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Background: Major depressive disorder (MDD) is the leading cause of disability worldwide. Of individuals with MDD, 30% to 50% are unresponsive to common antidepressants, highlighting untapped causal biological mechanisms. Dysfunction in the microbiota-gut-brain axis has been implicated in MDD pathogenesis. Exposure to chronic stress disrupts blood-brain barrier integrity; still, little is known about intestinal barrier function in these conditions, particularly for the small intestine, where absorption of most foods and drugs takes place., Methods: We investigated how chronic social or variable stress, two mouse models of depression, impact the jejunum intestinal barrier in males and females. Mice were subjected to stress paradigms followed by analysis of gene expression profiles of intestinal barrier-related targets, fecal microbial composition, and blood-based markers., Results: Altered microbial populations and changes in gene expression of jejunum tight junctions were observed depending on the type and duration of stress, with sex-specific effects. We used machine learning to characterize in detail morphological tight junction properties, identifying a cluster of ruffled junctions in stressed animals. Junctional ruffling is associated with inflammation, so we evaluated whether lipopolysaccharide injection recapitulates stress-induced changes in the jejunum and observed profound sex differences. Finally, lipopolysaccharide-binding protein, a marker of gut barrier leakiness, was associated with stress vulnerability in mice, and translational value was confirmed on blood samples from women with MDD., Conclusions: Our results provide evidence that chronic stress disrupts intestinal barrier homeostasis in conjunction with the manifestation of depressive-like behaviors in a sex-specific manner in mice and, possibly, in human depression., (© 2023 The Authors.)

Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD., (© 2022. The Author(s).)

Guanosine is a purine nucleoside that has been shown to exhibit antidepressant effects, but the mechanisms underlying its effect are not well established. We investigated if the antidepressant-like effect induced by guanosine in the tail suspension test (TST) in mice involves the modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-dependent calcium channel (VDCC), and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway. We also evaluated if the antidepressant-like effect of guanosine is accompanied by an acute increase in hippocampal and prefrontocortical BDNF levels. Additionally, we investigated if the ability of guanosine to elicit a fast behavioral response in the novelty suppressed feeding (NSF) test is associated with morphological changes related to hippocampal synaptogenesis. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) in the TST was prevented by DNQX (AMPA receptor antagonist), verapamil (VDCC blocker), K-252a (TrkBantagonist), or BDNF antibody. Increased P70S6K phosphorylation and higher synapsin I immunocontent in the hippocampus, but not in the prefrontal cortex, were observed 1 h after guanosine administration. Guanosine exerted an antidepressant-like effect 1, 6, and 24 h after its administration, an effect accompanied by increased hippocampal BDNF level. In the prefrontal cortex, BDNF level was increased only 1 h after guanosine treatment. Finally, guanosine was effective in the NSF test (after 1 h) but caused no alterations in dendritic spine density and remodeling in the ventral dentate gyrus (DG). Altogether, the results indicate that guanosine modulates targets known to be implicated in fast antidepressant behavioral responses (AMPA receptor, VDCC, and TrkB/BDNF pathway).

