Delia M. Vazquez

Low cortisol and a flattening of expected daytime rhythm: Potential indices of risk in human development

Since the work of Hans Selye, stress has been associated with increased activity of the limbic-hypothalamic-pituitary-adrenocortical (LHPA) axis. Recently, a number of studies in adults have shown that this neuroendocrine axis may be hyporesponsive in a number of stress-related states. Termed hypocortisolism, the paradoxical suppression of the LHPA axis under conditions of trauma and prolonged stress presently challenges basic concepts in stress research. Adverse conditions that produce elevated cortisol levels early in life are hypothesized to contribute to the development of hypocortisolism in adulthood. However, as reviewed in this paper, hypocortisolism also may be a common phenomenon early in human childhood. Although preliminary at this point, the ubiquity of these findings is striking. We argue that developmental studies are needed that help explicate the origins of low cortisol and to determine whether the development of hypocortisolism is, in fact, preceded by periods of frequent or chronic activation of the LHPA axis. We also argue that developmental researchers who incorporate measures of salivary cortisol into their studies of at-risk populations need to be aware of the hypocortisolism phenomenon. Lower than expected cortisol values should not necessarily be relegated to the file drawer because they contradict the central dogma that stress must be associated with elevations in cortisol. Lastly, we note that evidence of low cortisol under adverse early life conditions in humans adds to the importance of understanding the implications of hypocortisolism for health and development.

Selective Serotonin Reuptake Inhibitor (SSRI) Use during Pregnancy and Effects on the Fetus and Newborn: A Meta-Analysis

Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat depression during pregnancy and the postpartum period. These drugs are capable of crossing the placenta and being transferred to the newborn during lactation. This report reviews the available information regarding the effects of SSRIs on the fetus and newborn; including long-term neurodevelopmental outcomes.

Pituitary-adrenal response to ether vapor in the weanling animal: Characterization of the inhibitory effect of glucocorticoids on adrenocorticotropin secretion

ABSTRACT: The hypothalamic-pituitary-adrenal axis is hyporesponsive to stimuli during early life in the rat. Once the adrenocortical response is established, failure to terminate the corticosterone (B) rise is evident after certain stressors, such as ether. The purpose of this study was 2-fold: 1) to investigate the B and ACTH response to ether vapor in young animals and 2) to test the ability of glucocorticoids to inhibit the ether ACTH-stimulated secretion in weanling animals. Rats aged 14, 18, and 25 d and adult rats were subjected to ether vapor for 3 min. Plasma was collected for B and ACTH determination by RIA at 0, 5, 15, 30, 60, and 120 min after ether exposure. Maximum B levels were observed at different times after exposure: 15 min in the adult and 30 min in the younger animals. In addition, B levels were significantly elevated at 60 min in the d 25 and d 18 rats compared with the adult (d 25 = 672.4 ± 28.9, d 18 = 744.6 ± 31.7, adult = 323.2 ± 8.7 mol/L ± SEM; d 25 = 23.3 ± 1.0, d 18 = 25.8 ± 1.1, adult = 11.2 ± 0.3 μg/dL ± SEM). The B delay observed in the younger animals was not due to a delayed ACTH response because maximal ACTH values were observed 5 min after ether exposure in all ages (d 14 = 21.9 ± 4.8, d 18 = 35.8 ± 21.3, d 25 = 82.01 ± 16.5, adult = 98.9 ± 25.2 χ 10−12 mol/L ± SEM). However, in the d 25 rats the ACTH level remained significantly elevated 30 min after the ether vapor challenge (5 min = 86.9 ± 25.2, 30 min = 61.8 ± 4.8, 60 min = 15.3 ± 4.1 χ 10−12 mol/L ± SEM). The delay to return to resting ACTH levels was consistent with the time delay observed for the B release from the adrenal. However, a rapid increase of plasma steroid achieved with an acute administration of the glucocorticoid cortisol suppresses ACTH release effectively (d 25 = 74%, adult = 70%). Unlike the fast feedback in the adult, the cortisol-induced ACTH inhibition in the weanling animal appears to require a greater cortisol rate of increase (d 25 versus adult = 118.6 versus 71.73 mol/L/min, 4.3 versus 2.6 μg/dL/min) and a longer time before basal ACTH levels are achieved (d 25 versus adult = 30 versus 15 min). We conclude that in the weanling rat the inability to rapidly terminate the adrenocortical response after ether vapor results from a combination of adrenal and pituitary and/or brain factors that result in decreased responsiveness to negative feedback even when the rate of steroid is high. Thus, the weaning period represents a distinct phase of the organization of the rat developing stress axis.

