Pituitary Adrenal Axis Response Research Articles

The Impact of the FKBP5 Gene Polymorphisms on the Relationship between Traumatic Life Events and Psychotic-Like Experiences in Non-Clinical Adults

Common variations of the FKBP5 gene are implicated in psychotic disorders, by modulating the hypothalamic–pituitary–adrenal axis reactivity to stress. It has been demonstrated that some of them might moderate the effects of childhood trauma on psychosis proneness. However, these associations have not been investigated with respect to traumatic life events (TLEs). Therefore, we aimed to explore whether the FKBP5 polymorphisms moderate the effects of TLEs on the level of psychotic-like experiences (PLEs). A total of 535 non-clinical adults were approached for participation, and genotyping of six FKBP5 polymorphisms (rs3800373, rs9470080, rs4713902, rs737054, rs1360780 and rs9296158) was performed. The Prodromal Questionnaire-16 (PQ-16) and the Traumatic Events Checklist (TEC) were administered to assess PLEs and TLEs, respectively. Among the rs1360780 CC homozygotes, a history of physical abuse was associated with significantly higher PQ-16 scores. This difference was not significant in the rs1360780 T allele carriers. Similarly, a history of physical abuse was associated with significantly higher PQ-16 scores in the rs9296158 GG homozygotes but not in the rs9296158 A allele carriers. Finally, emotional neglect was related to significantly higher PQ-16 scores in the rs737054 T allele carriers but not in the rs737054 CC homozygotes. The present study indicates that variation in the FKBP5 gene might moderate the effects of lifetime traumatic events on psychosis proneness.

Acute restraint stress does not alter corticosteroid receptors or 11β-hydroxysteroid dehydrogenase gene expression at hypothalamic–pituitary-adrenal axis regulatory sites in captive male white-crowned sparrows (Zonotrichia leucophrys gambelii)

Capture-restraint is often used to investigate the acute hypothalamic–pituitary-adrenal axis (HPA) response to stress in wild and captive animals through the production of glucocorticoids. Although this approach is useful for understanding changes in glucocorticoids, it overlooks potential changes in the complex regulatory systems associated with the glucocorticoid response, including genomic receptors, steroid metabolizing enzymes, carrier proteins, and downstream target proteins (e.g. gonadotropin-inhibitory hormone; GnIH). The present study in captive male white-crowned sparrows (Zonotrichia leucophrys) tests the hypothesis that corticosteroid receptors (mineralocorticoid - MR and glucocorticoid - GR), 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) and 2 (11βHSD2), corticosteroid binding globulin (CBG), and GnIH undergo rapid changes in expression to mediate the glucocorticoid response to acute stress. To determine dynamic changes in gene mRNA expression in the hippocampus, hypothalamus, pituitary gland, and liver, birds were sampled within 3 min of entering the room and after 10, 30, and 60 min of capture restraint stress in a cloth bag. Restraint stress handling increased CBG and decreased GnIH mRNA expression in the liver and hypothalamus, respectively. MR, GR, 11βHSD1, and 11βHSD2 mRNA expression in the brain, pituitary gland, and liver did not change. No correlations were found between gene expression and baseline or stress-induced plasma corticosterone levels. No rapid changes of MR, GR, 11βHSD1, and 11βHSD2 mRNA expression during a standardized acute restraint protocol suggests that tissue level sensitivity may remain constant during acute stressors. However, the observed rise in CBG mRNA expression could act to facilitate transport to target tissues or buffer the rise in circulating glucocorticoids. Further studies on tissue specific sensitivity are warranted.

Anxiolytic and antioxidant effects of Euterpe oleracea Mart. (açaí) seed extract in adult rat offspring submitted to periodic maternal separation.