Glibenclamide is a second-generation sulfonylurea used in the treatment of Type 2 Diabetes Mellitus. The primary target of glibenclamide is ATP-sensitive potassium channels inhibition; however, other possible targets include the control of inflammation and blood-brain barrier permeability, which makes this compound potentially interesting for the management of brain-related disorders. Here, we showed that systemic treatment with glibenclamide (5 mg/kg, p.o., for 21 days) could prevent the behavioral despair and the cognitive dysfunction induced by chronic unpredictable stress (CUS) in mice. In nonhypoglycemic doses, glibenclamide attenuated the stress-induced weight loss, decreased adrenal weight, and prevented the increase in glucocorticoid receptors in the prefrontal cortex, suggesting an impact in hypothalamic-pituitary-adrenal (HPA) axis function. Additionally, we did not observe changes in Iba-1, NLRP3 and caspase-1 levels in the prefrontal cortex or hippocampus after CUS or glibenclamide treatment. Thus, this study suggests that chronic treatment with glibenclamide prevents the emotional and cognitive effects of chronic stress in female mice. On the other hand, the control of neuroinflammation and NLRP3 inflammasome pathway is not the major mechanism mediating these effects. The behavioral effects might be mediated, in part, by the normalization of glucocorticoid receptors and HPA axis., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Resilience is an adaptation process presented by an individual despite facing adversities. Epigenetic changes, such as histone acetylation/methylation and DNA methylation, have been demonstrated to mediate stress response. In this review, we summarize recent findings on epigenetic mechanisms contributing to stress resilience., Recent Findings: Epigenetic modifications of genes involved in synaptic plasticity, endocrine, immune, and vascular systems are linked to resilience. For instance, increased DNA methylation of the nonneuronal growth factor Gdnf in specific brain regions promotes stress resilience. Additionally, high DNA methylation at the glucocorticoid receptor gene was associated with resilience in both rodents and humans. At the immune level, chronic stress induces increased DNA methylation at IL6 gene, a mediator of stress vulnerability. Moreover, epigenetic adaptations of the blood--brain barrier have been recently associated with stress resilience, which could lead to innovative therapeutic approaches to treat depression., Summary: Identification of both central and peripheral epigenetic changes promoting stress resilience represent promising novel targets in the development of preventive and personalized medicine. Nevertheless, more research is needed to establish sex specific differences and to identify novel epigenetic mechanisms, such as serotonylation and dopaminylation, that hold great promises for the field of psychiatry.

Major depressive disorder (MDD) is a chronic and recurrent psychiatric condition characterized by depressed mood, social isolation and anhedonia. It will affect 20% of individuals with considerable economic impacts. Unfortunately, 30-50% of depressed individuals are resistant to current antidepressant treatments. MDD is twice as prevalent in women and associated symptoms are different. Depression's main environmental risk factor is chronic stress, and women report higher levels of stress in daily life. However, not every stressed individual becomes depressed, highlighting the need to identify biological determinants of stress vulnerability but also resilience. Based on a reverse translational approach, rodent models of depression were developed to study the mechanisms underlying susceptibility vs resilience. Indeed, a subpopulation of animals can display coping mechanisms and a set of biological alterations leading to stress resilience. The aetiology of MDD is multifactorial and involves several physiological systems. Exacerbation of endocrine and immune responses from both innate and adaptive systems are observed in depressed individuals and mice exhibiting depression-like behaviours. Increasing attention has been given to neurovascular health since higher prevalence of cardiovascular diseases is found in MDD patients and inflammatory conditions are associated with depression, treatment resistance and relapse. Here, we provide an overview of endocrine, immune and vascular changes associated with stress vulnerability vs. resilience in rodents and when available, in humans. Lack of treatment efficacy suggests that neuron-centric treatments do not address important causal biological factors and better understanding of stress-induced adaptations, including sex differences, could contribute to develop novel therapeutic strategies including personalized medicine approaches., (© 2019 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Generalized Anxiety Disorder (GAD) presents a high prevalence in the population, leading to distress and disability. Immune system alterations have been associated with anxiety-related behaviors in rodents and GAD patients. CD300f immune receptors are highly expressed in microglia and participate not only in the modulation of immune responses but also in pruning and reshaping synapses. It was recently demonstrated that CD300f might be influential in the pathogenesis of depression in a sex-dependent manner. Here, we evaluated the role of CD300f immune receptor in anxiety, using CD300f knockout mice (CD300f-/-) and patients with GAD. We observed that male CD300f-/- mice had numerous behavioral changes associated with a low-anxiety phenotype, including increased open field central locomotion and rearing behaviors, more exploration in the open arms of the elevated plus-maze test, and decreased latency to eat in the novelty suppressed feeding test. In a cross-sectional population-based study, including 1111 subjects, we evaluated a common single-nucleotide polymorphism rs2034310 (C/T) in the cytoplasmatic tail of CD300f gene in individuals with GAD. Notably, we observed that the T allele of the rs2034310 polymorphism conferred protection against GAD in men, even after adjusting for confounding variables. Overall, our data demonstrate that CD300f immune receptors are involved in the modulation of pathological anxiety behaviors in a sex-dependent manner. The biological basis of these sex differences is still poorly understood, but it may provide significant clues regarding the neuropathophysiological mechanisms of GAD and can pave the way for future specific pharmacological interventions., Competing Interests: None., (© 2020 The Authors.)

