Psychoneuroendocrinology

Editorial Board

2012-06-01

The temporal impact of chronic intermittent psychosocial stress on high-fat diet-induced alterations in body weight

Beate C. Finger, Timothy G. Dinan, John F. Cryan — 2012-06-01

Summary: Background: Chronic stress and diet can independently or in concert influence the body's homeostasis over time. Thus, it is crucial to investigate the interplay of these parameters to gain insight into the evolution of stress-induced metabolic and eating disorders.Methods: C57BL/6J mice were subjected to chronic psychosocial (mixed model of social defeat and overcrowding) stress in combination with either a high- or low-fat diet for three or six weeks. To determine the evolution of stress and dietary effects, changes in body weight, caloric intake and caloric efficiency were determined as well as circulating leptin, insulin, glucose and corticosterone levels and social avoidance behaviour.Results: Exposure to stress for three weeks caused an increase in weight gain, in caloric intake and in caloric efficiency only in mice on a low-fat diet. However, after six weeks, only stressed mice on a high-fat diet displayed a pronounced inhibition of body weight gain, accompanied by reduced caloric intake and caloric efficiency. Stress decreased circulating leptin levels in mice on a low-fat diet after three weeks and in mice on a high-fat diet after three and six weeks of exposure. Plasma levels of insulin and markers of insulin resistance were blunted in mice on high-fat diet following six weeks of stress exposure. Social avoidance following chronic stress was present in all mice after three and six weeks.Conclusions: This study describes the evolution of the chronic effects of social defeat/overcrowding stress in combination with exposure to high- or low-fat diet. Most importantly, we demonstrate that a six week chronic exposure to social defeat stress prevents the metabolic effects of high-fat diet, by inhibiting an increase in weight gain, caloric intake and efficiency and insulin resistance as well as in plasma leptin and insulin levels. This study highlights the importance of considering the chronic aspects of both parameters and their time-dependent interplay.

Ovarian morphology in premenstrual dysphoria

2012-06-01

Summary: Ovarian cyclicity is a prerequisite for premenstrual dysphoria (PMD), as illustrated by the fact that this condition is effectively eliminated by ovariectomy or by treatment with a GnRH agonist. Despite the possibility of differences in ovarian function between women with and without PMD, no study comparing ovarian morphology in these two groups has ever been published. Fifty-two women were recruited for this study; 26 had premenstrual dysphoria, fulfilling criteria slightly modified from those of the premenstrual dysphoric disorder, and 26 were asymptomatic age-matched controls. Ovarian morphology was assessed using transvaginal 7MHz ultrasonography on day 5 after the start of menses, and venous blood was sampled for hormone analysis on days 3 and 8, the expected day of ovulation, and day −4 of the menstrual cycle. There were no significant differences between the groups with respect to the prevalence of polycystic ovaries (PCO), the total number of follicles, the total ovarian volume or serum levels of androgen hormones. In addition, serum free testosterone levels in late premenstrual phase showed an inverse association to premenstrual symptoms of irritability and a similar inverse association trend to symptoms of depressed mood. Unexpectedly, the prevalence of ovaries with fewer than five antral or growing follicles was significantly higher in women with PMD than in controls (p=0.016). While the results do not support a role for PCO or androgen hormones in eliciting late luteal phase irritability, the possible relationship between oligofollicular ovaries and PMD deserves further study.

Genetic and hormonal sensitivity to threat: Testing a serotonin transporter genotype×testosterone interaction

2012-06-01

Summary: Background: Striking parallels are observed when comparing the literature on the 5-HTTLPR of the serotonin transporter gene (SLC6A4) to the testosterone (T) literature on measures of stress reactivity and neural activity. Short (S) allele carriers and individuals higher in testosterone levels show exaggerated stress responses, amygdala hyperactivity, and reduction of amygdala–prefrontal cortex coupling when exposed to threat.Methods: Three studies tested the hypothesis that higher T, S carriers would show increased cortisol responses to threat.Results: Supporting the hypothesis, a T×5-HTTLPR interaction was obtained across all studies. Threats to status via social exclusion (Study 1), cognitive/perceptual failure (Study 2), and physical competence (Study 3) all produced elevated cortisol levels in S carriers with higher T levels. An unexpected result was that 5-HTTLPR long (L) allele homozygotes with higher T showed lower cortisol levels in response to threat—a pattern of response that closely parallels that reported for psychopathic individuals. Finally, combining effect sizes across studies showed that the likelihood that these effects were due to Type 1 errors was quite low.Conclusions: What emerges from these studies is a novel yet reliable, and synergistic relationship between 5-HTTLPR genotype and testosterone on stress reactivity, possibly conferring vulnerability for multiple neuropsychiatric disorders.