Many studies suggest a protective role of phenolic compounds in mood disorders. We aimed to assess the effect of Euterpe oleracea (açaí) seed extract (ASE) on anxiety induced by periodic maternal separation (PMS) in adult male rats. Animals were divided into 6 groups: control, ASE, fluoxetine (FLU), PMS, PMS+ASE, and PMS+FLU. For PMS, pups were separated daily from the dam for 3 h between postnatal day (PN) 2 and PN21. ASE (200 mg·kg-1·day-1) and FLU (10 mg·kg-1·day-1) were administered by gavage for 34 days after stress induction, starting at PN76. At PN106 and PN108, the rats were submitted to open field (OF) and forced swim tests, respectively. At PN110, the rats were sacrificed by decapitation. ASE increased time spent in the center area in the OF test, glucocorticoid receptors in the hypothalamus, tropomyosin receptor kinase B (TRKB) levels in the hippocampus, and nitrite levels and antioxidant activity in the brain stem (PMS+ASE group compared with PMS group). ASE also reduced plasma corticotropin-releasing hormone levels, adrenal norepinephrine levels, and oxidative damage in the brain stem in adult male offspring submitted to PMS. In conclusion, ASE treatment has an anti-anxiety effect in rats submitted to PMS by reducing hypothalamic-pituitary-adrenal axis reactivity and increasing the nitric oxide (NO)-brain-derived neurotrophic factor (BDNF)-TRKB pathway and antioxidant defense in the central nervous system. Novelty ASE has anti-anxiety and antioxidant effects in early-life stress. ASE reduces hypothalamic-pituitary-adrenal axis reactivity. The anxiolytic effect of ASE may involve activation of the NO-BDNF-TRKB pathway in the central nervous system.

Alcohol Use Disorder Masks the Effects of Childhood Adversity, Lifetime Trauma, and Chronic Stress on Hypothalamic-Pituitary-Adrenal Axis Reactivity.

Individuals with alcohol use disorder (AUD) and those who have experienced traumas or chronic stress exhibit dysregulated hypothalamic-pituitary-adrenal (HPA) axis reactivity. Whether and how trauma and stress histories interact with AUD to affect HPA axis reactivity has not been assessed. In the present study, 26 healthy male controls and 70 abstinent men with AUD were administered a pharmacologic probe [ovine corticotropin-releasing hormone (oCRH)] and psychosocial stressor to assess HPA axis reactivity. Plasma adrenocorticotropin hormone (ACTH) and cortisol were assessed every 10-20minutes. Hierarchical clustering of multiple measures of trauma and stress identified 3 distinct clusters: childhood adversity, lifetime trauma, and chronic stress. General linear model procedures were used to examine main effects of group (AUD/control) and interaction effects of the 3 clusters upon net-integrated ACTH and cortisol response. We found that higher levels of childhood adversity, lifetime trauma, and chronic stress were each associated with blunted oCRH-induced ACTH reactivity in controls, but not in the AUD group. Recent chronic stress within the prior 6months had the strongest influence upon ACTH reactivity in the control group, and lifetime trauma, the least. Childhood adversity, lifetime trauma, and chronic stress likely exert persistent, measurable effects upon HPA axis functioning in healthy controls. This association appears to be masked in individuals with AUD, potentially confounding studies examining the effects of stress, adversity, and/or trauma upon the HPA axis in this population during the protracted withdrawal phase of recovery. Future work targeting stress exposure and reactivity should consider the heightened effect of previous alcohol use relative to past adversity and trauma.

Effects of dietary protein and fat concentrations on hormonal and oxidative blood stress biomarkers in guide dogs during training

We compared the effects of different feeding strategies on hormonal and oxidative stress biomarkers in guide dogs during specialized training programs. Eight neutered adult dogs belonging to the Labrador retriever breed were divided during the training work into two homogeneous groups for sex (2 males, 2 females), age (17 months ± 1), initial body weight (26.3 kg ± 1), and BCS (4.5 of 9 ± 0.11) and fed two commercial diets with different concentration of energetic nutrients. One diet was a performance diet (HPF) characterized by low-carbohydrate/high-protein and fat content (29:39:19% as-fed) and the other a normal maintenance diet (LPF), characterized by high-carbohydrate/low-protein and fat content (50:24:12% as-fed). The trial lasted 84 days. At days 0, 28, 56, and 84, 180 min before the training work (T0) and immediately after (T1) and after 120 min (T2), blood adrenocorticotrophic hormone (ACTH), cortisol, d-ROMS (reactive oxygen metabolites–derived compounds), and BAP (biological antioxidant potential) were evaluated. Lactate was measured at T0 and T1. The statistical model included the effects of diet (HPF vs. LPF), time (from day 0 to day 84, end of the trial), and exercise (T0, T1, and T2) and their interaction. ACTH (P = 0.002) and cortisol (P = 0.013) showed higher values in the HPF than in the LPF group; there were no significant differences observed for lactate. Time showed no significant difference for any hormones or blood lactate. Exercise significantly (P < 0.001) influenced ACTH and cortisol concentrations, showing higher values at T1 than T0 and T2, and with lactate higher (P < 0.0001) at T1 than T0. Diet did not influence biomarkers of oxidative stress. Time did significantly (P < 0.05) influence BAP results but not d-ROMs. Exercise had no effect on BAP results, but d-ROMs were higher at T0 than T2 (P = 0.001). There was no interaction effect. The pituitary-adrenal (HPA) axis response and the oxidative stress indices could represent an objective method to identify optimal dietary protocols for creating a successful guide dog during the early training period.