AZD6765 (lanicemine) is a non-competitive NMDA receptor antagonist that induces a fast-acting antidepressant effect without presenting psychotomimetic effects. However, the mechanisms underlying its effects remain to be established. In this context, we demonstrated that a single administration of AZD6765 (1 mg/kg, i.p.) was able to induce an antidepressant-like effect in mice submitted to tail suspension test (TST), an effect reversed by LY294002 (a reversible PI3K inhibitor, 10 nmol/site, i.c.v.), wortmannin (an irreversible PI3K inhibitor, 0.1 μg/site, i.c.v.) and rapamycin (a selective mTOR inhibitor, 0.2 nmol/site, i.c.v.). In addition, the administration of sub-effective doses of AZD6765 (0.1 mg/kg, i.p.) in combination with lithium chloride (non-selective GSK-3β inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, (0.01 μg/site, i.c.v.) caused a synergistic antidepressant-like effect. These results suggest the involvement of PI3K/Akt/mTOR/GSK3β signaling in the AZD6765 antidepressant-like effect. In addition, western blotting analysis showed an increased immunocontent of synapsin in the prefrontal cortex and a tendency to an increased immunocontent of this protein in the hippocampus 30 min after AZD6765 administration, but no significant effect of AZD6765 was observed in P70S6K (Thr 389 ) phosphorylation and GluA1 immunocontent. A single dose of AZD6765 (3 mg/kg, i.p.), similarly to ketamine (1 mg/kg, i.p.), decreased the latency to feed in the novelty suppressed feeding (NSF) test, a behavioral paradigm that evaluates depression/anxiety-related behavior. This effect was reversed by rapamycin administration, suggesting the activation of mTOR signaling in the effect of AZD in the NSF test. In addition, a single administration of AZD6765 (1 mg/kg, i.p.) or ketamine (1 mg/kg, i.p.) reversed the depressive-like behavior induced by chronic unpredictable stress (CUS). Altogether, the results provide evidence for the fast-acting antidepressant profile of AZD6765, by a mechanism likely dependent on PI3K/Akt/mTOR/GSK3β., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB 1 receptor (CB 1 R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB 1 R ligands evolve in the frontal cortex of young adult male Wistar rats, in the first 8 weeks of streptozotocin-induced type-1 diabetes (T1D). We report that frontocortical CB 1 R protein density was biphasically altered in the first month of T1D, which was accompanied with a reduction of resting glucose uptake ex vivo in acute frontocortical slices that was normalized after eight weeks in T1D. This early reduction of glucose uptake in slices was also restored by ex vivo treatment with both the non-selective CB 1 R agonists, WIN55212-2 (500 nM) and the CB 1 R-selective agonist, ACEA (3 μM) while it was exacerbated by the CB 1 R-selective antagonist, O-2050 (500 nM). These results suggest a gain-of-function for the cerebrocortical CB 1 Rs in the control of glucose uptake in diabetes. Although insulin and IGF-1 receptor protein densities remained unaffected, phosphorylated GSKα and GSKβ levels showed different profiles 2 and 8 weeks after T1D induction in the frontal cortex. Altogether, the biphasic response in frontocortical CB 1 R density within a month after T1D induction resolves previous controversial reports on forebrain CB 1 R levels in T1D rodent models. Furthermore, this study also hints that cannabinoids may be useful to alleviate impaired glucoregulation in the diabetic cortex., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The funding agencies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f -/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming., Competing Interests: The authors declare no competing interest.