Social deprivation stress is a triggering factor for the emergence of anxiety- and depression-like behaviours and leads to reduced brain BDNF levels in C57BL/6J mice

2012-06-01

Summary: Stress is a main risk factor that can trigger psychiatric disorders, including anxiety and major depression. Neurotrophins, such as Brain-Derived Neurotrophic Factor (BDNF), have been identified as neuroendocrine effectors involved in the response to stress and in the neurobehavioural changes associated with depression. Aim of this paper was to study the relationship between neuroendocrine activation (circulating corticosterone and brain BDNF levels) and a wide array of depression- and anxiety-like behaviours (anhedonia, behavioural despair, generalised and social anxiety) resulting from exposure to chronic stress. To this end, 3-month-old C57BL/6J male mice were exposed to either chronic disruption of the social structure (SS), to a stable social structure (SG) or to social deprivation (SD), a condition lacking social stimuli. Results show that, despite not developing anhedonia (decreased preference for a sucrose solution), SD mice were characterised by increased emotionality and hypothalamic–pituitary–adrenal axis reactivity in addition to reduced BDNF levels. By contrast, SG and SS mice showed increased anhedonia accompanied by no alterations in the behavioural and neuroendocrine profile. The results here reported indicate that mice exposed to different social housing conditions use different behavioural strategies to cope with external challenges. In addition they suggest that social deprivation might represent a stressful condition triggering the emergence of both anxiety- and depression-like behaviours and clearly indicate BDNF as a main neurobiological variable mediating these responses.

Pharmacokinetics of three doses of sublingual testosterone in healthy premenopausal women

2012-06-01

Summary: Context: Sublingual testosterone is a single-dose treatment often used in studies regarding social, cognitive and sexual behavior. It is hypothesized that an increase in the ratio of free to total testosterone (free fraction) is indirectly, via genomic effects, responsible for the behavioral effects after sublingual testosterone administration.Objective: To characterize the pharmacokinetics of three doses sublingual testosterone in premenopausal women. Also, to investigate the SHBG saturation threshold influencing the free level and free fraction of testosterone.Design: We conducted an investigator-blind, randomized, cross-over placebo controlled study.Setting: This study was undertaken at the research and development department of a scientific company for research regarding female sexual dysfunction.Participants: 16 healthy premenopausal women (mean age 27.3±5.3years).Interventions: Sublingual testosterone solution; 0.25, 0.50 and 0.75mg.Main outcomes measure: The pharmacokinetics of three single doses sublingual testosterone solution; the influence of SHBG levels on free and total levels of testosterone.Results: After sublingual testosterone administration, serum free and total testosterone levels peaked at 15min and reached baseline levels within 150min. The AUCs and Cmax of free and total testosterone differed significantly between the three doses (p<0.0001) and increased dose-dependently.A dose-dependent increase in free fraction of testosterone was found in women with low SHBG levels, but not in women with high SHBG levels.Conclusions: The three doses sublingual testosterone are rapidly absorbed and quickly metabolized in premenopausal women. These data demonstrate the influence of SHBG levels on the treatment induced alterations in plasma free testosterone.

Associations between DNA methylation of a glucocorticoid receptor promoter and acute stress responses in a large healthy adult population are largely explained by lifestyle and educational differences

2012-06-01

Summary: Background: Glucocorticoids are the key regulators of the biological stress response and act by binding to glucocorticoid receptors (GR). Expression of GR is altered by DNA methylation. Methylation patterns in GR promoters have been shown to be highly variable between individuals, but little is known about the functional consequences of this variation for the acute stress response. The present study investigated associations between methylation status of the GR 1-C promoter and cortisol, cardiovascular and perceived stress responses to a psychosocial stress protocol in a large healthy adult population.Methods: A total of 725 overall healthy men and women, aged 55–60years, participated in a standardized psychosocial stress protocol consisting of three different stressors. At different stages during the stress protocol, salivary cortisol levels, continuous blood pressure and heart rate (HR) levels as well as perceived stress were measured. Stress reactivity was calculated as the increase between basal and peak measurements. Methylation status of the GR 1-C promoter was assessed in DNA isolated from peripheral blood samples using a methylation sensitive PCR assay for 675 of the 725 participants.Results: A decrease in methylation of the GR 1-C promoter was associated with a decrease in stress reactivity as indicated by lower cortisol and lower HR reactivity. A 1% decrease in GR 1-C methylation corresponded with a cortisol decrease by 0.14% (95% CI: 0.03–0.25, p=0.02) and an HR decrease by 0.10bpm (0.03–0.16, p=0.003). Adjusting for sex, lifestyle and education largely abolished these associations. A decrease in methylation of the GR 1-C promoter was also associated with an increase in stress perception as indicated by higher perceived stress (0.03 points [0.00–0.06, p=0.05]), lower perceived performance (−0.03 points [−0.05 to −0.01], p=0.02), and lower perceived control (−0.03 points [−0.05 to 0.00], p=0.04). After adjusting for sex and educational level the associations were no longer statistically significant. GR 1-C methylation status was not associated with blood pressure responses to the stress protocol.Discussion: Although effects were small, variation in methylation status in the GR 1-C promoter was associated with physical and perceived acute stress responses. Interestingly, these associations could largely be explained by differences in lifestyle and education.

