Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Plasticity of the GABAA receptor subunit cassette in response to stressors in reactive versus resilient mice

GABAA functioning has been implicated in anxiety and depressive disorders. In this regard, we suggested that in addition to analyzing GABAA and the subunits that comprise the GABAA receptor, it might be profitable to assess the coordinated expression of subunits that comprise the GABAA receptor cassette. We demonstrate that certain subunits within stress-sensitive brain regions were higher in stressor reactive BALB/cByJ than in hardy C57BL/6ByJ mice, and that a chronic, intermittent, variable stressor (6 days/week over 7 weeks) differentially influenced subunit expression in these strains. Further, mRNA expression of GABAA subunits were highly coordinated (inter-correlated), and markedly altered by stressors, once again varying with brain region. At the central amygdala of BALB/cByJ mice the ordinarily high subunit inter-relations were reduced in acutely stressed mice, and this outcome was exacerbated with a chronic stressor. In C57BL/6ByJ mice subunit inter-relations were lower than in BALB/cByJ mice; the acute stressor increased subunit organization, which returned to control levels with following a chronic stressor. The profile of amygdala subunit inter-relations was recapitulated in a step-down behavioral test; anxiety was increased by acute and chronic stressors in BALB/cByJ mice, but in the C57BL/6ByJ strain the elevated anxiety associated with an acute s

Effects of stressors and immune activating agents on peripheral and central cytokines in mouse strains that differ in stressor responsivity

The impact of inflammatory immune activation on behavioral and physiological processes varies with antecedent stressor experiences. We assessed whether immune activation would differentially influence such outcomes as a function of stressor reactivity related to genetic differences. To this end, we assessed the influence of a social stressor (exposure to a dominant mouse) in combination with an acute immune challenge on behavior and on peripheral and central cytokines in stressor-reactive BALB/cByJ mice and the less reactive C57BL/6ByJ strain. As C57BL/6ByJ and BALB/cByJ mice are highly T helper type-1 (Th1) and Th2 responsive, respectively, the stressor effects were assessed in response to different challenges, namely the viral analogue poly I:C and the bacterial endotoxin lipopolysaccharide (LPS). The stressor enhanced the effects of LPS on sickness behaviors and plasma corticosterone particularly in BALB/cByJ mice, whereas the effects of poly I:C, which primarily affects Th1 processes, were not augmented by the stressor. As well, the stressor increased circulating cytokines in LPS treated C57BL/6ByJ mice, whereas the effects of poly I:C were diminished. Finally, like circulating cytokines, mRNA expression of pro-inflammatory cytokines within the prefrontal cortex and hippocampus varied with the mouse strain and with the stressor experience, and with the specific cytokine considered. Together, the experiments indicated that the impact of stressors vary with the nature of the immune challenge to which animals had been exposed. Moreover, given the diversity of the stressor effects on central and peripheral processes, it seems likely that the cytokine changes, HPA activity and sickness operate through independent mechan

Synergistic and additive actions of a psychosocial stressor and endotoxin challenge: Circulating and brain cytokines, plasma corticosterone and behavioral changes in mice

Activation of the inflammatory immune response may provoke neuroendocrine and central neurochemical effects that are reminiscent of those elicited by traditional stressors, and when administered concurrently may have synergistic effects. The present investigation assessed whether a psychosocial stressor, comprising social disruption, would augment the effects of lipopolysaccharide in mice. It was indeed observed that the social disruption engendered by a period of 2-4 weeks of social isolation (but not 1-7 days of this treatment) followed by regrouping, enhanced the effects of lipopolysaccharide (LPS: 10 μg) in the provocation of sickness behavior, as well as plasma corticosterone, IL-6, TNF-α and IL-10 levels. Similar effects were not apparent with respect to IL-1β, IL-4, or IFN-γ. Synergy between LPS and other stressors (restraint, tail pinch, and loud noise) was not apparent with respect to sickness or plasma corticosterone, provisionally suggesting that social stressors, such as regrouping, may be more powerful or may engage unique neural or neuroendocrine circuits that favour synergistic outcomes. Within the CNS, the LPS and the regrouping stressor synergistically enhanced NE utilization withi

Cytotoxicity and cytoprotective activity of naphthalenediols in rat cortical neurons

Some members of the naphthalenediol family have been shown in previous work on PC-12 cells to act as effective antioxidants while being relatively nontoxic. In the present work, we extend that study to examine the effect of naphthalenediols on rat primary cortical neurons exposed to AAPH (2,2′-azobis (2-amidinopropane) hydrochloride), a source of peroxyl radicals. Compounds tested included the acetylated forms of 1,2-naphthalenediol, that is, 1,2-ND, as well as 1,4-ND, 2,3-ND, 1,8-ND, and the known highly potent antioxidant (-)-epigallocatechin gallate (EGCG). In cytoxicity studies, cells were exposed to the compounds for 24 h, leading to observed toxicity in the order of 1,4-ND > 1,2 ND ≫ 2,3-ND ≈ EGCG > 1,8-ND. In cytoprotection studies, the desired compounds were incubated with neurons prior to AAPH exposure, and live cell counts were determined by trypan blue and/or MTT assays. Excellent protection, superior to EGCG, was provided by 2,3-ND and 1,8-ND. Additional studies using glutamate as a stressor showed that 1,8-ND had a significant protective effect at concentrations as low as 500 nM. The results can be understood on the basis of the tendency (or lack thereof) to form the corresponding quinone, which in turn depends on whether or not there is a loss of aromaticity in the ring adjacent to the quinone moiety. Thus, certain members of the family of naphthalenediols are quite cytotoxic, whereas others show promise as neuroprotective antioxidants

CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling

5-HT2 and corticotrophin releasing factor (CRF) receptors both regulate stress responses and anxiety behavior; however, potential cross-talk between the two pathways is poorly understood. Magalhaes et al. find that CRF receptor activation causes cell-surface recruitment of constitutively internalized 5-HT2 receptor and that this mechanism is relevant to anxiety-related behaviors