Regulation of glucocorticoid and mineralocorticoid receptor mRNAs in the hippocampus of the maternally deprived infant rat

The hypothalamic-pituitary-adrenal (HPA) axis in the developing rat has a limited response to acute challenges between days 3 and 14 of life. Several hypotheses have been proposed to explain this quiescent state. Immaturity of brain, pituitary and adrenal elements or excessive feedback inhibition are common explanations. Recently, a series of studies by Levine and co-workers has shown that prolonged maternal deprivation (24 h) results in increased basal and stress induced corticosterone (CS) levels. An increased adrenal response to ACTH along with an enhanced and sustained ACTH response have been implicated in this phenomenon. A brain structure that appears to be important for normal HPA function is the hippocampus, a structure rich in corticosteroid receptors, which has been hypothesized to play a role in the basal tone of the HPA and in the magnitude and duration of stress responses. Thus, to study further the possible mechanisms leading to an enhanced and sustained ACTH response that is seen in maternally deprived pups, we used in situ hybridization to investigate hippocampal mineralocorticoid (MR) and glucocorticoid receptor (GR) gene expression in 12 groups of animals: six groups involved 24 h maternally deprived (DEP) and non-deprived (NDEP) rat pups at three ages (6-, 9-, and 12-days-old); the other six groups included pups similarly treated, but challenged with an exposure to a mild stressor (saline injection) and sacrificed 1 h thereafter. We found: (1) an age effect for almost every hippocampal subfield for both MR and GR mRNAs: MR increases with age, while GR decreases: (2) down-regulation of MR mRNA in CA1 region in the DEP animals; and (3) down-regulation of GR mRNA, also in CA1, in the saline-injected DEP and NDEP animals. Our results indicate that corticoid receptors in the developing CA1 hippocampal region appear to be sensitive to circulating CS. They also suggest that the relative ratio of GR and MR in the CA1 region may contribute to the enhanced and sustained CS response seen after a mild stressor in deprived animals.

Maternal deprivation regulates serotonin 1A and 2A receptors in the infant rat

UNLABELLED Several studies have demonstrated that 5-HT1A and 5-HT2A receptors are altered in rat brain following chronic stress. While this is true in the adult animal, this may be different in the developing animal, which has a limited corticosterone response to acute challenges between days 3 and 14 of life. METHODS We investigated the effect of maternal deprivation on 5-HT2A and 5-HT1A receptor mRNA levels in the developing brain. In situ hybridization was used to quantify gene expression in rat pups at three ages: 6, 9, and 12 days old. In each age group, half were maternally deprived for 24 h and half were kept with their mothers. Maternally deprived animals showed elevated ACTH and corticosterone plasma levels when compared to NDEP animals, significantly elevated 5-HT1A mRNA levels in the CA1 hippocampal region and, significantly elevated 5-HT2A mRNA levels in the parietal cortex. No changes were observed in 5-HT1A or 5-HT-transporter mRNA levels in the dorsal raphe. Our results indicate that post-synaptic 5-HT receptors in the developing hippocampus and cortex are sensitive to maternal deprivation. Because hippocampal 5-HT1A gene expressions are known to decrease in the adult animal after chronic glucocorticoid elevation, this data also suggests that other mechanisms, perhaps central, predominate during development.

Regulation of 5-HT Receptors and the Hypothalamic-Pituitary-Adrenal Axis

ABSTRACT: Disturbances in the serotonin (5‐HT) system is the neurobiological abnormality most consistently associated with suicide. Hyperactivity of the hypothalmic‐pituitary‐adrenal (HPA) axis is also described in suicide victims. The HPA axis is the classical neuroendocrine system that responds to stress and whose final product, corticosteroids, targets components of the limbic system, particularly the hippocampus. We will review resulsts from animal studies that point to the possibility that many of the 5‐HT receptor changes observed in suicide brains may be a result of, or may be worsened by, the HPA overactivity that may be present in some suicide victims. The results of these studies can be summarized as follows: (1) chronic unpredictable stress produces high corticosteroid levels in rats; (2) chronic stress also results in changes in specific 5‐HT receptors (increases in cortical 5‐HT2A and decreases in hipocampal 5‐HT1A and 5‐HT1B); (3) chronic antidepressant administration prevents many of the 5‐HT receptor changes observed after stress; and (4) chronic antidepressant administration reverses the overactivity of the HPA axis. If indeed 5‐HT receptors have a partial role in controlling affective states, then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance.

Hypothalamic Pituitary Adrenal Axis Functioning in Reactive and Proactive Aggression in Children.

The purpose of this study was to examine the association between hypothalamic-pituitary-adrenal axis (HPA-axis) reactivity and proactive and reactive aggression in pre-pubertal children. After a 30-min controlled base line period, 73 7-year-old children (40 males and 33 females) were randomly assigned to one of two experimental tasks designed to elicit fear (N = 33) or frustration (N = 32), or a validity check condition (N = 8). This was followed by a 60-min controlled regulation phase. A total of 17 saliva samples for cortisol analysis were collected including 12 post-stress samples at 5-min intervals. Reactive and proactive aggression levels were assessed via the teacher-completed Aggression Behavior Teacher Checklist (Dodge and Coie, J Pers Soc Psychol, 53(6), 1146–1158, 1987). Reactive aggression significantly predicted total and peak post-stress cortisol regardless of stress modality. Proactive aggression was not a predictor of any cortisol index. Examination of pure reactive, proactive, combined, or non-aggressive children indicated that reactive aggressive children had higher cortisol reactivity than proactive and non-aggressive children. Our data suggest that while an overactive HPA-axis response to stress is associated with reactive aggression, stress induced HPA-axis variability does not seem to be related to proactive aggression.

