Pre- and Post-Synaptic protein in the major depressive Disorder: From neurobiology to therapeutic targets.

Major depressive disorder (MDD) has demonstrated its negative impact on various aspects of the lives of those affected. Although several therapies have been developed over the years, it remains a challenge for mental health professionals. Thus, understanding the pathophysiology of MDD is necessary to improve existing treatment options or seek new therapeutic alternatives. Clinical and preclinical studies in animal models of depression have shown the involvement of synaptic plasticity in both the development of MDD and the response to available drugs. However, synaptic plasticity involves a cascade of events, including the action of presynaptic proteins such as synaptophysin and synapsins and postsynaptic proteins such as postsynaptic density-95 (PSD-95). Additionally, several factors can negatively impact the process of spinogenesis/neurogenesis, which are related to many outcomes, including MDD. Thus, this narrative review aims to deepen the understanding of the involvement of synaptic formations and their components in the pathophysiology and treatment of MDD.

Peripheral biomarkers as a predictor of poor prognosis in severe cases of COVID-19.

We evaluated glycemia and triglyceride, hepatic, muscular, and renal damage markers, redox profile, and leptin and ghrelin hormone levels in COVID-19 patients. We also conducted statistical analysis to verify the potential of biomarkers to predict poor prognosis and the correlation between them in severe cases. We assessed glycemia and the levels of triglycerides, hepatic, muscular, and renal markers in automatized biochemical analyzer. The leptin and ghrelin hormones were assessed by the ELISA assay. Severe cases presented high glycemia and triglyceride levels. Hepatic, muscular, and renal biomarkers were altered in severe patients. Oxidative stress status was found in severe COVID-19 patients. Severe cases also had increased levels of leptin. The ROC curves indicated many biomarkers as poor prognosis predictors in severe cases. The Spearman analysis showed that biomarkers correlate between themselves. Patients with COVID-19 showed significant dysregulation in the levels of several peripheral biomarkers. We bring to light that a robust panel of peripheral biomarkers and hormones predict poor prognosis in severe cases of COVID-19 and biomarkers correlate with each other. Early monitoring of these biomarkers may lead to appropriate clinical interventions in patients infected by SARS-CoV2.

COVID-19, Anxiety, and Body Mass Index Increase Leptin Levels: a Cross-sectional Multicentric Study.

Although many efforts have been made to understand the pathophysiological mechanisms of COVID-19, critical gaps remain to be explored. This study aimed to investigate potential alterations in adipokine levels (specifically adiponectin, leptin, and resistin) among individuals with COVID-19. Within this population, we further assessed the association between these markers with both, body mass index (BMI) and psychiatric symptoms. This cross-sectional study included an age- and sex-matched sample of adults with COVID-19 (cases) and without COVID-19 (controls). We evaluated the severity of psychiatric symptoms, BMI, and adipokines. Individuals with COVID-19 presented greater BMI, stress levels, and leptin levels when compared to controls. Leptin levels were greater in individuals with moderate/severe COVID-19 as compared to individuals with COVID-19 who were asymptomatic or having mild symptoms. Leptin levels were positively correlated with BMI, severity of depressive and anxiety symptoms, and stress levels in the total sample. Leptin levels were also positively correlated with BMI, severity of anxiety symptoms, and stress levels in controls. In cases, there was a positive correlation between adiponectin and the severity of depressive symptoms and stress levels and leptin/resistin with BMI. A linear regression model revealed that BMI, severity of anxiety symptoms, and the diagnosis of COVID-19 are independently associated with increased leptin levels. Thus, leptin levels seem to be impacted by the COVID-19 infection, anxiety, and BMI.

Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities.