Neonatal pain and reduced maternal care alter adult behavior and hypothalamic-pituitary-adrenal axis reactivity in a sex-specific manner.

Preterm infants often spend a significant amount of time in the neonatal intensive care unit (NICU) where they are exposed to many stressors including pain and reduced maternal care. These early-life stressful experiences can have negative consequences on brain maturation during the neonatal period; however, less is known about the long-term cognitive and affective outcomes. Thus, this study was conducted to investigate the impact of neonatal pain and reduced maternal care on adult behavior and HPA axis reactivity in an animal model. Male and female rats underwent a series of repetitive needle pokes and/or reduced maternal care (through a novel tea ball infuser encapsulation method) during the first 4days of life and were then assessed in a battery of behavioral tests as adults. We found that early-life pain enhanced spatial learning independent of the animal's sex, but altered HPA recovery from an acute stressor in females only. Moreover, reduced maternal care altered long-term spatial memory and reversal learning in males. These findings indicate that neonatal stressors have unique sex-dependent long-term biobehavioral effects in rodents. Continued examination of the behavioral consequences of these stressors may help explain varying vulnerability and resiliency in preterm infants who experienced early stress in the NICU.

The blockade of corticotropin-releasing factor 1 receptor attenuates anxiety-related symptoms and hypothalamus-pituitary-adrenal axis reactivity in mice with mild traumatic brain injury.

Recent studies have shown that mild traumatic brain injury (mTBI) is associated with higher risk for anxiety-related disorders. Dysregulation in the hypothalamus-pituitary-adrenal (HPA) axis following mTBI has been proposed to be involved in the development of neurobehavioral abnormalities; however, the underlying mechanisms are largely unknown. The aim of this study was to determine whether the corticotropin-releasing-factor-1 (CRF-1) receptor is involved in the regulation of anxiety-related symptoms in a mouse model of mTBI. Animals with or without mTBI received intracerebroventricular injections of a CRF-1 receptor agonist (CRF; 0.01 nmol/mouse) or antagonist (antalarmin; 1 µg/mouse) for 5 days, and then the animals were subjected to anxiety tests (light-dark box and zero maze). The levels of adrenocorticotropic hormone and corticosterone, the most important markers of HPA axis, were also measured after behavioral tests. Our results indicated that mTBI-induced anxiety-related symptoms in mice through increased levels of adrenocorticotropic hormone and corticosterone, showing HPA axis hyperactivity. Interestingly, activation of CRF receptor by a subthreshold dose of CRF resulted in significant increases in anxiety-like behaviors and HPA axis response to stress, whereas blockade of CRF receptors by a subthreshold dose of antalarmin decreased anxiety-related symptoms and HPA axis response to stress in mTBI-induced mice. Collectively, these findings suggest that the CRF-1 receptor plays an important role in the regulation of anxiety-related behaviors following mTBI induction in mice and support the hypothesis that blockade of the CRF-1 receptor may be a promising therapeutic target for anxiety-related disorders in patients with TBI.

