Anna Skórzewska

Post-traumatic stress disorder (PTSD) is characterized by re-experiencing a traumatic event, avoidance, negative alterations in cognitions and mood, hyperarousal, and severe functional impairment. Women have a two times higher risk of developing PTSD than men. The neurobiological basis for the sex-specific predisposition to PTSD might be related to differences in the functions of stress-responsive systems due to the interaction between gonadal hormones and stress peptides such as corticotropin-releasing factor (CRF), orexin, oxytocin, and neuropeptide Y. Additionally, in phases where estrogens levels are low, the risk of developing or exacerbating PTSD is higher. Most studies have revealed several essential sex differences in CRF function. They include genetic factors, e.g., the CRF promoter contains estrogen response elements. Importantly, sex-related differences are responsible for different predispositions to PTSD and diverse treatment responses. Fear extinction (the process responsible for the effectiveness of behavioral therapy for PTSD) in women during periods of high endogenous estradiol levels (the primary form of estrogens) is reportedly more effective than in periods of low endogenous estradiol. In this review, we present the roles of selected neuropeptides in the sex-related predisposition to PTSD development.

Purpose: Presentation of the role of the dopaminergic system and microRNAs in the development of depression alter glucocorti-coids (GCs) therapy. Views: GCs are steroid hormones secreted by the adrenal glands, and their synthesis is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. The secretion of GCs (cortisol in humans and corticosterone in rodents) is dependent directly on corticotropin, secreted from the pituitary gland and indirectly on the corticotropin-releasing factor, a hormone released from the paraventricular nuclei of the hypothalamus. Prolonged treatment with GCs disrupts the functions of the HPA axis, impairs the dopaminergic sys-tem, suppresses hippocampal neurogenesis and sensitizes the amygdala, leading to an increased susceptibility to depression. This is an important problem because GCs are commonly prescribed for a broad range of medical conditions, including inflammatory and autoimmune disorders. The action of GCs may be at least partially regulated by epigenetic mechanisms (microRNAs), in addition to which microRNAs modulate GCs production and cellular response to GCs. Conclusions: The administration of GCs may lead to changes in dopaminergic system activity (e.g. D2 receptors activity), which significantly contribute to the predisposition to depression. Additionally, GCs therapy may cause changes in the activity of micro-RNAs (e.g. miR-124), which exacerbates symptoms of depression. Searching for specific changes in microRNA expression will provide clinically practical and easily applicable biomarkers of depression risk and new forms of pharmacotherapy in GC-induced depression.

This study aimed to test the hypothesis that high-anxiety (HR) rats are more sensitive to the effects of chronic corticosterone administration and antalarmin (corticotropin-releasing factor (CRF) receptor 1, CRF₁ antagonist) injections than low-anxiety (LR) rats, and this effect is accompanied by changes in CRF system activity in brain regions involved in the control of emotions and the hypothalamic-pituitary-adrenal (HPA) axis. Male rats were divided into LR (n = 25) and HR (n = 30) groups according to the duration of conditioned freezing in a contextual fear test. Chronic corticosterone administration (by injection, 20 mg/kg) for 21 d (except weekends) increased freezing duration and number of GR (glucocorticoid receptor)-immunoreactive nuclei in the basal amygdala (BA) and decreased GR-immunoreactive nuclei in the infralimbic cortex (IL), dentate gyrus (DG), and CA3 area, only in the HR group. Moreover, in this group, corticosterone administration decreased number of CRF-immunoreactive neurons of the parvocellular paraventricular hypothalamic nucleus (pPVN), DG, and CA1. Antalarmin (10 mg/kg, i.p., 2 injections) significantly attenuated conditioned fear responses, increased plasma corticosterone concentration, and decreased GR-immunoreactive nuclei in the BA, only in the HR group. Moreover, in this group, antalarmin increased number of GR-immunoreactive nuclei in the IL, DG, and CA3 and increased number of CRF-immunoreactive cells in the pPVN, DG, and CA1. Hence, antalarmin attenuated the fear response and restored HPA axis function in HR rats, which were more sensitive to corticosterone exposure. These data suggest that individual differences in central local CRF system activity may determine the neurobiological mechanisms related to mood and emotional disorders.

Changes in the expression of the GABA-A receptor subunits involved in phasic and tonic inhibition have been studied in a wide spectrum of animal models of epilepsy. However, there is no exhaustive data regarding the pentylenetetrazole (PTZ) kindling model of epilepsy. The aim of our study was to analyse the hippocampal changes in the expression of GABA-A receptor subunits involved in phasic (α1, γ2) or tonic (α4 and δ) inhibition in rats subjected to the PTZ kindling using immunohistochemistry method as well as in animals subjected to a single injection of a subconvulsive (30mg/kg) or convulsive (55mg/kg) dose of PTZ. Moreover, the expression of GABA transporters (GAT-1 and GAT-3) was also assessed. In kindled animals, we observed an increase in the expression of α1 (in CA1, DG (dentate gyrus) and CA3 regions) and γ2 (CA1 and CA3) subunits as well as in the expression of GAT-1 (CA1). On the other hand, the expression of the δ subunit in the DG was reduced. The single injection of PTZ at a dose of 30mg/kg increased the expression of the α4 subunit in the DG, while at a dose of 55mg/kg, PTZ increased the expression of the α1 and α4 subunits in the DG and reduced expression of the γ2 subunit in the CA1 and CA3 regions. The pattern of changes observed in our study indicates that changes in tonic inhibition are involved in abnormal neuronal activity observed in PTZ model of epilepsy.