Notwithstanding advances in understanding the pathophysiology of major depressive disorder (MDD), no single mechanism can explain all facets of this disorder. An expanding body of evidence indicates a putative role for the inflammatory response. Several meta-analyses showed an increase in systemic peripheral inflammatory markers in individuals with MDD. Numerous conditions and circumstances in the modern world may promote chronic systemic inflammation through mechanisms, including alterations in the gut microbiota. Peripheral cytokines may reach the brain and contribute to neuroinflammation through cellular, humoral, and neural pathways. On the other hand, antidepressant drugs may decrease peripheral levels of inflammatory markers. Anti-inflammatory drugs and nutritional strategies that reduce inflammation also could improve depressive symptoms. The present study provides a critical review of recent advances in the role of inflammation in the pathophysiology of MDD. Furthermore, this review discusses the role of glial cells and the main drivers of changes associated with neuroinflammation. Finally, we highlight possible novel neurotherapeutic targets for MDD that could exert antidepressant effects by modulating inflammation.

Circadian Rhythms and Sleep Disorders Associated to Major Depressive Disorder: Pathophysiology and Therapeutic Opportunities.

Major depressive disorder (MDD) is a complex mood disorder. While much progress has been made in understanding the pathophysiology of MDD, no single mechanism can explain all facets of this disorder. Several studies show that disturbances in biological rhythms can lead to the development of MDD. Indeed, insomnia or hypersomnia are symptoms included in the MDD diagnostic criteria. Clinical studies and meta-analyses showed a strong relationship between MDD and sleep disorders. Sleep disorder and MDD are associated with activation in the hypothalamicpituitary-adrenal (HPA) axis and inflammation. The increase in inflammatory response can activate the kynurenine pathway, decrease serotonin synthesis, and affect other factors involved in the pathophysiology of neuropsychiatric conditions. Moreover, sleep disorders and MDD can change the gut microbiota and alter the microbiota-gut-brain axis. Thus, this review discusses the relationship between MDD, circadian rhythms, and sleep disorders, describing the potential pathophysiological mechanism shared in these conditions. In addition, therapeutic opportunities based on antiinflammatory, antioxidant, HPA axis regulatory, and synapse-modulating actions are raised. For the article search, we used the PubMed database. Both sleep disorders and changes in biological rhythms have a bidirectional relationship with MDD. Although some pathophysiological mechanisms, including inflammation, changes in the gut microbiota, and decreased neuroplasticity, may be involved in the relationship between sleep, circadian rhythms, and MDD, other mechanisms are not yet well understood. Therapeutic opportunities based on anti-inflammatory, antioxidant, HPA regulatory axis, and synapse modulating actions appear to be promising targets in preventing MDD, circadian rhythm disturbances, and sleep disorders.

ABO Blood Type and Metabolic Markers in COVID-19 Susceptibility and Severity: A Cross-Sectional Study.

Background and Aims: To evaluate the effect of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus on the function and metabolic changes, as well as the relationship of the virus with blood groups. Methods and Results: This cross-sectional study included a matched sample of adult individuals with coronavirus disease 2019 (COVID-19) (n = 114) or without (controls; n = 236). Blood samples were collected and processed for triglycerides (TGs), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, and blood typing analysis. The results showed that subjects with COVID-19 had higher TG and lower HDL-C levels compared with the control group. As for blood typing, the risk of COVID-19 was higher in subjects with blood group A than in those with blood group B and in those with other blood groups. In addition, an association of COVID-19 with blood type and Rh A- was observed. When related to the severity of COVID-19 symptoms, blood type A was more protective against moderate/severe symptoms compared with blood type O. In addition, individuals with blood type O were 2.90 times more likely to have symptoms moderate/severe symptoms of COVID-19 than those with other blood groups and individuals with type A blood were less likely to have severe/moderate symptoms of COVID-19 compared with individuals without type A blood. Conclusion: The results suggest that blood type may play a role in susceptibility to SARS-CoV-2 infection and add evidence that infection with the novel coronavirus may be associated with changes in lipid metabolism.

Energy metabolism and behavioral parameters in female mice subjected to obesity and offspring deprivation stress.

