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Fear-related disorders, including post-traumatic stress disorder (PTSD), and anxiety disorders are pervasive psychiatric conditions marked by persistent fear, stemming from its dysregulated acquisition and extinction. The primary treatment for these disorders, exposure therapy (ET), relies heavily on fear extinction (FE) principles. Adolescence, a vulnerable period for developing psychiatric disorders, is characterized by neurobiological changes in the fear circuitry, leading to impaired FE and increased susceptibility to relapse following ET. Ketamine, known for relieving anxiety and reducing PTSD symptoms, influences fear-related learning processes and synaptic plasticity across the fear circuitry. Our study aimed to investigate the effects of ketamine (10 mg/kg) on FE in adolescent male C57 BL/6 mice at the behavioral and molecular levels. We analyzed the protein and gene expression of synaptic plasticity markers in the hippocampus (HPC) and prefrontal cortex (PFC) and sought to identify neural correlates associated with ketamine's effects on adolescent extinction learning. Ketamine ameliorated FE in the adolescent males, likely affecting the consolidation and/or recall of extinction memory. Ketamine also increased the Akt and mTOR activity and the GluA1 and GluN2A levels in the HPC and upregulated BDNF exon IV mRNA expression in the HPC and PFC of the fear-extinguished mice. Furthermore, ketamine increased the c-Fos expression in specific brain regions, including the ventral HPC (vHPC) and the left infralimbic ventromedial PFC (IL vmPFC). Providing a comprehensive exploration of ketamine's mechanisms in adolescent FE, our study suggests that ketamine's effects on FE in adolescent males are associated with the activation of hippocampal Akt-mTOR-GluA1 signaling, with the vHPC and the left IL vmPFC as the proposed neural correlates. [ABSTRACT FROM AUTHOR]

Adolescence is a key phase of development for perturbations in fear extinction, with inability to adequately manage fear a potent factor for developing psychiatric disorders in adulthood. However, while behavioral correlates of adolescent fear regulation are established to a degree, molecular mediators of extinction learning in adolescence remain largely unknown. In this study, we observed fear acquisition and fear extinction (across 4 and 7 days) of adolescent and adult mice of both sexes and investigated how hippocampal levels of different plasticity markers relate to extinction learning. While fear was acquired evenly in males and females of both ages, fear extinction was found to be impaired in adolescent males. We also observed lower levels of GluA1, GLUN2A and GLUN2B subunits in male adolescents following fear acquisition, with an increase in their expression, as well as the activity of Erk-mTOR pathway over subsequent extinction sessions, which was paralleled with improved extinction learning. On the other hand, we detected no changes in plasticity-related proteins after fear acquisition in females, with alterations in GluA1, GluA4 and GLUN2B levels across fear extinction sessions. Additionally, we did not discern any pattern regarding the Erk-mTOR activity in female mice associated with their extinction performance. Overall, our research identifies sex-specific synaptic properties in the hippocampus that underlie developmentally regulated differences in fear extinction learning. We also point out hippocampal NMDA-Erk-mTOR signaling as the driving force behind successful fear extinction in male adolescents, highlighting this pathway as a potential therapeutic target for fear-related disorders in the adolescent population. • Adolescent males exhibit impaired fear extinction (FE) consolidation. • GluA1, GluN2A and GluN2B mediate successful FE in adolescent males. • GluA1, GluA4 and GluN2B are involved in FE of adolescent and adult females. • psaNCAM is primarily developmentally regulated in both male and female mice. • Erk-mTOR pathway potentiates extinction learning of adolescent males. [ABSTRACT FROM AUTHOR]

Depression is a disease of an abnormal brain energy metabolism also marked with increased apoptosis in specific brain regions. Mounting evidence indicates that the mitochondrial oxidative phosphorylation and apoptosis are novel targets for the actions of estrogen receptors (ERs). In this study, we examined the effects of antidepressant (AD) fluoxetine (FLU) treatment on the mitochondrial ER alpha (ERα), ER beta (total and phospho-pERβ) and their association with cytochrome c (cyt c ) oxidase activity and apoptotic Bcl2/Bax-molecules in the hippocampal mitochondria of chronically isolated (CPSI) female and male rats depicting depression. Impaired behaviour induced by CPSI was followed by decreased corticosterone (CORT) in both sexes and downregulation of cyt c oxidase in males. CPSI did not affect the ERα in either of sexes, but it decreased mitochondrial ERβ and increased pERβ in both sexes. Stress-reduced ERβ is associated with a decrease in mitochondrial energetic processes in males and with apoptotic mechanisms in females. FLU normalized behaviour in both sexes and increased cyt c oxidase in females. FLU elevated ERα in males, increased ERβ and decreased pERβ in both sexes. The AD-induced alterations of ERβ paralleled with bioenergetics and pro-survival pathways in females. In conclusion, sex-unspecific regulation of ERβ by the stress and by AD and its differential convergence with bioenergetics and apoptotic pathways in females and males implies its role as a vulnerability factor in the stress response and emphasizes mitochondrial ERβ-dependent pathways as an important gateway of ADs action, at least in females. [ABSTRACT FROM AUTHOR]

