Christiane Waller

Oxytocin modulates neural reactivity to children's faces as a function of social salience.

Oxytocin (OT) enhances social behaviors such as attachment and parental caretaking. Neural correlates of maternal attachment are found in reward-related brain regions, for example, in the globus pallidus (GP). The present work investigates the effects of OT on the neural correlates of parental attachment. Fathers viewed pictures of their own child (oC), a familiar child (fC), and an unfamiliar child (uC) after intranasal application of OT vs placebo. OT reduced activation and functional connectivity of the left GP with reward- and attachment-related regions responsive to pictures of the oC and the uC. The present results emphasize the key role of OT in human parental attachment and suggest that OT reduces neural reactivity to social cues as a function of social salience. Our results together with previous findings speak to a selective reduction of neural reactivity to social stimuli, irrespective of their valence. We argue that one major pathway by which OT exerts its positive effects on affiliative and social behaviors is the attenuation of automatic neural responses, which in turn leads to increased approach behaviors and decreased social avoidance.

Inflammation in adult women with a history of child maltreatment: The involvement of mitochondrial alterations and oxidative stress.

The experience of maltreatment during childhood is associated with chronic low-grade inflammation in adulthood. However, the molecular mechanisms underlying this pro-inflammatory phenotype remain unclear. Mitochondria were recently found to principally coordinate inflammatory processes via both inflammasome activation and inflammasome-independent pathways. To this end, we hypothesized that alterations in immune cell mitochondrial functioning and oxidative stress might be at the interface between the association of maltreatment experiences during childhood and inflammation. We analyzed pro-inflammatory biomarkers (levels of C-reactive protein, cytokine secretion by peripheral blood mononuclear cells (PBMC) in vitro, PBMC composition, lysophosphatidylcholine levels), serum oxidative stress levels (arginine:citrulline ratio, l-carnitine and acetylcarnitine levels) and mitochondrial functioning (respiratory activity and density of mitochondria in PBMC) in peripheral blood samples collected from 30 women (aged 22-44years) with varying degrees of maltreatment experiences in form of abuse and neglect during childhood. Exposure to maltreatment during childhood was associated with an increased ROS production, higher levels of oxidative stress and an increased mitochondrial activity in a dose-response relationship. Moreover, the increase in mitochondrial activity and ROS production were positively associated with the release of pro-inflammatory cytokines by PBMC. Decreased serum levels of lysophosphatidylcholines suggested higher inflammasome activation with increasing severity of child maltreatment experiences. Together these findings offer preliminary evidence for the association of alterations in immune cell mitochondrial functioning, oxidative stress and the pro-inflammatory phenotype observed in individuals with a history of maltreatment during childhood. The results emphasize that the early prevention of child abuse and neglect warrants more attention, as the experience of maltreatment during childhood might have life-long consequences for physical health.

A Collagen α2(I) Mutation Impairs Healing after Experimental Myocardial Infarction

Collagen breakdown and de novo synthesis are important processes during early wound healing after myocardial infarction (MI). We tested the hypothesis that collagen I, the main constituent of the extracellular matrix, affects wound healing after MI. The osteogenesis imperfecta mouse (OIM), lacking procollagen-α2(I) expression, represents a model of the type III form of the disease in humans. Homozygous (OIM/OIM), heterozygous (OIM/WT), and wild-type (WT/WT) mice were subjected to a permanent myocardial infarction protocol or sham surgery. Baseline functional and geometrical parameters determined by echocardiography did not differ between genotypes. After MI but not after sham surgery, OIM/OIM animals exhibited significantly increased mortality, due to early ventricular rupture between day 3 and 7. Echocardiography at day 1 demonstrated increased left ventricular dilation in OIM/OIM animals. Less collagen I mRNA within the infarct area was found in OIM/OIM animals. At 2 days after MI, MMP-9 expression in the infarct border zone was higher in OIM/OIM than in WT/WT animals. Increased granulocyte infiltration into the infarct border zone occurred in OIM/OIM animals. Neither granulocyte depletion nor MMP inhibition reduced mortality in OIM/OIM animals. In this murine model, deficiency of collagen I leads to a myocardial wound-healing defect. Both structural alterations within pre-existing collagen matrix and impaired collagen de novo expression contribute to a high rate of early myocardial rupture after MI.