This study aimed to evaluate the behavioral and energy metabolism parameters in female mice subjected to obesity and offspring deprivation (OD) stress. Eighty female Swiss mice, 40 days old, were weighed and divided into two groups: Control group (control diet, n = 40) and Obese group (high-fat diet, n = 40), for induction of the animal model of obesity, the protocol was based on the consumption of a high-fat diet and lasted 8 weeks. Subsequently, the females were subjected to pregnancy, after the birth of the offspring, were divided again into the following groups (n = 20): Control non-deprived (ND), Control + OD, Obese ND, and Obese + OD, for induction of the stress protocol by OD. After the offspring were 21 days old, weaning was performed and the dams were subjected to behavioral tests. The animals were humanely sacrificed, the brain was removed, and brain structures were isolated to assess energy metabolism. Both obesity and OD led to anhedonia in the dams. It was shown that the structures most affected by obesity and OD are the hypothalamus and hippocampus, as evidenced by the mitochondrial dysfunction found in these structures. When analyzing the groups separately, it was observed that OD led to more pronounced mitochondrial damage; however, the association of obesity with OD, as well as obesity alone, also generated damage. Thus, it is concluded that obesity and OD lead to anhedonia in animals and to mitochondrial dysfunction in the hypothalamus and hippocampus, which may lead to losses in feeding control and cognition of the dams.

Stress levels, psychological symptoms, and C-reactive protein levels in COVID-19: A cross-sectional study.

BACKGROUND: Although many studies have pointed out a possible relationship between COVID-19 and the presence of psychiatric disorders, the majority of the studies have significant limitations. This study investigates the influence of COVID-19 infection on mental health. METHODS: This cross-sectional study included an age- and sex-matched sample of adult individuals positive (cases) or negative (controls) for COVID-19. We evaluated the presence of psychiatric conditions and C-reactive protein (CRP). RESULTS: Findings showed greater severity of depressive symptoms, higher levels of stress, and greater CRP in cases. The severity of depressive and insomnia symptoms, as well as the CRP were more remarkable in individuals with moderate/severe COVID-19. We found a positive correlation between stress and severity of anxiety, depression, and insomnia in individuals with or without COVID-19. There was a positive correlation between CRP levels and severity of depressive symptoms in cases and controls, and a positive correlation between CRP levels and the severity of anxiety symptoms and stress levels only in individuals with COVID-19. Individuals with COVID-19 and depression had greater CRP than those with COVID-19 without current major depressive disorder. LIMITATIONS: We cannot infer causality because this is a cross-sectional study, and the majority of COVID-19 sample was asymptomatic or had mild symptoms, which may limit the generalizability of our findings for moderate/severe cases. CONCLUSIONS: Individuals with COVID-19 showed greater severity of psychological symptoms, which may impact on the development of psychiatric disorders in the future. CPR seem to be a promising biomarker for earlier detection of post-COVID depression.

Environmental Enrichment Rescues Oxidative Stress and Behavioral Impairments Induced by Maternal Care Deprivation: Sex- and Developmental-Dependent Differences.

Stress is related to major depressive disorder (MDD). This study investigated the action that early stress, represented by maternal deprivation (MD), has on the behavior and oxidative stress of Wistar female and male rats. Also, it was evaluated whether changes induced by MD could be reversed by environmental enrichment (EE). Male and female rats were divided into a non-MD and MD group. The MD group was subdivided into 3 groups: (1) assessed on the 31st day after exposure to EE for 10 days, (2) assessed on the 41st day after exposure to EE for 20 days, and (3) assessed on the 61st day after exposure to EE for 40 days. Behavioral tests were performed (memory habituation and elevated plus maze). Oxidative stress parameters were evaluated peripherally. MD was able to promote anxiety-like behavior at postnatal day (PND) 41 and impair memory at PND 31 and PND 61 in male and PND 41 and PND 61 in female rats. MD was associated with increased oxidative stress parameters (reactive species to thiobarbituric acid levels (TBARS), carbonylated proteins, nitrite/nitrate concentration), and altered antioxidant defenses (superoxide dismutase (SOD) and catalase (CAT), and sulfhydryl content) in different stages of development. The EE was able to reverse almost all behavioral and biochemical changes induced by MD; however, EE effects were sex and developmental period dependent. These findings reinforce the understanding of the gender variable as a biological factor in MDD related to MD and EE could be considered a treatment option for MDD treatment and its comorbidities.