Increasing evidence supports a role for inflammation in the development of mood disorders. In this issue of Neuron, Leng et al. (2018) show that reduction of menin expression in astrocytes of stress-related brain regions exacerbates neuroinflammation, promoting the establishment of depression-like behaviors in mice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This narrative review will present and discuss clinical data from 16 cross-sectional and 6 longitudinal studies examining the relationship between body mass index (BMI), symptoms of depression and peripheral inflammation. Our aim is to determine which of obesity and depression contributes best to the peripheral low-grade inflammation frequently associated to both conditions. Studies including a complete evaluation of inflammatory markers are scarce and high levels of interleukin-6 (IL-6) and C-reactive protein (CRP) are the most consistent findings associated with obesity and symptoms of depression. Among the cross-sectional studies, seven studies, including a total of 9421 individuals, pointed to BMI as the major factor associated with systemic low-grade inflammation. However, in four studies, including 16,837 individuals, CRP levels remained associated with the symptoms of depression even after correction for BMI, suggestion that in the absence of overweight or obesity other sources of peripheral inflammation might contribute to presence of depressive symptoms. Additionally, another five studies, including 5569 individuals failed to find an association between depression and peripheral inflammation, reinforcing the heterogeneity of this condition. In the longitudinal data, changes in BMI were associated with a reduction in depressive scores at follow-up, after bariatric surgery or after diet. In four longitudinal studies, high levels of CRP were found to be associated with depression even after adjustment for BMI and weight loss, further corroborating the idea that other sources of peripheral inflammation might contribute to depressive symptoms. Thus it seems that both obesity and depressive symptoms can contribute to peripheral inflammation, and once installed the presence of inflammation can contribute to several behavioral alterations that reinforce the cyclic pattern of co-occurrence observed in patients with obesity and MDD. Future clinical studies should focus on strategic efforts to collect new data and to improve or standardize methods for the evaluation of depression, body composition and a more complete inflammatory profile. These approaches are essential for the development of pharmacological and/or non-pharmacological strategies designed to break this cyclic pattern of co-occurrence., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Over the past three decades, an intricate interaction between immune activation, release of pro-inflammatory cytokines and changes in brain circuits related to mood and behavior has been described. Despite extensive efforts, questions regarding when inflammation becomes detrimental or how we can target the immune system to develop new therapeutic strategies for the treatment of psychiatric disorders remain unresolved. In this context, novel aspects of the neuroinflammatory process activated in response to stressful challenges have recently been documented in major depressive disorder (MDD). The Nod-like receptor pyrin containing 3 inflammasome (NLRP3) is an intracellular multiprotein complex responsible for a number of innate immune processes associated with infection, inflammation and autoimmunity. Recent data have demonstrated that NLRP3 activation appears to bridge the gap between immune activation and metabolic danger signals or stress exposure, which are key factors in the pathogenesis of psychiatric disorders. In this review, we discuss both preclinical and clinical evidence that links the assembly of the NLRP3 complex and the subsequent proteolysis and release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) in chronic stress models and patients with MDD. Importantly, we also focus on the therapeutic potential of targeting the NLRP3 inflammasome complex to improve stress resilience and depressive symptoms., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Considering the high prevalence of psychiatric disorders, its social burden and the limitations of currently available treatments, alternative therapeutic approaches targeting different biological pathways have been investigated. Curcumin is a natural compound with multi-faceted pharmacological properties, interacting with several neurotransmitter systems and intracellular signaling pathways involved in mood regulation. Also, curcumin has anti-inflammatory, antioxidant and neurotrophic effects, suggesting a strong potential to manage conditions associated with neurodegeneration, such as psychiatric disorders. Most literature data focused on the potential of curcumin to counteract behavioral and neurochemical alterations in preclinical models of depression. The findings still need to be further