Implication of NOTCH1 gene in susceptibility to anxiety and depression among sexual abuse victims.

Sexual abuse contributes to the development of multiple forms of psychopathology, including anxiety and depression, but the extent to which genetics contributes to these disorders among sexual abuse victims remains unclear. In this translational study, we first examined gene expression in the brains of rodents exposed to different early-life conditions (long, brief or no maternal separation). Hypothesizing that genes revealing changes in expression may have relevance for psychiatric symptoms later in life, we examined possible association of those genes with symptoms of anxiety and depression in a human sample of sexual abuse victims. Changes in rodent brain gene expression were evaluated by means of correspondence and significance analyses of microarrays by comparing brains of rodents exposed to different early-life conditions. Tag single-nucleotide polymorphisms (SNPs) of resulting candidate genes were genotyped and tested for their association with symptoms of anxiety and depression (Hospital Anxiety and Depression Scale) in a sample of 361 sexual abuse victims, using multinomial logistic regression. False discovery rate was applied to account for multiple testing in the genetic association study, with q-value of 0.05 accepted as significant. We identified four genes showing differential expression among animals subjected to different early-life conditions as well as having potential relevance to neural development or disorders: Notch1, Gabrr1, Plk5 and Zfp644. In the human sample, significant associations were observed for two NOTCH1 tag SNPs: rs11145770 (OR=2.21, q=0.043) and rs3013302 (OR=2.15, q=0.043). Our overall findings provide preliminary evidence that NOTCH1 may be implicated in the susceptibility to anxiety and depression among sexual abuse victims. The study also underscores the potential importance of animal models for future studies on the health consequences of early-life stress and the mechanisms underlying increased risk for psychiatric disorders.

Neonatal maternal separation in male rats increases intestinal permeability and affects behavior after chronic social stress.

Prolonged maternal separation in rats has several effects on health and behavior. Here we investigated how maternal separation might interact with social stress in adulthood on behavior and gastrointenstinal permeability. The effects of either daily 180 min long term pup-dam separation (LMS) during the stress hyporesponsive period or daily 10 min brief maternal separation (BMS) on behavior, corticosterone and intestinal permeability were investigated, compared to a non-handling (NH) condition in male offspring. The animals from each separation condition were then randomly assigned to adult stress and control conditions, where the stress condition was exposure to 14 days of social instability (CSI). Sucrose preference, elevated plus maze behavior and corticosterone were measured. Colitis was experimentally induced by dextran sulfate sodium for 7 days, followed by measurement of intestinal permeability using the (51)CrEDTA method. Granulocyte marker protein was measured in feces and colons were examined histologically for inflammation. Prior to the social stress, the LMS offspring showed elevated corticosterone levels, lower elevated plus maze activity and less fluid consumption. After social stress, corticosterone levels were suppressed in LMS animals and again they showed less fluid consumption. LMS animals had significantly higher intestinal permeability, but only when also exposed to the social stress in adulthood. The current results support a two-hit model, whereby early life events interact with adult life events in altering animals' vulnerability.

Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion.

Short non-lethal ischemic episodes administered to hearts prior to (ischemic preconditioning, IPC) or directly after (ischemic postconditioning, IPost) ischemic events facilitate myocardial protection. Transferring coronary effluent collected during IPC treatment to un-preconditioned recipient hearts protects from lethal ischemic insults. We propose that coronary IPC effluent contains hydrophobic cytoprotective mediators acting via PI3K/Akt-dependent pro-survival signaling at ischemic reperfusion. Ex vivo rat hearts were subjected to 30 min of regional ischemia and 120 min of reperfusion. IPC effluent administered for 10 min prior to index ischemia attenuated infarct size by ≥55% versus control hearts (P < 0.05). Effluent administration for 10 min at immediate reperfusion (reperfusion therapy) or as a mimetic of pharmacological postconditioning (remote postconditioning, RIPost) significantly reduced infarct size compared to control (P < 0.05). The IPC effluent significantly increased Akt phosphorylation in un-preconditioned hearts when administered before ischemia or at reperfusion, while pharmacological inhibition of PI3K/Akt-signaling at reperfusion completely abrogated the cardioprotection offered by effluent administration. Fractionation of coronary IPC effluent revealed that cytoprotective humoral mediator(s) released during the conditioning phase were of hydrophobic nature as all hydrophobic fractions with molecules under 30 kDa significantly reduced infarct size versus the control and hydrophilic fraction-treated hearts (P < 0.05). The total hydrophobic effluent fraction significantly reduced infarct size independently of temporal administration (before ischemia, at reperfusion or as remote postconditioning). In conclusion, the IPC effluent retains strong cardioprotective properties, containing hydrophobic mediator(s) < 30 kDa offering cytoprotection via PI3K/Akt-dependent signaling at ischemic reperfusion.