The relationship between personality and the response to acute psychological stress

The present study examined the relationship between personality traits and the response to acute psychological stress induced by a standardized laboratory stress induction procedure (the Trier Social Stress Test, TSST). The stress response was measured with a combination of cardiovascular reactivity, hypothalamic–pituitary–adrenal axis reactivity, and subjective affect (including positive affect, negative affect and subjective controllability) in healthy individuals. The Generalized Estimating Equations (GEE) approach was applied to account for the relationship between personality traits and stress responses. Results suggested that higher neuroticism predicted lower heart rate stress reactivity, lower cortisol stress response, more decline of positive affect and lower subjective controllability. Individuals higher in extraversion showed smaller cortisol activation to stress and less increase of negative affect. In addition, higher openness score was associated with lower cortisol stress response. These findings elucidate that neuroticism, extraversion and openness are important variables associated with the stress response and different dimensions of personality trait are associated with different aspects of the stress response.

Pituitary-Adrenal Axis Responses to Routine Management Procedures in Sheep (Ovis aries)

Background: Shearing is considered as a stressful factor in sheep, capable of causing some behavioural changes including variations of body condition and hormonal and haematochemical parameters. On these basis, circulating ACTH and cortisol concentrations were determined in sheep before and after exposure to aversive stimuli in order to evaluate the potential use of these hormones to objectively measure physical and mental stress responses to isolation, restraint and shearing.Materials, Methods &amp; Results: Forty Pinzirita sheep, used as experimental group, were evaluated in baseline conditions, 24 h before isolation, restraint and shearing (T0), after isolation (T1), after restraint and shearing (T2), by taking into account the influence of previous shearing experience (just shorn). A control group of forty sheep (intact) was evaluated in baseline condition (T0). According to previous experience the experimental subjects were divided in two groups, respectively group A represented by 20 sheep (10 males and 10 females), aged 1-2 years, without previous shearing experience (intact); and group B represented by 20 sheep (10 males and 10 females), aged older than 2 years, previously exposed to shearing (just shorn). A control group C of 40 sheep splitted into two sub-groups represented by 10 intact males and 10 intact females, aged 1-2 years, and 10 males and 10 females just shorn, aged older than 2 years, was evaluated in baseline conditions (T0). Blood samples were collected 24 h before experimental practices (T0: 08:00 h), after 1 h after of isolation (T1) and after restraint and shearing, around an average of 5 min (T2). All samples were taken in quiet conditions by the same operator. Serum ACTH concentrations were assayed by a commercial radioimmunoassay (RIA). Serum cortisol concentrations were assayed by amplified Enzyme Immunoassay (EIA). Two-way RM ANOVA showed a significant effect of husbandry procedures on ACTH changes, with higher ACTH and cortisol concentrations of just shorn than intact males (F = 15.76; P &lt; 0.0001) and females (F = 17.34; P &lt; 0.0005), and on cortisol changes, with higher cortisol concentrations of just shorn than intact males (F = 6.54; P &lt; 0.01) and females (F = 22.66; P &lt; 0.0001).Discussion: The highest ACTH and cortisol values after isolation, with an appreciable increase especially after restraint and shearing in just shorn sheep, showed that the previous shearing exposure could not induce a habituation to the stimulus, probably promoting a larger release of ACTH and cortisol hormones, so inducing an early and marked coping response to stress in just shorn specimens. Thus, it would appear that different ACTH and cortisol responses of sheep with or without previous shearing experience over the study period resulted in some significant differences when exposed to isolation, restraint and shearing, probably due to changes in pituitary-adrenal axis reactivity. Nevertheless, it is possible to interpret the increase in ACTH and cortisol concentrations related to intrinsic endocrine control mechanisms as an increase due to a rise in the stressful stimulus or coping response. The magnitude of ACTH and cortisol changes following isolation, restraint and shearing suggests that measurements of both hormones are useful in assessing husbandry procedures stress in sheep, with marked elevations in just shorn sheep, indicating that experience can induce an early much larger coping response to stressful practice of shearing.

Novel mechanism within the paraventricular nucleus reduces both blood pressure and hypothalamic pituitary-adrenal axis responses to acute stress.