The association between long-term accumulation of temporary employment, the cortisol awakening response and circadian cortisol levels

Per E. Gustafsson, Urban Janlert, Pekka Virtanen, Anne Hammarström — 2012-06-01

Summary: Temporary employment is an increasingly common contract type, which has not been investigated in a psychoneuroendocrinological context despite previous observations of associations between adverse work and employment conditions and hypothalamic-pituitary-adrenal (HPA) axis dysregulations. The present study aims to examine whether the 12-year accumulation of temporary employment is related to circadian cortisol levels, and if any association is independent of current employment conditions. Participants were drawn from the prospective Northern Swedish Cohort (n=791, 74% of the original cohort). At age 43 years, retrospective reports of employments over the last 12 years and of current social conditions were collected by questionnaire, and one-day salivary cortisol profile was measured (at awakening, +15min post-awakening, pre-lunch, bedtime). Results indicated a gradually higher magnitude of the cortisol awakening response (CAR) in subjects with no (0 months in temporary employment; mean CAR=34%), moderate (1–25 months in temporary employment; mean CAR=41%) and heavy (>25 months in temporary employment; mean CAR=51%) exposure (p=.020), remaining after adjustment for potential confounders and for current employment conditions (p=.028). The higher CAR was explained by lower awakening rather than higher post-awakening cortisol levels. Cortisol levels at all times of the day except post-awakening displayed tendencies to negative relations to temporary employment; as indicated by a lower Area Under of Curve (regression coefficient=5.0%, p=.038 after adjustment). This study thus suggests that the long-term exposure to temporary employment might confer HPA dysregulations in the form of increased dynamics of the CAR and circadian suppression.

The relationships of working conditions, recent stressors and childhood trauma with salivary cortisol levels

Michiel Holleman, Sophie A. Vreeburg, Jack J.M. Dekker, Brenda W.J.H. Penninx — 2012-06-01

Summary: Background: An etiological model has been suggested where stress leads to high cortisol levels and hypothalamic–pituitary–adrenal (HPA) axis dysregulation, resulting in somatic diseases and psychopathology. To evaluate this model we examined the association of different stressors (working conditions, recent life events and childhood trauma) with various cortisol indicators in a large cohort study.Methods: Data are from 1995 participants of the Netherlands Study of Depression and Anxiety (NESDA). Most of the selected participants had a current or remitted anxiety and/or depressive disorder. Working conditions were assessed with self-report questionnaires, life-events and childhood trauma were assessed with interview questionnaires. Cortisol levels were measured in seven saliva samples, determining the 1-h cortisol awakening response (CAR), evening cortisol levels and cortisol suppression after a 0.5mg dexamethasone suppression test (DST).Results: Regression analyses – adjusted for covariates – showed two significant associations: low social support at work and high job strain were associated with more cortisol suppression after the DST. No other associations were found with any of the cortisol variables.Conclusions: Working conditions, recent stressors and childhood trauma were not convincingly associated with cortisol levels.

Altered salivary alpha-amylase awakening response in Bosnian War refugees with posttraumatic stress disorder

2012-06-01

Summary: In posttraumatic stress disorder (PTSD), chronic activation of the sympathetic nervous system (SNS) has been suggested. No study so far has investigated diurnal secretion patterns of salivary alpha-amylase (sAA) in PTSD, a promising candidate for non-invasive assessment of SNS activity. We compared sAA diurnal profiles between a group of Bosnian War refugees with PTSD and a healthy control group, and further analyzed for associations with psychiatric symptoms and glucocorticoid (GC) sensitivity of inflammatory regulation. PTSD patients showed a sAA awakening response profile that was opposite to those seen in healthy controls, i.e. an increase instead of a sharp decrease. Patterns of sAA secretion were further positively associated with psychiatric symptoms of PTSD. Finally, higher sAA awakening responses were associated with higher GC sensitivity of inflammatory cytokine production. These findings are in line with altered SNS function in PTSD, and lend further support for employing assessment of diurnal sAA profiles as non-invasive biomarkers in stress-related disease.