Inflammation plays a critical role in pathogenesis of depression and can affect the hypothalamic-pituitary-adrenal axis activity. Accordingly, in this study we investigated the role of hippocampal glucocorticoid receptor in mediating the effects of inflammation on behaviour of female and male Wistar rats. We studied the effects of lipopolysaccharide on the levels of glucocorticoid receptors and its co-chaperones FK506 binding protein 52 and FK506 binding protein 51, the levels of glucocorticoid receptor phospho-isoforms, pGR-232 and pGR-246, and glucocorticoid receptor up-stream kinases. In order to assess transcriptional activity of glucocorticoid receptor, we measured mRNA levels of several glucocorticoid receptor-regulated genes. We demonstrated that lipopolysaccharide induced depressive-like behaviour and elevated serum corticosterone in both sexes. However, it affected glucocorticoid receptor signalling in the nucleus of females and males differently - in females it elevated levels of glucocorticoid receptors, pGR-246 and FK506 binding protein 52, while in males it decreased levels of glucocorticoid receptor, both co-chaperons and pGR-246. Alterations in pGR-246 were associated with alterations of c-Jun N-terminal kinases. Altered nuclear levels of total glucocorticoid receptors and pGR-246 were accompanied by sex-specific reduction in brain-derived neurotrophic factor and cyclooxygenase-2 mRNA and sex-unspecific reduction in the expression of p11 and glucocorticoid receptor genes. These alterations may ultimately affect different glucocorticoid receptor -associated processes involved in depressive-like behaviour in males and females. [ABSTRACT FROM AUTHOR]

Accumulating evidence strongly suggest that impaired glucocorticoid receptor (GR) signaling is involved in stress-related mood disorders, and nominate GR as a potential target for antidepressants (ADs). It is known that different classes of ADs affects the GR action via modifying its phosphorylation, while the mechanism through which ADs alter GR phosphorylation targeted by GSK3β, a kinase modulated via serotonin neurotransmission, are unclear. On this basis, we investigated whether GSK3β-GR signaling could be a convergence point of fluoxetine action on brain function and behavior, by examining its effect on GSK3β targeted-GR phosphorylation on threonine 171 (pGR171), and expression of GR-regulated genes in the hippocampus of female and male rats exposed to chronic isolation stress. Stress induced sex-specific GSK3β-targeted phosphorylation of pGR171 in the nucleus of the hippocampus of stressed animals. Namely, while in females stress triggered coupled action of GSK3β-pGR171 signaling, in males changes in pGR171 levels did not correspond to GSK3β activity. On the other hand, fluoxetine managed to up-regulate this pathway in sex-unbiased manner. Furthermore, fluoxetine reverted stress-induced changes in most of the analyzed genes in males, CRH, 5-HT1a and p11, while in females its effect was limited to CRH. These data further suggest that pGR171 signaling affects cellular localization of GR in response to chronic stress and fluoxetine in both sexes. Collectively, our results describe a novel convergence point between GR signaling and GSK3β pathway in rat hippocampus in response to stress and fluoxetine in both sexes and its involvement in fluoxetine-regulated brain function in males. [ABSTRACT FROM AUTHOR]

ABSTRACT [ABSTRACT FROM AUTHOR]