Macrophage migration inhibitory factor (MIF) counteracts pressor effects of angiotensin II (ANG II) in the paraventricular nucleus of the hypothalamus (PVN) in normotensive rats, but this mechanism is absent in spontaneously hypertensive rats (SHRs) due to a lack of MIF in PVN neurons. Since endogenous ANG II in the PVN modulates stress reactivity, we tested the hypothesis that replacement of MIF in PVN neurons would reduce baseline blood pressure and inhibit stress-induced increases in blood pressure and plasma corticosterone in adult male SHRs. Radiotelemetry transmitters were implanted to measure blood pressure, and then an adeno-associated viral vector expressing either enhanced green fluorescent protein (GFP) or MIF was injected bilaterally into the PVN. Cardiovascular responses to a 15-min water stress (1-cm deep, 25°C) and a 60-min restraint stress were evaluated 3-4 wk later. MIF treatment in the PVN attenuated average restraint-induced increases in blood pressure (37.4 ± 2.0 and 27.6 ± 3.5 mmHg in GFP and MIF groups, respectively, P < 0.05) and corticosterone (42 ± 2 and 36 ± 3 μg/dl in GFP and MIF groups, respectively, P < 0.05). MIF treatment in the PVN also reduced stress-induced elevations in the number of c-Fos-positive cells in the rostral ventrolateral medulla (71 ± 5 in GFP and 47 ± 5 in MIF SHRs, P < 0.01) and corticotropin-releasing factor mRNA expression in the PVN. However, MIF had no significant effects on the cardiovascular responses to water stress in SHRs or to either stress in Sprague-Dawley rats. Therefore, viral vector-mediated restoration of MIF in PVN neurons of SHRs attenuates blood pressure and hypothalamic pituitary adrenal axis responses to stress.

CYP7B1 Enzyme Deletion Impairs Reproductive Behaviors in Male Mice.

In addition to androgenic properties mediated via androgen receptors, dihydrotestosterone (DHT) also regulates estrogenic functions via an alternate pathway. These estrogenic functions of DHT are mediated by its metabolite 5α-androstane-3β, 17β-diol (3β-diol) binding to estrogen receptor β (ERβ). CYP7B1 enzyme converts 3β-diol to inactive 6α- or 7α-triols and plays an important role as a regulator of estrogenic functions mediated by 3β-diol. Using a mutant mouse carrying a null mutation for the CYP7B1 gene (CYP7B1KO), we examined the contribution of CYP7B1 on physiology and behavior. Male, gonadectomized (GDX) CYP7B1KO and their wild type (WT) littermates were assessed for their behavioral phenotype, anxiety-related behavioral measures, and hypothalamic pituitary adrenal axis reactivity. No significant effects of genotype were evident in anxiety-like behaviors in open field (OFA), light-dark (L/D) exploration, and elevated plus maze (EPM). T significantly reduced open arm time on the EPM while not affecting L/D exploratory and OFA behaviors in CYP7B1KO and WT littermates. T also attenuated the corticosterone response to EPM in both genotypes. In GDX animals, T was able to reinstate male-specific reproductive behaviors (latencies and number of mounts, intromission, and ejaculations) in the WT but not in the CYP7B1KO mice. The male reproductive behavior defect in CYP7B1KO seems to be due to their inability to distinguish olfactory cues from a behavioral estrus female. CYP7B1KO mice also showed a reduction in androgen receptor mRNA expression in the olfactory bulb. Our findings suggest a novel role for the CYP7B1 enzyme in the regulation of male reproductive behaviors.

Eye tracking indices of attentional bias in children of depressed mothers: Polygenic influences help to clarify previous mixed findings.

Information-processing biases may contribute to the intergenerational transmission of depression. There is growing evidence that children of depressed mothers exhibit attentional biases for sad faces. However, findings are mixed as to whether this bias reflects preferential attention toward, versus attentional avoidance of, sad faces, suggesting the presence of unmeasured moderators. To address these mixed findings, we focused on the potential moderating role of genes associated with hypothalamic-pituitary-adrenal axis reactivity. Participants included children (8-14 years old) of mothers with (n = 81) and without (n = 81) a history of depression. Eye movements were recorded while children passively viewed arrays of angry, happy, sad, and neutral faces. DNA was obtained from buccal cells. Children of depressed mothers exhibited more sustained attention to sad faces than did children of nondepressed mothers. However, it is important that this relation was moderated by children's genotype. Specifically, children of depressed mothers who carried reactive genotypes across the corticotropin-releasing hormone type 1 receptor (CHRH1) TAT haplotype and FK506 binding protein 5 (FKBP5) rs1360780 (but not the solute carrier family C6 member 4 [SLC6A4] of the serotonin transporter linked polymorphic region [5-HTTLPR]) exhibited less sustained attention to sad faces and more sustained attention to happy faces. These findings highlight the role played by specific genetic influences and suggest that previous mixed findings may have been due to genetic heterogeneity across the samples.