Maternal prenatal anxiety and downregulation of placental 11β-HSD2

2012-06-01

Summary: Background: Raised maternal anxiety during pregnancy is associated with increased risk of adverse neurodevelopmental outcomes for her child. The mechanisms underlying this are not known but animal studies suggest prenatal stress may alter the function of the placenta. Here we determined whether maternal prenatal anxiety was associated with a downregulation of placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the enzyme which metabolises cortisol.Methods: We recruited mothers the day before delivery by elective caesarean, and gave them the Spielberger Trait and State anxiety and Edinburgh Depression self-rating scales. Placentae were collected and aliquots stored for later analysis.Results: Prenatal Trait anxiety was negatively correlated with placental 11β-HSD2 mRNA expression (r=−0.40, p<0.01, n=56). Results were similar with male and female fetuses (r=−0.39, p=0.04, n=28; r=−0.40, p=0.03, n=28) respectively. Results were also significant with State anxiety (r=−0.27, p=0.05, n=56) but somewhat weaker for depression (r=−0.20, p=0.13, n=56). Preliminary analyses on a subset of cases (n=25) suggested parallel results for enzyme activity.Conclusions: These findings provide evidence for an association between prenatal maternal mood and downregulation of placental 11β-HSD2. Results are consistent with raised maternal anxiety being associated with increased fetal exposure to maternal cortisol, and support the hypothesis that this may be one mechanism underlying fetal programming by prenatal stress.

Age and cortisol levels modulate judgment of positive and negative facial expressions

Joanne Feeney, Peter Gaffney, Shane M. O’Mara — 2012-06-01

Summary: There is some evidence that older adults respond to emotional stimuli differently to young adults, and that they may exhibit better performance on measures of memory and attention when stimuli are positive rather than negative in valence. A relation between cortisol levels and attention/memory for emotional stimuli in young adults has also been reported. The relationship between cortisol levels and the judgment of facial expressions of emotion in aging, however, has yet to be explored. The aim of this study was to investigate performance on a simple emotional face judgment task in young (N=37) and middle-aged (N=37) adults in association with salivary cortisol levels. Middle-aged participants were slower in responding to stimuli than younger participants. Cortisol levels were found to be associated with shorter response latencies to categorise emotional but not neutral faces, and with a greater tendency to judge neutral faces as being emotional. An interaction between age and cortisol levels emerged in response to angry faces; such that higher cortisol levels predicted significantly shorter reaction times to angry faces in young adults, but not in middle-aged adults. Thus, cortisol may be differently related to the processing of emotional facial expressions, particularly of anger, in middle-aged and young individuals. The findings are discussed in relation to the hypothesised changes in emotion regulation with aging.

Anxiety phenotype in mice that overexpress protein kinase A

2012-06-01

Summary: The role of cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling in the molecular pathways involved in fear and memory is well established. Prior studies in our lab reported that transgenic mice with an inactivating mutation in Prkar1a gene (codes for the 1-alpha regulatory subunit (R1α) of PKA) exhibited behavioral abnormalities including anxiety and depression. In the present study, we examined the role of altered PKA signaling on anxiety-like behaviors in Prkar1a+/− mice compared to wild-type (WT) littermates. The elevated plus maze (EPM) and marble bury (MB) tests were used to assess anxiety-like behavior. The hotplate test was performed to evaluate analgesia. We further examined the impact of the Prkar1a inactivating mutation on PKA activity in specific nuclei of the brain associated with anxiety-like behavior. Results for the MB test showed a genotype effect, with increased anxiety-like behavior in Prkar1a+/− mice, compared to WT littermates (p<0.05). MANOVA analysis showed a significant genotype difference in anxiety-like behavior in the EPM between WT and Prkar1a+/− mice on combined dependent variables (open arm time and open to total time ratio; p<0.05). Results of hotplate testing showed no genotype effect however; the expected sex difference was noted. Analysis of PKA activity showed the loss of one Prkar1a allele led to an increase in basal and cAMP-stimulated kinase activity in both the basolateral and central amygdala. These results suggest that the alteration in PKA signaling in Prkar1a+/− mice is not a ubiquitous effect; and supports the importance of cAMP/PKA pathway in neurobiological processes involved in anxiety and fear sensitization.

