Bruce McEwen's discovery of receptors for corticosterone in the rat hippocampus introduced higher brain circuits in the neuroendocrinology of stress. Subsequently, these receptors were identified as mineralocorticoid receptors (MRs) that are involved in appraisal processes, choice of coping style, encoding and retrieval. The MR-mediated actions on cognition are complemented by slower actions via glucocorticoid receptors (GRs) on contextualization, rationalization and memory storage of the experience. These sequential phases in cognitive performance depend on synaptic metaplasticity that is regulated by coordinate MR- and GR activation. The receptor activation includes recruitment of coregulators and transcription factors as determinants of context-dependent specificity in steroid action; they can be modulated by genetic variation and (early) experience. Interestingly, inflammatory responses to damage seem to be governed by a similarly balanced MR:GR-mediated action as the initiating, terminating and priming mechanisms involved in stress-adaptation. We conclude with five questions challenging the MR:GR balance hypothesis.

Stress exposure activates the HPA-axis and results in the release of corticosteroids which bind to two receptor types in the brain: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). While the role of the GR in stress reactivity has been extensively studied, the MR has received less attention. Nevertheless, pioneering in-depth studies over the past two decades have shown the importance of the brain MR in the processing of stressful information. Moreover, a membrane-bound MR mediating the rapid effects of cortisol was recently discovered. This review summarizes how the MR may play a role in stress resilience. Both preclinical and clinical studies suggest that the MR is an important stress modulator and influences basal as well as stress-induced HPA-axis activity, stress appraisal, and fear-related memories. These MR effects are mediated by both genomic and non-genomic MRs and appear to be at least partially sex-dependent. Moreover, the majority of studies indicate that high MR functionality or expression may confer resilience to traumatic stress. This has direct clinical implications. First, increasing activity or expression of brain MRs may prevent or reverse symptoms of stress-related depression. Second, individuals with a relatively low MR functionality may possess an increased stress susceptibility for depression. Nevertheless, the number of clinical MR studies is currently limited. In conclusion, the recent emergence of the MR as a putative stress resilience factor is important and may open up new avenues for the prevention and treatment of psychiatric disorders.

Depression and cognitive decline have been associated with changes in circulating cortisol concentrations. Cortisol exerts its functions through mineralocorticoid (MR) and glucocorticoid (GR) receptors. However, data on the influence of variations in the MR and GR genes on depressive symptoms and cognitive functioning in older adults are scarce. Therefore, we explored the impact of MR-215G/C, MR-I180V, GR-ER22/23EK, GR-N363S, and GR-BclI polymorphisms on these end points in the population-based Leiden 85-plus Study. This prospective study includes 563 participants aged 85 years and older, with a mean follow-up of 4.2 years. In this study, high morning cortisol levels (per 1 SD cortisol) associated with impairments in global cognitive functioning (p ¼ 0.002) at baseline (age 85). These impairments were mainly attributable to lower attention (p ¼ 0.057) and slower processing speed (p ¼ 0.014). Similar effects were also observed during follow-up (age 85-90), where participants with higher cortisol levels (per 1 SD cortisol) had impaired global cognitive functioning (p ¼ 0.003), as well as impairments in attention (p ¼ 0.034) and processing speed (p ¼ 0.013). Changes in depressive symptoms were observed for the MR-I180V single-nucleotide polymorphism (SNP), where during follow-up the prevalence of depressive symptoms was higher in the 180V-allele carriers (p ¼ 0.049) compared to noncarriers. Dependent on these polymorphisms, no differences in overall and in specific domains of cognitive functioning were observed. In conclusion, the MR-I180V SNP has a specific effect on depressive symptoms, independent from cognitive functioning, and other polymorphisms in the MR and GR genes. In contrast, these genetic variants in the MR and GR genes do not influence cognitive functioning in old age.

SUMMARYSpraying tobacco plants with salicylic acid induces both the synthesis of 'pathogenesis-related' (PR) proteins and resistance to viruses that can induce necrotic lesions. We show that spraying Samsun NN tobacco with salicylic acid induced the production of PR-1 mRNAs and inhibited the systemic multiplication of alfalfa mosaic virus (A1MV) by 90%. Salicylic acid treatment also induced the synthesis of PR proteins in bean and cowpea plants, and reduced by 75 % the production of local lesions in A1MV-infected bean plants. Salicylic acid inhibited the replication of A1MV in cowpea protoplasts by up to 99%, depending on the mode of application. In A1MV-inoculated cowpea protoplasts, the production of viral minus-strand RNA, plus-strand RNA and coat protein was abolished, indicating that salicylic acid inhibits an early step in the A1MV replication cycle. The viability of the cells and the synthesis of host proteins were not affected by salicylic acid. Another aromatic compound, p-coumaric acid, induced neither PR proteins nor resistance to virus infection.

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The aim of the study is to test whether fluvoxamine affects the function of the hypothalamic pituitary adrenal (HPA) axis in female borderline (borderline personality disorder, BPD) patients with and without a history of sustained childhood abuse. Special attention is given to the presence of comorbid major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The HPA axis of 30 female BPD patients with (n ¼ 17) and without (n ¼ 13) a history of sustained childhood abuse was challenged with a combined dexamethasone and corticotropin releasing hormone test (DEX/CRH test) before and after 6 (n ¼ 14) and 12 (n ¼ 16) weeks of fluvoxamine treatment (150 mg/day). Both 6-and 12-week fluvoxamine treatments were associated with a significant and robust reduction of the adrenocorticotrophic hormone (ACTH) and cortisol response to the DEX/CRH test. The magnitude of the reduction was dependent on the presence of sustained childhood abuse, but not on the presence of comorbid MDD or PTSD: patients with a history of sustained childhood abuse showed the strongest reduction in ACTH and cortisol. In conclusion, Fluvoxamine treatment reduces the hyperresponsiveness of the HPA axis in BPD patients with a history of sustained childhood abuse. This effect is likely to be obtained in the first 6 weeks of treatment.