Post-training corticosterone inhibits the return of fear evoked by platform stress and a subthreshold conditioning procedure in Sprague–Dawley rats

The return of fear is an important issue in anxiety disorder research. Each time a fear memory is reactivated, it may further strengthen overactivation of the fear circuit, which may contribute to long-term maintenance of the fear memory. Recent evidence indicates that glucocorticoids may help attenuate pathological fear, but its role in the return of fear is unclear. In the present study, systemic corticosterone (CORT; 25mg/kg) administration 1h after fear conditioning did not impair the consolidation process but significantly suppressed the return of fear evoked by a subthreshold conditioning (SC) procedure and elevated platform (EP) stress. Compared with the SC-induced return of fear, acute stress-induced return was state-dependent. In addition, post-training CORT treatment increased the adrenocorticotropic response after EP stress, which indicates that the drug-induced suppression of the return of fear may possibly derive from its regulation effect of the hypothalamic–pituitary–adrenal axis reactivity to stress. These results suggest that post-training CORT administration may help inhibit the return of fear evoked by EP or SC stress. The possible mechanisms involved in the high-dose CORT-induced suppression of the SC- and EP-induced return of fear are discussed.

Corticosterone stress response shows long-term repeatability and links to personality in free-living Nazca boobies

The concept of “coping styles”, or consistently different responses to stressors, is of broad interest in behavioral ecology and biomedicine. Two critical predictions of this concept are individual consistency of neurophysiological and behavioral responses (relative to population variability) and a negative relationship between aggression/proactivity and hypothalamic–pituitary–adrenal axis reactivity. Recent studies failed to provide strong support for these predictions, especially outside of strictly controlled conditions, and long-term measures to test the first prediction are rare. Here, we demonstrate individual repeatability across 2–3years of maximum circulating corticosterone concentration [CORT] and area under the [CORT] response curve (AUCI) during a standard capture-restraint test in wild, free-living adult Nazca boobies (Sula granti). We also show that the stress response predicts the personality traits aggression and anxiety in these birds (measured in the wild); however, the strength of these results was weak. Maximum [CORT] and AUCI showed higher repeatability between years than baseline [CORT]. After controlling breeding status, sex, mass, date sampled, and their interactions, baseline [CORT] was most closely related to personality traits, followed by AUCI, and then maximum [CORT]. The direction of these relationships depended on whether the testing context was social or non-social. [CORT] parameters had little to no relationship with cross-context plasticity in personality traits. Our results generally affirm two critical predictions of coping styles, but match the emerging trend that these relationships are weak in the wild, and may depend on testing context.

Acute Stress Contributes to Individual Differences in Pain and Pain-Related Brain Activity in Healthy and Chronic Pain Patients

Individual differences in pain sensitivity and reactivity are well recognized but the underlying mechanisms are likely to be diverse. The phenomenon of stress-induced analgesia is well documented in animal research and individual variability in the stress response in humans may produce corresponding changes in pain. We assessed the magnitude of the acute stress response of 16 chronic back pain (CBP) patients and 18 healthy individuals exposed to noxious thermal stimulations administered in a functional magnetic resonance imaging experiment and tested its possible contribution to individual differences in pain perception. The temperature of the noxious stimulations was determined individually to control for differences in pain sensitivity. The two groups showed similar significant increases in reactive cortisol across the scanning session when compared with their basal levels collected over 7 consecutive days, suggesting normal hypothalamic-pituitary-adrenal axis reactivity to painful stressors in CBP patients. Critically, after controlling for any effect of group and stimulus temperature, individuals with stronger cortisol responses reported less pain unpleasantness and showed reduced blood oxygenation level-dependent activation in nucleus accumbens at the stimulus onset and in the anterior mid-cingulate cortex (aMCC), the primary somatosensory cortex, and the posterior insula. Mediation analyses indicated that pain-related activity in the aMCC mediated the relationship between the reactive cortisol response and the pain unpleasantness. Psychophysiological interaction analysis further revealed that higher stress reactivity was associated with reduced functional connectivity between the aMCC and the brainstem. These findings suggest that acute stress modulates pain in humans and contributes to individual variability in pain affect and pain-related brain activity.