Attachment representation modulates oxytocin effects on the processing of own-child faces in fathers

Oxytocin (OT) plays a crucial role in parental-infant bonding and attachment. Recent functional imaging studies reveal specific attachment and reward related brain regions in individuals or within the parent-child dyad. However, the time course and functional stage of modulatory effects of OT on attachment-related processing, especially in fathers, are poorly understood. To elucidate the functional and neural mechanisms underlying the role of OT in paternal-child attachment, we performed an event-related potential study in 24 healthy fathers who received intranasal OT in a double-blind, placebo-controlled, within-subject experimental design. Participants passively viewed pictures of their own child (oC), a familiar (fC) and an unfamiliar child (ufC) while event-related potentials were recorded. Familiarity of the childs face modulated a broad negativity at occipital and temporo-parietal electrodes within a time window of 300-400ms, presumably reflecting a modulation of the N250 and N300 ERP components. The oC condition elicited a more negative potential compared to the other familiarity conditions suggesting different activation of perceptual memory representations and assignment of emotional valence. Most importantly, this familiarity effect was only observed under placebo (PL) and was abolished under OT, in particular at left temporo-parietal electrodes. This OT induced attenuation of ERP responses was related to habitual attachment representations in fathers. In summary, our results demonstrate an OT-specific effect at later stages of attachment-related face processing presumably reflecting both activation of perceptual memory representations and assignment of emotional value.

Effects of the Adult Attachment Projective Picture System on Oxytocin and Cortisol Blood Levels in Mothers

Oxytocin, a small neuropeptide of nine amino acids, has been characterized as the “hormone of affiliation” and is stimulated, for instance, in mothers when interacting with their offspring. Variations in maternal oxytocin levels were reported to predict differences in the quality of care provided by mothers. In this study, the Adult Attachment Projective Picture System (AAP) as a valid measure to assess attachment representations was used as an activating attachment-related stimulus. We investigated whether the AAP induces a release of oxytocin in mothers with a secure attachment representation and a stress-related cortisol response in mothers with an insecure attachment representation. Therefore, pre-post effects of AAP administration on plasma oxytocin and serum cortisol levels were investigated in n = 44 mothers 3 months after parturition. Oxytocin levels increased from pre to post in the significant majority of 73% participants (p = 0.004) and cortisol decreased in the significant majority of 73% participants (p = 0.004). Interestingly, no association between alterations in oxytocin and cortisol were found; this suggests taking a model of two independent processes into considerations. These results show that the AAP test procedure induces an oxytocin response. Concerning the results within the four AAP representation subgroups, our hypothesis of a particularly strong increase in oxytocin in secure mothers was not confirmed; however, in secure mothers we observed a particularly strong decrease in cortisol. Effect sizes are reported, allowing the replication of results in a larger study with sufficient sample size to draw final conclusions with respect to differences in OT and cortisol alterations depending on attachment representation. When interpreting the results, one should keep in mind that this study investigated lactating mothers. Thus, the generalizability of results is limited and future studies should investigate non-lactating healthy females as well as males and include a control stimulus condition.

