We found that NLH rats showed a robust EGFR activity adaptive miRNA response to inescapable shocks whereas LH rats showed a markedly blunted miRNA response. One set of miRNAs showed large, significant, and consistent alterations in NLH rats, consisting of miR-96, miR-141, miR-182, miR-183, miR-183*, miR-198,

miR-200a, miR-200a*, miR-200b, miR-200b*, miR-200c, and miR-429. All were downregulated in NLH rats relative to tested controls (no shock group), and all showed a blunted response in LH rats (more like tested controls). These miRNAs were encoded at a few shared polycistronic loci, suggesting that their downregulation Inhibitors,research,lifescience,medical was coordinately controlled at the level of transcription. Most of these miRNAs have previously been shown to be enriched in synaptic fractions.65 Moreover, almost all of these miRNAs share 5′-seed motifs Inhibitors,research,lifescience,medical with other members of the same set, suggesting that they will hit similar or overlapping sets of target mRNAs. Interestingly, half of this set are predicted to hit Crebl as a target, and binding sites for CREB lie upstream of

miR-96, miR-182, miR-183, miR-200a, miR200b, miR-200c, miR-220a*, and miR-200b*. This suggests that a similar feedback loop arrangement may also exist for Creb, similar to what has Inhibitors,research,lifescience,medical been described for other Creb-stimulated miRNAs and target genes.114 Since these miRNAs are downregulated in NLH rats, but not LH rats, this can be interpreted as a homeostatic response intended to minimize the repressive effects on Crebl. Inhibitors,research,lifescience,medical In addition, we identified a large core coexpression module, consisting of miRNAs that are strongly correlated with each other across individuals of

the LH group, but not with either the NLH or tested control group. The presence of such a module implies that the normal homeostatic miRNA response to repeated inescapable shock is not merely absent or blunted in LH rats; rather, gene expression networks are actively reorganized in LH rats, which may Inhibitors,research,lifescience,medical support their distinctive persistent phenotype. Another piece of evidence comes from studies of stress-sensitive F344 rats (which show a higher stress response to restraint stress) compared with Sprague-Dawley rats (which show lower hypothalamic-pituitary adrenal axis activity over a period of time). In old this context, it is important to mention that glucocorticoids regulate the hypothalamic-pituitary adrenal axis through a negative feedback mechanism while binding to soluble GRs in the pituitary and the hypothalamus and inhibit the release of corticotropin-releasing factor and adrenocorticotropic hormone. Several studies have reported that the GR expression of is downregulated in depressed individuals.130 The GR protein is under constant miRNA regulation.131 More specifically, miR-124a and miR-18a bind to the 3′ UTR of GR and downregulate its expression.131 Overexpression of miR-18a attenuates the glucocorticoid -induced leucine zipper, a gene induced by stress-like levels of glucocorticoid.