Transcriptional Profiling of the Developing Rat Brain Reveals That the Most Dramatic Regional Differentiation in Gene Expression Occurs Postpartum

Neural development involves the expression of ensembles of regulatory genes that control the coordinate and region-specific expression of a host of other genes, resulting in the unique structure, connectivity, and function of each brain region. Although the role of some specific genes in neural development has been studied in detail, we have no global view of the orchestration of spatial and temporal aspects of gene expression across multiple regions of the developing brain. To this end, we used transcriptional profiling to examine expression levels of 9955 genes in the hypothalamus, hippocampus, and frontal cortex across seven stages of postnatal development and up to four stages of prenatal development in individual male rats (six per group). The results reveal dramatic changes across development in >97% of the neurally expressed genes. They also uncover a surprising degree of regional differentiation occurring after birth and through the first 2 weeks of life. Cluster analysis identifies 20 clusters of transcripts enriched in genes related to particular functions, such as DNA metabolism, nuclear function, synaptic vesicle transport, myelination, and neuropeptide hormone activity. Thus, groups of genes with related functions change in the brain at specific times, possibly marking critical periods for each function. These findings can broadly serve as a backdrop for studying the role of individual genes in neural development. They also underscore the importance of early postnatal life in the rat, which corresponds to late gestation in the human, as a critical late phase of neural organization and differentiation, even in subcortical regions.

Serotonin 1A receptor messenger RNA regulation in the hippocampus after acute stress.

BACKGROUND When rats are subjected to chronic stress for 2 weeks, a significant decrease in hippocampal serotonin (5-HT)1A messenger RNA (mRNA) is observed. We wanted to investigate whether stress, administered for shorter periods of time, would result in decreases in 5-HT1A gene expression in hippocampus. METHODS In one experiment, rats were either stressed daily for 1 week or implanted with two corticosterone pellets to produce elevated corticosterone levels. In another experiment, rats were subjected to a severe acute stressor and sacrificed 1 day or 1 week after the stressor. RESULTS We found that 24 hours after the acute stress, rats showed a significant decrease in 5-HT1A mRNA levels in CA1 and the dentate gyrus compared to controls. No significant changes in 5-HT1A mRNA levels were detected in any of the other groups. CONCLUSIONS Although 1 week of chronic stress is not sufficient to cause significant decreases in hippocampal 5-HT1A mRNA levels, a severe and prolonged acute stress is capable of down-regulating, at least transiently, 5-HT1A mRNA gene expression in hippocampus.

The Role of the Hippocampal Mineralocorticoid and Glucocorticoid Receptors in the Hypothalamo-Pituitary-Adrenal Axis of the Aged Fisher Rat

The aging process has been frequently associated with hippocampal neurodegeneration, loss of corticosteroid receptors, and, at the same time, dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis. We were interested in characterizing simultaneously the activity of the HPA axis and status of both corticosteroid receptors (mineralocorticoid or MR and glucocorticoid or GR) in the hippocampus of aged male Fisher-344 rats. We compared intact, adrenalectomized (ADX), and corticosterone-replaced ADX young (5-6 months) and old (26-27 months) rats, examining all the parameters in the same animals. Aged rats exhibited an unaltered basal rhythm and initial corticosterone response to restraint stress. However, the same old animals showed a delayed turn-off of the stress response and did so at different points of the corticosterone circadian cycle. The aged hippocampus showed a 40-50% lower MR and GR binding under all the conditions studied. This aging effect was not attributable to changes in the kinetics, affinity, or nuclear translocation of MR or GR. Intact aged rats exhibited also a 30-40% reduction of hippocampal MR and GR steady-state mRNA levels. Interestingly, after 36 h ADX only the aged hippocampus showed upregulation of MR and GR mRNA content to levels comparable to those in young rats. However, this increase in MR and GR mRNA content was not accompanied by a proportional increase in the Bmax of these receptors, suggesting age-related translational or post-translational alterations. Moreover, corticosterone replacement was able to reverse the ADX-induced increase of MR and GR Bmax in young and old hippocampi but it only reversed the upregulated mRNA levels of MR (and not GR) in the older group. The fact that corticosterone was able to modulate the biosynthetic rate of MR and GR strongly suggests that the decrease of receptors is functional and not simply due to cell death in the aged hippocampus. We propose that in the aged Fisher rat the loss of hippocampal corticosteroid receptors is previous to any change in the circadian rhythm of circulating corticosterone. Furthermore, the altered turn-off of the corticosterone stress response observed in the same animals may be related to the reduction of functional MR and GR but it is not due to high basal levels of corticosterone.