavior and hippocampal cell proliferation in the dam. Only the high dose of CORT administered during the postpartum increased depressive-like behavior in the dam. Furthermore the high dose of CORT altered maternal care (reduced time spent on the nest and nursing) regardless of whether administration of CORT was during gestation or postpartum. Gestational and/or postpartum treatment with high CORT and postpartum low CORT reduced cell proliferation in the dentate gyrus of postpartum dams compared to oil-treated controls. Thus prolonged treatment with high levels of CORT postpartum reduced maternal care, hippocampal cell proliferation and induced depressive-like behavior in the dam and therefore might be considered an animal model of postpartum depression. More research is needed to understand the effects of stress hormones during different phases of reproduction and how they affect the brain and behavior of the mother and her offspring.

Chronic restraint stress in adolescence differentially influences hypothalamic‐pituitary‐adrenal axis function and adult hippocampal neurogenesis in male and female rats

Previous studies have shown a relationship between adversity in adolescence and health outcomes in adulthood in a sex‐specific manner. Adolescence is characterized by major changes in stress‐responsive regions of the brain, including the hippocampus, the site of ongoing neurogenesis throughout the lifespan. Prepubertal male and female rats exhibit different acute reactions to chronic stress compared to adults, but less is known about whether these stress‐induced changes persist into adulthood. Therefore, in this study, we investigated the effects of chronic, intermittent stress during adolescence on basal corticosterone levels, dentate gyrus (DG) volume, and neurogenesis in the hippocampus of adult male and female Sprague‐Dawley rats. Adolescent male and female rats were either restrained for 1 h every other day for 3 weeks from postnatal days (PDs) 30–52 at unpredictable times or left undisturbed. All rats received a single injection of bromodeoxyuridine (BrdU; 200 mg/kg) in adulthood on PD70 and were perfused 3 weeks later. Brains were processed for Ki67 (endogenous marker of cell proliferation) and BrdU (to estimate effects on cell survival). In addition, blood samples were taken during the restraint stress period and in adulthood. Results show that males and females exhibit different corticosterone responses to chronic stress during adolescence and that only adult female rats exposed to stress during adolescence show higher basal corticosterone levels compared to nonstressed controls. Furthermore, stressed females showed a reduced number of proliferating and surviving cells in the DG in adulthood compared to nonstressed same‐sex controls. The majority of BrdU‐labeled cells were co‐labeled with NeuN, an endogenous marker of mature neurons, indicating that neurogenesis was decreased in the DG of adult female rats that had undergone chronic restraint stress in adolescence. Although male rats were more responsive to the chronic stress as adolescents showing higher corticosterone levels and reduced body weight, as adults they showed a slight increase in cellsurvival and no effect of adolescent stress on basal corticosterone levels. These results suggest that stress during adolescence can have effects on hypothalamic‐pituitary‐adrenal axis function and hippocampus plasticity in adulthood, particularly in female rats. ©2010 Wiley‐Liss,Inc.

Endocrine regulation of cognition and neuroplasticity: our pursuit to unveil the complex interaction between hormones, the brain, and behaviour.

Gonadal and stress hormones modulate neuroplasticity and behaviour. This review focuses on our findings over the past decade on the effects of estrogens and androgens on hippocampal neurogenesis, hippocampus-dependent learning and memory and the effects of reproductive experience in the rodent. Evidence suggests that acute estradiol initially enhances and subsequently suppresses cell proliferation in the dentate gyrus of adult female rodents. Repeated exposure to estradiol modulates hippocampal neurogenesis and cell death in adult female, but not male, rodents while, testosterone and dihydrotestosterone upregulate hippocampal neurogenesis in adult male rodents. Estradiol dose-dependently affects different brain regions involved in working memory (prefrontal cortex, hippocampus), reference memory (hippocampus) and conditioned place preference (amygdala). Pregnancy and motherhood differentially regulate adult hippocampal neurogenesis and spatial working memory in the dam after weaning. These studies and others demonstrate that the female brain responds to steroid hormones differently than the male brain. It is of the upmost importance to investigate the effects on neuroplasticity and behaviour in both the male and the female, particularly when modelling diseases that exhibit sex differences in incidence, etiology or treatment.

Neonatal pain in relation to postnatal growth in infants born very preterm

TOC summary Repetitive procedural pain in preterm infants appears to impact early body growth and head circumference, after accounting for multiple medical confounders. ABSTRACT Procedural pain is associated with poorer neurodevelopment in infants born very preterm (⩽32 weeks gestational age), however, the etiology is unclear. Animal studies have demonstrated that early environmental stress leads to slower postnatal growth; however, it is unknown whether neonatal pain‐related stress affects postnatal growth in infants born very preterm. The aim of this study was to examine whether greater neonatal pain (number of skin‐breaking procedures adjusted for medical confounders) is related to decreased postnatal growth (weight and head circumference [HC] percentiles) early in life and at term‐equivalent age in infants born very preterm. Participants were n = 78 preterm infants born ⩽32 weeks gestational age, followed prospectively since birth. Infants were weighed and HC measured at birth, early in life (median: 32 weeks [interquartile range 30.7–33.6]) and at term‐equivalent age (40 weeks [interquartile range 38.6–42.6]). Weight and HC percentiles were computed from sex‐specific British Columbia population‐based data. Greater neonatal pain predicted lower body weight (Wald χ2 = 7.36, P = 0.01) and HC (Wald χ2 = 4.36, P = 0.04) percentiles at 32 weeks postconceptional age, after adjusting for birth weight percentile and postnatal risk factors of illness severity, duration of mechanical ventilation, infection, and morphine and corticosteroid exposure. However, later neonatal infection predicted lower weight percentile at term (Wald χ2 = 5.09, P = 0.02). Infants born very preterm undergo repetitive procedural pain during a period of physiological immaturity that appears to impact postnatal growth, and may activate a downstream cascade of stress signaling that affects later growth in the neonatal intensive care unit.

Cortisol levels in former preterm children at school age are predicted by neonatal procedural pain-related stress.

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 childrens 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.

Neonatal Pain-Related Stress and NFKBIA Genotype Are Associated with Altered Cortisol Levels in Preterm Boys at School Age

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.