Objectives. To develop a structural equation model of negative affectivity (NA) that involves interaction of glucocorticoid receptor (GR) signaling, personality dimensions and recent stressful life events. Methods. Seventy participants − 35 diagnosed with major depression and 35 healthy controls, were enrolled in the study. Morning plasma cortisol levels were determined by chemiluminescent immunometric assays. Molecular parameters (total nuclear and cytoplasmatic GR, nuclear GR phosphorylated at serine 211 (pGR-211) and at serine 226 (pGR-226) and cytoplasmic FKBP51) were analysed from peripheral blood lymphocytes by Western blot. NA, personality dimensions and stressful life events were assessed by self-report instruments. Results. GR signalling parameters had direct independent effect on measures of NA, with pGR-226 levels showing the strongest correlation, followed by FKBP51 and pGR-211 levels. Neuroticism and extraversion also demonstrated strong independent effect on NA, while recent stressful events did not predict NA directly, but demonstrated a significant effect on personality dimensions. Cortisol, total nuclear GR and total cytoplasmatic GR levels were excluded from the model due to non-significant correlations with NA. Conclusions. Negative affectivity is a transdiagnostic factor in vulnerability to affective disorders and possible therapeutic target. Molecular signature of negative affectivity should incorporate GR phosphorylation with other known biological underpinnings. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress is reliably observed in major depressive disorder (MDD). However, molecular data on the principal cellular redox-sensitive transcriptional factors and the levels of their downstream-regulated antioxidant enzymes in MDD are scarce. Methods: In the peripheral blood mononuclear cells (PBMC) of subjects with a current episode of MDD (n = 30) and healthy controls (n = 35), we investigated alterations in the levels of redox-sensing nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein, its inhibitor Keap1, and nuclear factor-κB (NF-κB), along with their cognate downstream effectors, the antioxidant enzymes (AOEs): manganese and copper zinc superoxide dismutase (MnSOD and CuZnSOD, respectively), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR). Results: MDD subjects exhibited higher levels of Nrf2 and its regulator Keap1, as well as NF-κB in the cytoplasm of PBMC compared to controls. This state was further reflected by increased levels of MnSOD, CuZnSOD and CAT proteins and by the lack of correlation between MnSOD and CAT, which could indicate impaired oxidative detoxification capacity in MDD patients. Moreover, increased levels of MnSOD, CuZnSOD and CAT in MDD patients positively correlated with levels of Nrf2, while increased levels of SODs were also positively related to NF-κB. There were no differences regarding the levels of GPx and GLR proteins, but the ratio of GLR/GPx was reduced, suggesting diminished capacity of GPx in antioxidative defence in PBMC of MDD subjects. Conclusion: These data provide evidence that MDD is characterized by up-regulation of redox-sensitive transcriptional factors (Nrf2 and NF-κB) and AOEs (MnSOD, CuZnSOD and CAT), indicating pro-oxidative state in the PBMC of MDD patients. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) afflicts approximately 5 % of the world population, and about 30–50 % of patients who receive classical antidepressant medications do not achieve complete remission (treatment resistant depressive patients). Emerging evidence suggests that targeting opioid receptors mu (MOP), kappa (KOP), delta (DOP), and the nociceptin/orphanin FQ receptor (NOP) may yield effective therapeutics for stress-related psychiatric disorders. As depression and pain exhibit significant overlap in their clinical manifestations and molecular mechanisms involved, it is not a surprise that opioids, historically used to alleviate pain, emerged as promising and effective therapeutic options in the treatment of depression. The opioid signaling is dysregulated in depression and numerous preclinical studies and clinical trials strongly suggest that opioid modulation can serve as either an adjuvant or even an alternative to classical monoaminergic antidepressants. Importantly, some classical antidepressants require the opioid receptor modulation to exert their antidepressant effects. Finally, ketamine, a well-known anesthetic whose extremely efficient antidepressant effects were recently discovered, was shown to mediate its antidepressant effects via the endogenous opioid system. Thus, although opioid system modulation is a promising therapeutical venue in the treatment of depression further research is warranted to fully understand the benefits and weaknesses of such approach. [Display omitted] [ABSTRACT FROM AUTHOR]

Alterations in the antioxidative defense parameters upon chronic stress are considered critical for pathophysiology of stress related psychiatric disorders, and their status in blood serves as biomarker for effects of pharmacological treatments. The present study was designed to investigate the modulation of erythrocyte antioxidant enzymes (AOEs): CuZn superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR) activities and their protein expression in Wistar male rats subjected to chronic psychosocial isolation and/or to pharmacological treatment with fluoxetine. Chronically isolated animals exhibited decreased levels of serum corticosterone, as opposed to other chronic stress paradigms. In addition to that, SOD, CAT and GPx status was not altered either by chronic psychosocial isolation or by fluoxetine treatment. In contrast, GLR activity and its protein level were both markedly reduced by fluoxetine. Since, GLR is crucial for overall oxido-reductive balance through maintaining optimal ratio of reduced/oxidized glutathione level (GSH/GSSG) in erythrocytes, these results could indicate that in spite of numerous beneficial effects of fluoxetine, it may compromise both haemoglobin function and oxygen transport. [ABSTRACT FROM AUTHOR]

