Glucocorticoid receptor signaling in leukocytes after early life adversity.

Early life adversity (ELA) has been associated with inflammation and immunosenescence, as well as hyporeactivity of the HPA axis. Because the immune system and the HPA axis are tightly intertwined around the glucocorticoid receptor (GR), we examined peripheral GR functionality in the EpiPath cohort among participants who either had been exposed to ELA (separation from parents and/or institutionalization followed by adoption; n = 40) or had been reared by their biological parents (n = 72).Expression of the strict GR target genes FKBP5 and GILZ as well as total and 1F and 1H GR transcripts were similar between groups. Furthermore, there were no differences in GR sensitivity, examined by the effects of dexamethasone on IL6 production in LPS-stimulated whole blood. Although we did not find differences in methylation at the GR 1F exon or promoter region, we identified a region of the GR 1H promoter (CpG 1-9) that showed lower methylation levels in ELA.Our results suggest that peripheral GR signaling was unperturbed in our cohort and the observed immune phenotype does not appear to be secondary to an altered GR response to the perturbed HPA axis and glucocorticoid (GC) profile, although we are limited in our measures of GR activity and time points.

Blunted endocrine response to a combined physical-cognitive stressor in adults with early life adversity.

The negative health effects of early life adversity (ELA) continue long into adulthood. Changes in the physiological response to psychosocial stressors have been proposed to mediate this effect. However, many previous studies have come to contradicting conclusions as to whether ELA induces a long-term increase or decrease in stress reactivity. Therefore, we tested the association of ELA exposure and adult stress reactivity in a sample of early life adoptees and controls. Two previously validated stressful elements (bilateral feet CPT and the Paced Auditory Serial Addition Task (PASAT)) were combined in an extended Cold Pressor Test (CPT). This test was performed on 22 participants who had experienced severe ELA (separation from biological parents, institutionalization, and adoption in early childhood), and in 22 age-matched control participants. A prior history of ELA was associated with blunted reactivity of the hypothalamic-pituitary-adrenal (HPA) axis (Cohen´s d = 0.680). Cardiovascular reactivity remained unchanged, and affective reactivity (self-report ratings) were increased in participants exposed to ELA compared to the control group (range Cohen´s d: 0.642-0.879). Our results suggest that the activity of the HPA axis reactivity was inhibited in ELA participants. Importantly, cardiovascular stress responsiveness was not affected by ELA. This separation of the HPA axis and cardiovascular stress responses may best be explained by ELA selectively enhancing central feedback-sensitivity to glucocorticoids, but preserving cardiovascular/ autonomic stress reactivity.

T Cell Immunosenescence after Early Life Adversity: Association with Cytomegalovirus Infection.

Early life adversity (ELA) increases the risk for multiple age-related diseases, such as diabetes type 2 and cardiovascular disease. As prevalence is high, ELA poses a major and global public health problem. Immunosenescence, or aging of the immune system, has been proposed to underlie the association between ELA and long-term health consequences. However, it is unclear what drives ELA-associated immunosenescence and which cells are primarily affected. We investigated different biomarkers of immunosenescence in a healthy subset of the EpiPath cohort. Participants were either parent-reared (Ctrl, n = 59) or had experienced separation from their parents in early childhood and were subsequently adopted (ELA, n = 18). No difference was observed in telomere length or in methylation levels of age-related CpGs in whole blood, containing a heterogeneous mixture of immune cells. However, when specifically investigating T cells, we found a higher expression of senescence markers (CD57) in ELA. In addition, senescent T cells (CD57+) in ELA had an increased cytolytic potential compared to senescent cells in controls. With a mediation analysis we demonstrated that cytomegalovirus (CMV) infection, which is an important driving force of immunosenescence, largely accounted for elevated CD57 expression observed in ELA. Leukocyte telomere length may obscure cell-specific immunosenescence; here, we demonstrated that the use of cell surface markers of senescence can be more informative. Our data suggest that ELA may increase the risk of CMV infection in early childhood, thereby mediating the effect of ELA on T cell-specific immunosenescence. Thus, future studies should include CMV as a confounder or selectively investigate CMV seronegative cohorts.

Proinflammatory T Cell Status Associated with Early Life Adversity.