Maternal stimulation in infancy predicts hypothalamic–pituitary–adrenal axis reactivity in young men

Evidence from animal research has demonstrated the effect of early maternal care on the offspring's endocrine and behavioral stress response in adulthood. The present prospective study investigates, in humans, the long-term impact of maternal responsiveness and stimulation during early mother-child interaction on adrenocorticotropic hormone (ACTH) and cortisol response to a psychosocial laboratory stressor in adulthood. The data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3months, mothers and infants were videotaped during a 10-min standardized nursing and playing situation and evaluated by trained raters for maternal stimulation and infant and maternal responsiveness. At age 19years, 270 participants (146 females, 124 males) completed the Trier Social Stress Test. The results indicated that less maternal stimulation during early interaction at age 3months predicted diminished plasma ACTH and cortisol increase in response to acute psychosocial stress in male, but not female offspring. In contrast, maternal responsiveness was found to be unrelated to hypothalamic-pituitary-adrenal (HPA) reactivity. In accordance with the findings from animal research, the present study provides prospective evidence in humans of a long-term association between early maternal interaction behavior and the offspring's hormonal stress response in young adulthood, suggesting that poor maternal stimulation in early infancy may result in reduced HPA axis reactivity to an acute psychosocial stressor in males.

Cortisol awakening response and negative emotionality linked to asymmetry in major limbic fibre bundle architecture

The limbic system plays an important role in regulating the hypothalamic–pituitary–adrenal (HPA) axis as well as aspects of emotion, and both neuroendocrine disturbance and increased negative emotionality are associated with risk for developing affective disorders. However, the extent to which the architecture of connections between limbic structures may be linked to individual differences in basal HPA-axis reactivity and negative emotionality is unknown. Here we tested the hypotheses that microstructural asymmetry of the major limbic fibre bundles would be associated with cortisol awakening response (CAR) and neuroticism, a personality trait associated with the tendency to experience negative emotions. Sixty-nine healthy adults were studied with diffusion-weighted imaging, and fractional anisotropy (FA) was extracted from the cingulum and uncinate fasciculus. Higher neuroticism scores, which were associated with higher CAR, were also correlated with higher right relative to left cingulum FA. Elevated CAR was associated with the degree of FA asymmetry within both the cingulum and the uncinate fasciculus, but in opposing directions. These results suggest that the balance between left- and right-sided limbic circuits may bear an important relationship to hypothalamic–pituitary–adrenal axis reactivity, and to the tendency to experience negative emotions, and they raise important questions about the significance of limbic system architecture.

Pain behavior and spinal cell activation due to carrageenan-induced inflammation in two inbred rat strains with differential hypothalamic–pituitary–adrenal axis reactivity

Lewis (LEW) and Fischer (FIS) inbred rats were used to study the relationship of hypothalamic–pituitary–adrenal (HPA) axis reactivity with inflammation-related pain behavior. LEW rats are susceptible to the development of autoimmune and chronic inflammatory disorders, whereas FIS rats are resistant. Since contradictory data have previously been collected under conditions of acute inflammation, we investigated the onset and maintenance of thermal and mechanical hyperalgesia and spinal activation of neurons and glia cells in a model of ongoing inflammation in both strains. Hind paw volumes and mechanical and thermal pain thresholds were measured prior to and during one week after intraplantar injection of carrageenan. The activation of nociceptive neurons (FosB), astroglia (GFAP) and microglia (OX-42) in the spinal cord of segments L5/L6 was assessed using immunohistochemistry. Inflammation increased paw volume, pain sensitivity and cell activation in both strains. FIS rats were more sensitive to sensory stimulation and developed a more severe edema on day 1, but recovered faster up to day 7 than LEW rats. At that time a higher amount of activated nociceptive neurons and corticosterone was seen in FIS rats, but microglial activation was more pronounced in LEW rats. Our results suggest a biphasic role of the HPA axis in pain behavior and spinal cell activation associated with ongoing inflammation. In the acute stage, the stronger reaction in FIS rats might be explained by an activating effect of corticosteroids on neutrophil function. Under ongoing inflammatory conditions the immunosuppressive actions of corticosteroids may dominate and lead to a quicker recovery of paw volume and pain sensitivity in FIS rats.