Natural Phytochemicals for the Treatment of Major Depressive Disorder: A Mini-Review of Pre- and Clinical Studies.

Major Depressive Disorder (MDD) is a common mental illness that causes significant disability and declining quality of life. An overlap of multiple factors can be involved in the pathophysiology of this mood disorder, including increased inflammation and oxidative stress, change in neurotransmitters, decreased brain-derived neurotrophic factor (BDNF), activation of the hypothalamicpituitary- adrenal (HPA) axis, and changes in the microbiota-gut-brain axis. Although the classic treatment for MDD is safe, it is far from ideal, with delay to start the best clinic, side effects, and a large number of non-responses or partial-responses. Therefore, other alternatives are being studied to improve depressive symptoms, and, among them, the role of phytochemicals in food stands out. This mini-review will discuss the main phytochemicals present in foods with clinical and preclinical studies showing benefits for MDD treatment. In addition, the main mechanisms of action that are being proposed for each of these compounds will be addressed.

Beneficial effects and neurobiological aspects of environmental enrichment associated to major depressive disorder and autism spectrum disorder.

A suitable enriched environment favors development but can also influence behavior and neuronal circuits throughout development. Studies have shown that environmental enrichment (EE) can be used as an essential tool or combined with conventional treatments to improve psychiatric and neurological symptoms, including major depressive disorder (MDD) and autism spectrum disorder (ASD). Both disorders affect a significant percentage of the wofrld's population and have complex pathophysiology. Moreover, the available treatments for MDD and ASD are still inadequate for many affected individuals. Experimental models demonstrate that EE has significant positive effects on behavioral modulation. In addition, EE has effects on neurobiology, including improvement in synaptic connections and neuroplasticity, modulation of neurotransmissions, a decrease in inflammation and oxidative stress, and other neurobiology effects that can be involved in the pathophysiology of MDD and ASD. Thus, this review aims to describe the leading behavioral and neurobiological effects associated with EE in MDD and ASD.

Sex differences on the response to antidepressants and psychobiotics following early life stress in rats.

Major depressive disorder (MDD) is the most prevalent mood disorder globally. Most antidepressants available for the treatment of MDD increase the concentration of monoamines in the synaptic cleft. However, such drugs have a high latency time to obtain benefits. Thus, new antidepressants with fast action and robust efficacy are very important. This study evaluated the effects of escitalopram, ketamine, and probiotic Bifidobacterium infantis in rats submitted to the maternal deprivation (MD). MD rats received saline, escitalopram, ketamine, or probiotic for 10, 30, or 50 days, depending on the postnatal day (PND):21, 41, and 61. Following behavior, this study examined the integrity of the blood-brain barrier (BBB) and oxidative stress markers. MD induced depressive-like behavior in females with PND21 and males with PND61. All treatments reversed depressive-like behavior in females and escitalopram and ketamine in males. MD induced an increase in the permeability of the BBB, an imbalance between oxidative stress and antioxidant defenses. Treatments regulated the oxidative damage and the integrity of the BBB induced by MD. The treatment with escitalopram, ketamine, or probiotics may prevent behavioral and neurochemical changes associated with MDD, depending on the developmental period and gender.

Coadministration of tianeptine alters behavioral parameters and levels of neurotrophins in a chronic model of Maple Syrup Urine disease.

Maple Syrup Urine Disease (MSUD) is caused by the deficiency in the activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), resulting in the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, and their respective branched-chain α-keto acids. Patients with MSUD are at high risk of developing chronic neuropsychiatric disorders; however, the pathophysiology of brain damage in these patients remains unclear. We hypothesize that MSUD can cause depressive symptoms in patients. To test our hypothesis, Wistar rats were submitted to the BCAA and tianeptine (antidepressant) administration for 21 days, starting seven days postnatal. Depression-like symptoms were assessed by testing for anhedonia and forced swimming after treatments. After the last test, the brain structures were dissected for the evaluation of neutrophins. We demonstrate that chronic BCAA administration induced depressive-like behavior, increased BDNF levels, and decreased NGF levels, suggesting a relationship between BCAA toxicity and brain damage, as observed in patients with MSUD. However, the administration of tianeptine was effective in preventing behavioral changes and restoring neurotrophins levels.