Intense exercise increases circulating endocannabinoid and BDNF levels in humans—Possible implications for reward and depression

2012-06-01

Summary: The endocannabinoid system is known to have positive effects on depression partly through its actions on neurotrophins, such as Brain-Derived Neurotrophic Factor (BDNF). As BDNF is also considered the major candidate molecule for exercise-induced brain plasticity, we hypothesized that the endocannabinoid system represents a crucial signaling system mediating the beneficial antidepressant effects of exercise. Here we investigated, in 11 healthy trained male cyclists, the effects of an intense exercise (60min at 55% followed by 30min at 75% Wmax) on plasma levels of endocannabinoids (anandamide, AEA and 2-arachidonoylglycerol, 2-AG) and their possible link with serum BDNF. AEA levels increased during exercise and the 15min recovery (P<0.001), whereas 2-AG concentrations remained stable. BDNF levels increased significantly during exercise and then decreased during the 15min of recovery (P<0.01). Noteworthy, AEA and BDNF concentrations were positively correlated at the end of exercise and after the 15min recovery (r>0.66, P<0.05), suggesting that AEA increment during exercise might be one of the factors involved in exercise-induced increase in peripheral BDNF levels and that AEA high levels during recovery might delay the return of BDNF to basal levels. AEA production during exercise might be triggered by cortisol since we found positive correlations between these two compounds and because corticosteroids are known to stimulate endocannabinoid biosynthesis. These findings provide evidence in humans that acute exercise represents a physiological stressor able to increase peripheral levels of AEA and that BDNF might be a mechanism by which AEA influences the neuroplastic and antidepressant effects of exercise.

Effects of prolonged stress on salivary cortisol and dehydroepiandrosterone: A study of a two-week teaching practice

Shuhei Izawa, Keisuke Saito, Kentaro Shirotsuki, Nagisa Sugaya, Shinobu Nomura — 2012-06-01

Summary: This study investigated variations in salivary levels of cortisol and dehydroepiandrosterone (DHEA) in a prolonged stressful situation (a two-week teaching practice). Thirty-three women for whom a two-week teaching practice at a kindergarten was scheduled were asked to collect saliva samples at awakening, 30min after awakening, and bedtime at four time points: two weeks before the practice, the first week of the practice, the second week of the practice, and a few days after the practice. In addition, they completed questionnaires for assessing perceived stress and subjective moods on each day. A linear mixed model indicated that cortisol levels significantly increased during the first and second week of the practice compared with those before and after the practice period, and that DHEA levels significantly decreased after the practice period compared with those at the other time points. Further, cortisol awakening response after the practice period significantly reduced compared with that at the other time points. Scores of perceived stress and negative moods were also higher during the practice period. This study showed that prolonged stress affected cortisol and DHEA secretion during as well as after the stress period.

Morphine history sensitizes postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats

D.R. Staub, J.W. Lunden, A.M. Cathel, E.L. Dolben, L.G. Kirby — 2012-06-01

Summary: The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Previous work has shown that the dorsal raphe nucleus (DR)-5-HT system is inhibited by swim stress via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor (CRF). Additionally, the DR 5-HT system is regulated by opioids. The present study tests the hypothesis that the DR 5-HT system regulates stress-induced opioid relapse. In the first experiment, electrophysiological recordings of GABA synaptic activity in 5-HT DR neurons were conducted in brain slices from Sprague-Dawley rats that were exposed to swim stress-induced reinstatement of previously extinguished morphine conditioned place preference (CPP). Behavioral data indicate that swim stress triggers reinstatement of morphine CPP. Electrophysiology data indicate that 5-HT neurons in the morphine-conditioned group exposed to stress had increased amplitude of inhibitory postsynaptic currents (IPSCs), which would indicate greater postsynaptic GABA receptor density and/or sensitivity, compared to saline controls exposed to stress. In the second experiment, rats were exposed to either morphine or saline CPP and extinction, and then 5-HT DR neurons from both groups were examined for sensitivity to CRF in vitro. CRF induced a greater inward current in 5-HT neurons from morphine-conditioned subjects compared to saline-conditioned subjects. These data indicate that morphine history sensitizes 5-HT DR neurons to the GABAergic inhibitory effects of stress as well as to some of the effects of CRF. These mechanisms may sensitize subjects with a morphine history to the dysphoric effects of stressors and ultimately confer an enhanced vulnerability to stress-induced opioid relapse.