Depression is a chronic, recurrent and long-term disorder characterized by high rates of impairment and several comorbidities. Early life stress (ELS) is associated with the increased risk for developing depression in adulthood, influences its clinical course and predicts a poorer treatment outcome. Stressful life events play an important role in the pathogenesis of depression, being well established as acute triggers of psychiatric illness. The vulnerability for developing depression is associated to changes in neurobiological systems related to stress regulation. The hypothalamic-pituitaryadrenal (HPA) axis responds to external and internal stimuli. Reported results indicate that stress in early phases of development can induce persistent changes in the response of the HPA axis to stress in adulthood, leading to a raised susceptibility to depression. These abnormalities appear to be related to the HPA axis deregulation in depression, partially due to an imbalance between glucocorticoid receptors (GR) and mineral ocorticoid receptors (MR). While most studies have consistently demonstrated that GR function is impaired in major depression (reduced GR-mediated feedback in HPA axis), data about the MR role in depression are still limited and contr oversial. Thus, in this review article we summarize the main reported findings about the consequences of ELS in HPA axis functioning and in the responsivity of MR/GR receptors in depression.

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The posterodorsal medial amygdaloid nucleus (MePD) is a sexually dimorphic area in the rat brain and dendritic spines are specialized postsynaptic sites involved with local neural plasticity. Previous electrophysiological data showed that prepubertal males have more excitatory synapses than females in the left MePD. Besides, dorsal and ventral MePD neurons have a heterogeneous expression of estrogen receptors alpha or beta in mating-responsive neurons in females. Based on these findings, the "single-section" Golgi method was employed in adult rats (n=6 in each group) to reveal: (1) the effect of hemispheric laterality in the density of dendritic spines in the MePD of males and diestrus females, and (2) the density of dendritic spines in the MePD dorsal and ventral subregions in proestrus females (mean values from n=48 neurons for each experimental variable). There were no statistically significant differences for sex, laterality or the interaction of these factors in the dendritic spine density between males and diestrus females (p>0.2), nor for the dorsal and the ventral MePD dendritic spine density in proestrus females (p>0.1). These findings complement current knowledge about the rat MePD and suggest that the number of proximal dendritic spines is not lateralized at adulthood. Furthermore, the differential expression of estradiol receptors in the dorsal and ventral MePD did not lead to distinct spine number in these subregions when circulating ovarian steroids peak in proestrus.

The recently discovered peptide phoenixin (PNX) and its receptor GPR173 are novel factors that exhibit a large spectrum of regulatory activity, especially when considered as a central modulator of GnRH-related hormonal control of reproductive processes. It has been already proven that GnRH agonists and antagonists can modulate peptidergic signalling in the HPG axis. Despite these findings, there is so far no information regarding the influence of treatment with GnRH analogues on SMIM20/phoenixin signalling in the hypothalamic-pituitary-gonadal axis. In the current study, SMIM20/ phoenixin and GPR173 mRNA levels were measured in the hypothalamus, pituitary and ovaries of female rats in the dioestrus phase following treatment with GnRH-R agonist (buserelin) and antagonist (cetrorelix) using quantitative real-time PCR. The serum PNX concentrations were also estimated with ELISA technique. The hypothalamic, hypophyseal and especially ovarian levels of SMIM20 mRNA were increased after both buserelin and cetrorelix administration. The GPR173 expressions were in turn decreased in the hypothalamus and pituitary. Treatment with the GnRH analogues led to the modulation of SMIM20/phoenixin and GPR173 mRNA expression in the female rat hypothalamic-pituitary-gonadal axis. By identifying buserelin and cetrorelix as novel modulators of phoenixin signalling in the animal HPG axis, these results cast new light on the GnRH analogues mode of action and contribute to a better understanding of the mechanisms responsible for the hormonal control of reproduction.