Trans-generational stress regulation: Mother-infant cortisol and maternal mental health across the perinatal period

Understanding maternal mental health and cortisol regulation across pregnancy and the relationship to the development of the offspring’s stress regulation is critical to a range of health outcomes. The aim of this study was to investigate infant and maternal cortisol in women with depression. Data were obtained from 241 pregnant women within the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS), a selected pregnancy cohort study. Depression was measured using the Structured Clinical Interview for DSM-IV (SCID-IV) and repeat Edinburgh Postnatal Depression Scale (EPDS). Repeated measures of antidepressant use, stressful events, anxiety symptoms and maternal hair cortisol concentrations (HCC) and infant cortisol at 12 months postpartum in saliva and hair. Socio-emotional outcomes were measured at 12 months by maternal report on the Brief Infant and Toddler Socio-emotional Assessment (BITSEA). This study found that maternal depression was not associated with maternal HCC. Anxiety, stress and antidepressant use were not associated with maternal HCC. Independently, higher maternal 3rd trimester maternal depressive and anxiety symptoms were associated with lower infant cortisol response at 12 months of age. A higher number of postpartum stressful events was associated with lower infant cortisol response. Lower infant stress reactivity was associated with higher externalizing symptoms at 12 months of age. Future studies are required to understand implications for later mental health

Brain mineralocorticoid receptor function in control of salt balance and stress-adaptation

We will highlight in honor of Randall Sakai the peculiar characteristics of the brain mineralocorticoid receptor (MR) in its response pattern to the classical mineralocorticoid aldosterone and the naturally occurring glucocorticoids corticosterone and cortisol. Neurons in the nucleus tractus solitarii (NTS) and circumventricular organs express MR, which mediate selectively the action of aldosterone on salt appetite, sympathetic outflow and volume regulation. The MR-containing NTS neurons innervate limbic-forebrain circuits enabling aldosterone to also modulate reciprocally arousal, motivation, fear and reward. MR expressed in abundance in this limbic-forebrain circuitry, is target of cortisol and corticosterone in modulation of appraisal processes, memory performance and selection of coping strategy. Complementary to this role of limbic MR is the action mediated by the lower affinity glucocorticoid receptors (GR), which promote subsequently memory storage of the experience and facilitate behavioral adaptation. Current evidence supports the hypothesis that an imbalance between MR-and GR-mediated actions compromises resilience and adaptation to stress

Mineralocorticoid Receptors, Neuroinflammation and Hypertensive Encephalopathy

Worldwide, raised blood pressure is estimated to affect 35–40% of the adult population and is a main conditioning factor for cardiovascular diseases and stroke. Animal models of hypertension have provided great advances concerning the pathophysiology of human hypertension, as already shown for the deoxycorticosterone-salt treated rat, the Dahl-salt sensitive rat, the Zucker obese rat and the spontaneously hypertensive rat (SHR). SHR has been widely used to study abnormalities of the brain in chronic hypertension. This review summarises present and past evidence that in the SHR, hypertension causes hippocampal tissue damage which triggers a pro-inflammatory feedforward cascade affecting this vulnerable brain region. The cascade is driven by mineralocorticoid receptor (MR) activation responding to endogenous corticosterone rather than aldosterone. Increased MR expression is a generalised feature of the SHR which seems to support first the rise in blood pressure. Then oxidative stress caused by vasculopathy and hypoxia further increases MR activation in hippocampal neurons and glia cells, activates microglia activation and pro-inflammatory mediators, and down-regulates anti-inflammatory factors. In contrast to MR, involvement of the glucocorticoid receptor (GR) in SHR is less certain. GR showed normal expression levels and blockage with an antagonist failed to reduce blood pressure of SHR. The findings support the concept that MR:GR imbalance caused by vasculopathy causes a switch in MR function towards a proverbial “death” receptor.Fil: Brocca, María Elvira. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Consejo Superior de Investigaciones Cientificas. Centro de Ciencias Humanas y Sociales. Instituto de Historia.; EspañaFil: Pietranera, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; ArgentinaFil: De Kloet, Edo Ronald. Leiden University. Leiden University Medical Center.; Países BajosFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; Argentin

The perinatal origins of childhood anxiety disorders and the role of early-life maternal predictors