explored and clinical reports share some controversial results that might be associated with its low systemic bioavailability following oral administration. Other psychiatric disorders also have neurochemical alterations similar to those found in depression, including neurotoxicity, oxidative stress and neuroinflammation. Despite the limited number of reports, preclinical models investigated the potential role for curcumin in anxiety, bipolar disorder, post-traumatic stress disorder and autism spectrum disorders. Here, we will summarize the cellular targets of curcumin relevant to psychiatric disorders and its effects in preclinical and clinical studies with depression, anxiety disorders and other psychiatric related conditions., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Studies have already pointed out the contribution of oxidative stress in the pathophysiology of major depressive disorder (MDD). The aim of the present study was to investigate the oxidative-antioxidative systems in MDD and in response to cognitive psychotherapies. Oxidative stress were analyzed in 49 MDD patients at baseline, post-treatment, and follow-up; and 49 control subjects without history of psychiatric disorders., Results: MDD subjects presented an increase in oxidative damage related to control subjects for thiobarbituric acid reactive species (TBARS), nitric oxide, and a decrease in total thiol content. Cognitive psychotherapies were able to counteract peripheral oxidative stress in MDD patients, reducing TBARS levels (p<0.001) in the follow-up, nitric oxide (p<0.001) in the post-treatment and follow-up, and increasing the total thiol content (p<0.01) in the post-treatment and follow-up., Conclusion: Oxidative stress was associated with MDD and the regulation of these parameters might represent an important mechanism associated with the clinical improvement of cognitive psychotherapy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Cecropia species are widely used in traditional medicine by its anti-diabetic, anti-hypertensive and anti-inflammatory properties. In the present study, we investigated the neuroprotective and antioxidant effects of the crude aqueous extract from Cecropia pachystachya leaves in a rat model of mania induced by ketamine. The results indicated that ketamine treatment (25 mg/kg i.p., for 8 days) induced hyperlocomotion in the open-field test and oxidative damage in prefrontal cortex and hippocampus, evaluated by increased lipid peroxidation, carbonyl protein formation and decreased total thiol content. Moreover, ketamine treatment reduced the activity of the antioxidant enzymes superoxide dismutase and catalase in hippocampus. Pretreatment of rats with C. pachystachya aqueous extract (200 and 400 mg/kg p.o., for 14 days) or with lithium chloride (45 mg/kg p.o., for 14 days, used as a positive control) prevented both behavioral and pro-oxidant effects of ketamine. These findings suggest that C. pachystachya might be a useful tool for preventive intervention in bipolar disorder, reducing the episode relapse and the oxidative damage associated with the manic phase of this disorder .

Bipolar disorder (BD) is a chronic and debilitating illness characterized by recurrent manic and depressive episodes. Our research investigates the protective effects of curcumin, the main curcuminoid of the Indian spice turmeric, in a model of mania induced by ketamine administration in rats. Our results indicated that ketamine treatment (25 mg/kg, for 8 days) induced hyperlocomotion in the open-field test and oxidative damage in prefrontal cortex (PFC) and hippocampus (HP), evaluated by increased lipid peroxidation and decreased total thiol content. Moreover, ketamine treatment reduced the activity of the antioxidant enzymes superoxide dismutase and catalase in the HP. Pretreatment of rats with curcumin (20 and 50 mg/kg, for 14 days) or with lithium chloride (45 mg/kg, positive control) prevented behavioral and pro-oxidant effects induced by ketamine. These findings suggest that curcumin might be a good compound for preventive intervention in BD, reducing the episode relapse and the oxidative damage associated with the manic phase of this disorder., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Neuropathological hallmarks of Alzheimer's disease (AD) include amyloid plaque formation, neurofibrillary tangles, neuronal and synaptic loss. This study aims to identify the neuroprotective effects of the selenium compounds on the neurotoxicity of amyloid β(1-42) in primary cultures of murine hippocampal neurons. Samples were subjected to immunocytochemistry and western blotting techniques to determine the role of treatments on neuronal viability and synaptic protein SNAP-25. We observed a reduced cell viability amyloid β-peptide (1-42)-induced. When cells were co-treated with amyloid β-peptide (1-42) and selenium compounds, we verified a strong increase in relative cell viability and in the level of synaptic marker synaptosomal-associated protein SNAP-25 induced by selenium compounds.