Hypothalamic–pituitary–adrenal axis reactivity to social stress and adolescent cannabis use: the TRAILS study

To investigate the relationship of life-time and repeated cannabis use with hypothalamic-pituitary-adrenal (HPA) axis reactivity to social stress in a general population sample of adolescents. Adolescents who reported life-time or repeated cannabis use, life-time or repeated tobacco use and never use of either cannabis or tobacco were compared with respect to their HPA axis reactivity during the Groningen Social Stress Task (GSST), which was based on the Trier Social Stress Task. A large prospective population study of Dutch adolescents [the TRacking Adolescents' Individual Lives Survey (TRAILS) study]. A total of 591 adolescents (51% male) who participated in the GSST, which was an additional measurement during the third assessment wave. HPA axis stress-reactivity was indexed by four cortisol samples collected before, during and after the GSST. Furthermore, all adolescents in our study completed self-reported questionnaires on life-time and repeated cannabis and tobacco use. Models were adjusted for sex, recent alcohol use, experimental session risk status, socio-economic status, mood and time of the experimental session. Life-time cannabis users had significantly lower stress-reactivity levels when compared to abstainers [odds ratio (OR) = 0.68, confidence interval (CI) = 0.55-0.85, P < 0.01] and life-time tobacco users (OR = 0.79, CI = 0.64-0.98, P < 0.05). In addition, repeated cannabis users also exhibited lower stress-reactivity levels when compared to life-time ever users of either tobacco or cannabis (OR = 0.74, CI = 0.53-0.98, P < 0.05). Lower hypothalamic-pituitary-adrenal-axis stress-reactivity in adolescents is related specifically to life-time and repeated cannabis use.

Blunted Affect is Associated With Hypothalamic—Pituitary—Adrenal Axis (HPA) Hypoactivity and Elevated CSF-Interleukin-1 Beta (IL-1β) in Response to Lumbar Puncture

Proinflammatory activity has been suggested as one of the psychophysiological mechanisms responsible for the health risks associated with stress and mood disorders. There have been limited studies evaluating central immune and hypothalamic- pituitary-adrenal (HPA) axis responses to experimental stress in healthy women. The current study compared, under a controlled condition, the baseline measures and biological and psychological responses to a physical stressor (lumbar puncture [LP]) of healthy women who exhibited an abnormal serum cortisol response (nonresponders [NRs]) to the LP to those of normal controls (responders [Rs]), allowing assessment of stress responsivity and the functional integrity of the feedback system of the HPA axis, sympathetic nervous system (SNS), and neuroimmune axis. Serum adrenocorticotropic hormone (ACTH), cortisol, interleukin (IL)-6, IL-1sR, and central IL-1β, IL-6, norepineprhine (NE), corticotropin-releasing factor (CRF), and affective states (using the Stress Symptom Rating Questionnaire) were measured in five NRs and seven Rs. Compared with NR subjects, Rs had significantly higher levels of ACTH and central IL-1β, higher ratings of attention, and lower perceived stress and anxiety. There were no differences between the groups in serum cortisol, IL-6, or IL-1sR or in central IL-6, NE, and CRF. Women with significantly elevated IL-1β (NRs) responded to an extreme physical stressor with an attenuated HPA system and abnormal subjective ratings compared to healthy women with lower values of central IL-1β. These findings support the suppression of the effects of HPA-axis cortisol on proinflammatory cytokine production. It is possible that these differences in the psychoneuroimmunological profiles of NRs will lead to increased psychobiological vulnerability and predict future health risk.