Early life adversity (ELA) has been associated with an increased risk for diseases in which the immune system plays a critical role. The ELA immune phenotype is characterized by inflammation, impaired cellular immunity, and immunosenescence. However, data on cell-specific immune effects are largely absent. Additionally, stress systems and health behaviors are altered in ELA, which may contribute to the generation of the ELA immune phenotype. The present investigation tested cell-specific immune differences in relationship to the ELA immune phenotype, altered stress parameters, and health behaviors in individuals with ELA (n = 42) and those without a history of ELA (control, n = 73). Relative number and activation status (CD25, CD69, HLA-DR, CD11a, CD11b) of monocytes, NK cells, B cells, T cells, and their main subsets were assessed by flow cytometry. ELA was associated with significantly reduced numbers of CD69+CD8+ T cells (p = 0.022), increased numbers of HLA-DR+ CD4 and HLA-DR+ CD8 T cells (p < 0.001), as well as increased numbers of CD25+CD8+ T cells (p = 0.036). ELA also showed a trend toward higher numbers of CCR4+CXCR3-CCR6+ CD4 T cells. Taken together, our data suggest an elevated state of immune activation in ELA, in which particularly T cells are affected. Although several aspects of the ELA immune phenotype were related to increased activation markers, neither stress nor health-risk behaviors explained the observed group differences. Thus, the state of immune activation in ELA does not seem to be secondary to alterations in the stress system or health-risk behaviors, but rather a primary effect of early life programming on immune cells.

Enhanced startle reflexivity during presentation of visual nurture cues in young adults who experienced parental divorce in early childhood.

Adverse childhood experiences (ACE) may influence stress and affective processing in adulthood. Animal and human studies show enhanced startle reflexivity in adult participants with ACE. This study examined the impact of one of the most common ACE, parental divorce, on startle reflexivity in adulthood. Affective modulation of acoustically-elicited startle eye blink was assessed in a group of 23 young adults with self-reported history of parental divorce, compared to an age- and sex-matched control group (n=18). Foreground pictures were either aversive (e.g. mutilation and injury), standard appetitive (e.g. erotic, recreational sport), or nurture pictures (e.g. related to early life, parental care), intermixed with neutral pictures (e.g. household objects), and organized in three valence blocks delivered in a balanced, pseudo-randomized sequence. During picture viewing startle eye blinks were elicited by binaural white noise bursts (50ms, 105 dB) via headphones and recorded at the left orbicularis oculi muscle via EMG. A significant interaction of group×picture valence (p=0.01) was observed. Contrast with controls revealed blunted startle responsiveness of the ACE group during presentation of aversive pictures, but enhanced startle during presentation of nurture-related pictures. No group differences were found during presentation of standard appetitive pictures. ACE participants rated nurture pictures as more arousing (p=0.02) than did control participants. Results suggest that divorce in childhood led to altered affective context information processing in early adulthood. When exposed to unpleasant (vs. neutral) pictures participants with ACE showed less startle potentiation than controls. Nurture context, however, potentiated startle in ACE participants, suggesting visual cuing to activate protective behavioral responses.

The time course of pupil dilation evoked by visual sexual stimuli: Exploring the underlying ANS mechanisms.

The early processing of visual sexual stimuli shows signs of automaticity. Moreover, there is evidence for sex-specific patterns in cognitive and physiological responding to erotica. However, little is known about the time course of rapid pupillary responses to sexual stimuli and their correspondence with other measures of autonomic activity in women and men. To study pupil dilation as an implicit measure of sexual arousal at various stages of picture processing, we presented 35 heterosexual participants with pictures showing either erotic couples or single (male/female) erotic nudes, contrasted with people involved in everyday situations. Brightness-adjusted grayscale pictures were shown for a duration of 2,500 ms within the central visual field, alternating with perceptually matched patches. Left pupil diameter was recorded at 500 Hz using a video-based eye tracker. Skin conductance and heart rate were coregistered and correlated with latent components of pupil dilation (dissociated by temporal PCA). Whereas stimulus-evoked changes in pupil size indicated virtually no initial constriction, a rapid effect of appetence emerged (dilation to erotica within 500 ms). Responses at early stages of processing were remarkably consistent across both sexes. In contrast, later phases of pupil dilation, subjective ratings, and skin conductance responses showed a sex-specific pattern. Moreover, evidence for an association of early-onset pupil dilation and heart rate acceleration was found, suggestive of parasympathetic inhibition, whereas the late component was mainly related to sympathetically mediated skin conductance. Taken together, our results indicate that different temporal components of pupil responses to erotic stimuli may reflect divergent underlying neural mechanisms.