Child Maltreatment Is Associated with a Reduction of the Oxytocin Receptor in Peripheral Blood Mononuclear Cells

Background: Child maltreatment (CM) and attachment experiences are closely linked to alterations in the human oxytocin (OXT) system. However, human data about oxytocin receptor (OXTR) protein levels are lacking. Therefore, we investigated oxytocin receptor (OXTR) protein levels in circulating immune cells and related them to circulating levels of OXT in peripheral blood. We hypothesized reduced OXTR protein levels, associated with both, experiences of CM and an insecure attachment representation. Methods: OXTR protein expressions were analyzed by western blot analyses in peripheral blood mononuclear cells (PBMC) and plasma OXT levels were determined by radioimmunoassay (RIA) in 49 mothers. We used the Childhood Trauma Questionnaire (CTQ) to assess adverse childhood experiences. Attachment representations (secure vs. insecure) were classified using the Adult Attachment Projective Picture System (AAP) and levels of anxiety and depression were assessed with the German version of the Hospital Depression and Anxiety scale (HADS-D). Results: CM-affected women showed significantly lower OXTR protein expression with significantly negative correlations between the OXTR protein expression and the CTQ sum score, whereas plasma OXT levels showed no significant differences in association with CM. Lower OXTR protein expression in PBMC were particularly pronounced in the group of insecurely attached mothers compared to the securely attached group. Anxiety levels were significantly higher in CM-affected women. Conclusion: This study demonstrated a significant association between CM and an alteration of OXTR protein expression in human blood cells as a sign for chronic, long-lasting alterations in this attachment-related neurobiological system.

Less immune activation following social stress in rural vs. urban participants raised with regular or no animal contact, respectively

Significance Our results show that a standardized laboratory psychosocial stressor causes a greater inflammatory response in young healthy participants with an urban upbringing in the absence of pets, relative to young healthy participants with a rural upbringing in the presence of farm animals. In view of the known links between persistent inflammatory states and psychiatric disturbances, and considering that many stress-associated physical and mental disorders are more prevalent in environments offering a narrow range of microbial exposures, we feel that our findings are of general interest and significance. Moreover, we feel our study is timely, as urbanization and the associated socioeconomic consequences are increasing. Urbanization is on the rise, and environments offering a narrow range of microbial exposures are linked to an increased prevalence of both physical and mental disorders. Human and animal studies suggest that an overreactive immune system not only accompanies stress-associated disorders but might even be causally involved in their pathogenesis. Here, we show in young [mean age, years (SD): rural, 25.1 (0.78); urban, 24.5 (0.88)] healthy human volunteers that urban upbringing in the absence of pets (n = 20), relative to rural upbringing in the presence of farm animals (n = 20), was associated with a more pronounced increase in the number of peripheral blood mononuclear cells (PBMCs) and plasma interleukin 6 (IL-6) concentrations following acute psychosocial stress induced by the Trier social stress test (TSST). Moreover, ex vivo-cultured PBMCs from urban participants raised in the absence of animals secreted more IL-6 in response to the T cell-specific mitogen Con A. In turn, antiinflammatory IL-10 secretion was suppressed following TSST in urban participants raised in the absence of animals, suggesting immunoregulatory deficits, relative to rural participants raised in the presence of animals. Questionnaires, plasma cortisol, and salivary α-amylase, however, indicated the experimental protocol was more stressful and anxiogenic for rural participants raised in the presence of animals. Together, our findings support the hypothesis that urban vs. rural upbringing in the absence or presence of animals, respectively, increases vulnerability to stress-associated physical and mental disorders by compromising adequate resolution of systemic immune activation following social stress and, in turn, aggravating stress-associated systemic immune activation.

High prevalence of posttraumatic stress in patients with primary hypertension

OBJECTIVE Posttraumatic stress disorder (PTSD) is associated with a higher rate of arterial hypertension. However, data about prevalence rates of PTSD in patients suffering from arterial hypertension as well as the relation to blood pressure (BP) control are lacking. METHODS We recruited 145 patients with primary hypertension from March to November 2012 at the cardiologic outpatient clinic at Ulm University Medical Center. Symptoms of PTSD (assessed with the Posttraumatic Diagnostic Scale), perceived stress (Perceived Stress Scale; Trier Inventory for Chronic Stress), depression and anxiety (Hospital Anxiety and Depression Scale) were assessed by self-report. Office BP was measured and medical data were collected. RESULTS Criteria for a full PTSD syndrome were met by 13 patients (9%). Posttraumatic stress was higher in the group of patients with controlled (M=10.9, S.D.=9.8) than in those with uncontrolled hypertension (M=3.9, S.D.=5.4; P<.001). In linear regression, only status of hypertension control (beta=.39, P<.001) predicted posttraumatic stress significantly, even after controlling for important cofactors. CONCLUSIONS PTSD is highly prevalent in hypertensive patients, especially in those with controlled hypertension. An explaining mechanism could be the higher use of health care by patients suffering from PTSD. The mental needs of these patients should be focused in addition to the well-established somatic care.