Abstract Background The development of childhood anxiety disorders (CADs) is likely to depend on pathways that can be programmed by early-life risk factors. We test the hypothesis that early-life maternal factors can predict this programming effect on CAD. Methods Data were obtained from 198 women and children from the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS), a cohort study with data collected across pregnancy, postpartum and until 4 years of age. Maternal antenatal depression was measured using the Structured Clinical Interview for DSM-IV (SCID-IV), together with antenatal hair cortisol concentrations, maternal childhood trauma and parenting stress at 6 months postpartum. CAD was assessed with the Preschool Age Psychiatric Assessment and the Child Behaviour Checklist. Results Antenatal depression, a history of maternal childhood trauma and lower gestational age at birth were each associated with anxiety disorders at 4 years of age in their children. A multivariate binary logistic model with these early predictors explained approximately 9% of variance in CAD outcome at 4 years of age; however, only maternal trauma and gestational age were significant predictors in the model. The effect of early parenting stress on CAD was found to vary by the concentration of maternal antenatal hair cortisol, whereby postpartum parenting stress was associated with CAD only when there were higher maternal antenatal cortisol levels. Conclusions This study suggests the importance of maternal factors pre-conception, pregnancy and in the postnatal period, which predict CADs and this is consistent with a developmental programming hypothesis for CAD

Mineralocorticoid receptor associates with pro-inflammatory bias in the hippocampus of spontaneously hypertensive rats

Damage observed in the hippocampus of the adult spontaneously hypertensive rat (SHR) resembles the neuropathology of mineralocorticoid-induced hypertension, supporting a similar endocrine dysfunction in both entities. In the present study, we tested the hypothesis that increased expression of the hippocampal mineralocorticoid receptor (MR) in SHR animals is associated with a prevalent expression of pro-inflammatory over anti-inflammatory factors. Accordingly, in the hippocampus, we measured mRNA expression and immunoreactivity of the MR and glucocorticoid receptor (GR) using a quantitative polymerase chain reaction and histochemistry. We also measured serum-glucocorticoid-activated kinase 1 (Sgk1 mRNA), the number and phenotype of Iba1+ microglia, as well as mRNA expression levels of the pro-inflammatory factors cyclo-oxygenase 2 (Cox2), Nlrp3 inflammasome and tumour necrosis factor α (Tnfα). Expression of anti-inflammatory transforming growth factor (Tgf)β mRNA and the NADPH-diaphorase activity of nitric oxide synthase (NOS) were also determined. The results showed that, in the hippocampus of SHR rats, expression of MR and the number of immunoreactive MR/GR co-expressing cells were increased compared to Wistar-Kyoto control animals. Expression of Sgk1, Cox2, Nlrp3 and the number of ramified glia cells positive for Iba1+ were also increased, whereas Tgfβ mRNA expression and the NADPH-diaphorase activity of NOS were decreased. We propose that, in the SHR hippocampus, increased MR expression causes a bias towards a pro-inflammatory phenotype characteristic for hypertensive encephalopathy.Fil: Brocca, María Elvira. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Pietranera, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lima, Analia Ethel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Roig, Paulina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: De Kloet, Edo Ronald. Leiden University; Países BajosFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentin

Zebrafish development and regeneration: new tools for biomedical research

Basic research in pattern formation is concerned with the generation of phenotypes and tissues. It can therefore lead to new tools for medical research. These include phenotypic screening assays, applications in tissue engineering, as well as general advances in biomedical knowledge. Our aim here is to discuss this emerging field with special reference to tools based on zebrafish developmental biology. We describe phenotypic screening assays being developed in our own and other labs. Our assays involve: (i) systemic or local administration of a test compound or drug to zebrafish in vivo, (ii) the subsequent detection or "readout" of a defined phenotypic change. A positive readout may result from binding of the test compound to a molecular target involved in a developmental pathway. We present preliminary data on assays for compounds that modulate skeletal patterning, bone turnover, immune responses, inflammation and early-life stress. The assays use live zebrafish embryos and larvae as well as adult fish undergoing caudal fin regeneration. We describe proof-of-concept studies on the localised targeting of compounds into regeneration blastemas using microcarriers. Zebrafish are cheaper to maintain than rodents, produce large numbers of transparent eggs, and some zebrafish assays could be scaled-up into medium and high throughput screens. However, advances in automation and imaging are required. Zebrafish cannot replace mammalian models in the drug development pipeline. Nevertheless, they can provide a cost-effective bridge between cell-based assays and mammalian whole-organism model