Highlights • GluN2A KO mice displayed resiliance to depressive-like behaviour upon LPS. • GluN2A KO mice abolishes LPS induced inflammation. • LPS treated GluN2A KO mice showed elevated proBDNF in the PFC & hippocampus and increased NCAM in PFC. • GluN2A KO mice exhibited sustained PSA-NCAM levels in the PFC and hippocampus. • GluN2A KO potentiated synaptic stabilization through NCAM in the PFC upon LPS. Abstract Recent reports have demonstrated that lipopolysaccharide (LPS)-induced depressive-like behaviour is mediated via NMDA receptor. In this study, we further investigated the role of GluN2 A subunit of NMDA receptor in synaptic processes in the prefrontal cortex (PFC) and hippocampus of GluN2 A knockout (KO) mice in LPS-induced depressive-like behavior. Our data suggest that LPS-treated mice, lacking GluN2 A subunit, did not exhibit depressive-like behaviour. This was accompanied by unaltered levels of IL-6 and significant changes in neuroplasticity markers and glutamate receptor subunits composition in PFC and hippocampus. In particular, an immune challenge in GluN2 A KO mice resulted in unchanged PSA-NCAM levels and proBDNF increase in both brain structures as well as in increase in BDNF levels in hippocampus. Furthermore, the absence of GluN2 A resulted in increased levels of all NCAM isoforms in PFC upon LPS which was followed with a decrease in GluN1 and GluN2B subunits. The levels of AMPA receptor subunits (GluA1, GluA3, and GluA4) in the hippocampus of GluN2 A mice were unaltered upon the treatment and abundantly present in the PFC of KO mice. These results indicate that the GluN2 A subunit is critical in neuroinflammation-related depression, that its absence abolishes LPS-induced depressive phenotype, sustains PSA-NCAM levels, increases proBDNF signalling in the PFC and hippocampus and potentiates synaptic stabilization through NCAM in the PFC upon an immune challenge. [ABSTRACT FROM AUTHOR]

Knowledge of the antioxidant defense in the stress-responding structures of the CNS is of crucial importance, since oxidative damage is a phenomenon accompanying many stress-related disorders. Regulation of antioxidative and anti-inflammatory defense through Nrf2 (nuclear factor 2 eritroid related factor 2) pathway has emerged as a promising approach for neuroprotection. In this study, we used chronic social isolation of male Wistar rats to induce depressive-like behavior. We hypothesized that Nrf2–Keap1 pathway is compromised in the limbic brain after prolonged stress. Since subcellular trafficking of Nrf2 and its inhibitor Keap1 (Kelch ECH associating protein 1) is essential for the activation of Nrf2, we determined their protein level in cytosolic and nuclear compartments of hippocampus and prefrontal cortex (PFC). We also determined mRNA levels of Nrf2-regulated genes involved in the production and utilization of glutathione, glutamate cysteine ligase (Gclm), glutathione S-transferase (Gsta3) and glutathione reductase (Gsr). Our results showed that chronic isolation induced anxiety and depressive-like behavior, decreased Nrf2 and in parallel increased Keap1 and nuclear factor kappa B (NFκB) in the hippocampus, which were not accompanied by expression profiles of Nrf2-regulated genes. Chronically stressed rats challenged with acute stress failed to induce any response of examined genes in either of brain structures, even though Nrf2/Keap1 was altered, while in naïve animals Nrf2 activity corresponded with an expression of Nrf2-regulated genes. Our results reveal maladaptive character of chronic stress at Nrf2/Keap1 level followed by pro-inflammatory conditions, and suggest a possible role of these alterations in pathogenesis of depressive/anxiety disorders. [ABSTRACT FROM AUTHOR]

Background: Mounting evidence demonstrates enhanced systemic levels of inflammatory mediators in depression, indicating that inflammation may play a role in the etiology and course of mood disorders. Indeed, proinflammatory cytokines induce a behavioral state of conservation- withdrawal resembling human depression, characterized by negative mood, fatigue, anhedonia, psychomotor retardation, loss of appetite, and cognitive deficits. Neuroinflammation also contributes to non-responsiveness to current antidepressant (AD) therapies. Namely, response to conventional AD medications is associated with a decrease in inflammatory biomarkers, whereas resistance to treatment is accompanied by increased inflammation., Methods: In this review, we will discuss the utility and shortcomings of pharmacologic AD treatment strategies focused on inflammatory pathways, applied alone or as an adjuvant component to current AD therapies., Results: Mechanisms of cytokine actions on behavior involve activation of inflammatory pathways in the brain, resulting in changes of neurotransmitter metabolism, neuroendocrine function, and neuronal plasticity. Selective serotonin reuptake inhibitors exhibit the most beneficial effects in restraining the inflammation markers in depression. Different anti-inflammatory agents exhibit AD effects via modulating neurotransmitter systems, neuroplasticity markers and glucocorticoid receptor signaling. Anti-inflammatory add-on therapy in depression highlights such treatment as a candidate for enhancement strategy in patients with moderate-to-severe depression., Conclusion: The interactions between the immune system and CNS are not only involved in shaping behavior, but also in responding to therapeutics. Even though, substantial evidence from animal and human research support a beneficial effect of anti-inflammatory add-on therapy in depression, further research with special attention on safety, particularly during prolonged periods of antiinflammatory co-treatments, is required., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)