The association between cortisol, oxytocin, and immune cell mitochondrial oxygen consumption in postpartum women with childhood maltreatment

Childhood maltreatment (CM) is associated with an increased risk for the development of psychiatric and somatic diseases in later life. Individual risk and resilience factors may, however, influence how deep psychological stress gets under the skin. We hypothesized that the stress-related hormone cortisol and the attachment-related hormone oxytocin constitute biological factors that might moderate the biological sequelae and long-term health outcomes associated with CM. As biological outcome, we thereby focused on immunocellular oxygen consumption, which we previously found to be increased with a higher severity of CM experiences. In a study cohort of N = 49 postpartum women, we investigated the interaction between CM experiences, serum cortisol and plasma oxytocin levels, and the cellular oxygen consumption of intact peripheral blood mononuclear cells (PBMC) by high-resolution respirometry. Regression analyses revealed a significant interaction between the severity of CM experiences and cortisol as well as oxytocin on cellular oxygen consumption of PBMC three months postpartum: higher cortisol levels were thereby associated with an increase in oxygen consumption related to basal mitochondrial respiration and ATP turnover, while oxygen consumption related to basal mitochondrial respiration and ATP turnover were reduced with higher oxytocin levels in individuals with higher CM severity. These associations were not seen among women with no or low CM experiences. Together, the results suggest that cortisol and oxytocin might be associated with opposite effects on CM-related alterations in the bioenergetic profile of peripheral immune cells.

Interaction of the hydrogen sulfide system with the oxytocin system in the injured mouse heart

BackgroundBoth the hydrogen sulfide/cystathionine-γ-lyase (H2S/CSE) and oxytocin/oxytocin receptor (OT/OTR) systems have been reported to be cardioprotective. H2S can stimulate OT release, thereby affecting blood volume and pressure regulation. Systemic hyper-inflammation after blunt chest trauma is enhanced in cigarette smoke (CS)-exposed CSE−/− mice compared to wildtype (WT). CS increases myometrial OTR expression, but to this point, no data are available on the effects CS exposure on the cardiac OT/OTR system. Since a contusion of the thorax (Txt) can cause myocardial injury, the aim of this post hoc study was to investigate the effects of CSE−/− and exogenous administration of GYY4137 (a slow release H2S releasing compound) on OTR expression in the heart, after acute on chronic disease, of CS exposed mice undergoing Txt.MethodsThis study is a post hoc analysis of material obtained in wild type (WT) homozygous CSE−/− mice after 2-3 weeks of CS exposure and subsequent anesthesia, blast wave-induced TxT, and surgical instrumentation for mechanical ventilation (MV) and hemodynamic monitoring. CSE−/− animals received a 50 μg/g GYY4137-bolus after TxT. After 4h of MV, animals were exsanguinated and organs were harvested. The heart was cut transversally, formalin-fixed, and paraffin-embedded. Immunohistochemistry for OTR, arginine-vasopressin-receptor (AVPR), and vascular endothelial growth factor (VEGF) was performed with naïve animals as native controls.ResultsCSE−/− was associated with hypertension and lower blood glucose levels, partially and significantly restored by GYY4137 treatment, respectively. Myocardial OTR expression was reduced upon injury, and this was aggravated in CSE−/−. Exogenous H2S administration restored myocardial protein expression to WT levels.ConclusionsThis study suggests that cardiac CSE regulates cardiac OTR expression, and this effect might play a role in the regulation of cardiovascular function.