Combination of electroconvulsive stimulation with ketamine or escitalopram protects the brain against inflammation and oxidative stress induced by maternal deprivation and is critical for associated behaviors in male and female rats.

This study aimed at evaluating the treatment effects with ketamine, electroconvulsive stimulation (ECS), escitalopram, alone or in combination in adult rats of both sexes, subjected to the animal model of maternal deprivation (MD). All groups were subjected to the forced swimming test (FST), splash and open field tests. The prefrontal cortex (PFC), hippocampus and serum were collected to analyze oxidative stress and inflammatory parameters. MD induced depressive-like behavior in the FST test in males and reduced grooming time in male and female rats. The treatments alone or combined reversed depressive and anhedonic behavior in females. In males, all treatments increased grooming time, except for ECS + escitalopram + ketamine. MD increased lipid peroxidation and protein carbonylation, nitrite/nitrate concentration and myeloperoxidase activity in the PFC and hippocampus of males and females. However, the treatment's response was sex dependent. Catalase activity decreased in the PFC of males and the PFC and hippocampus of females, and most treatments were not able to reverse it. MD increased the inflammation biomarkers levels in the PFC and hippocampus of males and females, and most treatments were able to reverse this increase. In all groups, a reduction in the interleukin-10 levels in the PFC and hippocampus of female and male rats was observed. Our study shows different responses between the sexes in the patterns evaluated and reinforces the use of the gender variable as a biological factor in MDD related to early stress and in the response of the therapeutic strategies used.

The contribution of gut-brain axis to development of neurological symptoms in COVID-19 recovered patients: A hypothesis and review of literature.

The gut microbiota undergoes significant alterations in response to viral infections, particularly the novel SARS-CoV-2. As impaired gut microbiota can trigger numerous neurological disorders, we suggest that the long-term neurological symptoms of COVID-19 may be related to intestinal microbiota disorders in these patients. Thus, we have gathered available information on how the virus can affect the microbiota of gastrointestinal systems, both in the acute and the recovery phase of the disease, and described several mechanisms through which this gut dysbiosis can lead to long-term neurological disorders, such as Guillain-Barre syndrome, chronic fatigue, psychiatric disorders such as depression and anxiety, and even neurodegenerative diseases such as Alzheimer's and Parkinson's disease. These mechanisms may be mediated by inflammatory cytokines, as well as certain chemicals such as gastrointestinal hormones (e.g., CCK), neurotransmitters (e.g., 5-HT), etc. (e.g., short-chain fatty acids), and the autonomic nervous system. In addition to the direct influences of the virus, repurposed medications used for COVID-19 patients can also play a role in gut dysbiosis. In conclusion, although there are many dark spots in our current knowledge of the mechanism of COVID-19-related gut-brain axis disturbance, based on available evidence, we can hypothesize that these two phenomena are more than just a coincidence and highly recommend large-scale epidemiologic studies in the future.

Microbiota-Gut-Brain Communication in the SARS-CoV-2 Infection.

The coronavirus disease of 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome 2 (SARS-CoV-2). In addition to pneumonia, individuals affected by the disease have neurological symptoms. Indeed, SARS-CoV-2 has a neuroinvasive capacity. It is known that the infection caused by SARS-CoV-2 leads to a cytokine storm. An exacerbated inflammatory state can lead to the blood-brain barrier (BBB) damage as well as to intestinal dysbiosis. These changes, in turn, are associated with microglial activation and reactivity of astrocytes that can promote the degeneration of neurons and be associated with the development of psychiatric disorders and neurodegenerative diseases. Studies also have been shown that SARS-CoV-2 alters the composition and functional activity of the gut microbiota. The microbiota-gut-brain axis provides a bidirectional homeostatic communication pathway. Thus, this review focuses on studies that show the relationship between inflammation and the gut microbiota-brain axis in SARS-CoV-2 infection.

Sex differences on the behavior and oxidative stress after ketamine treatment in adult rats subjected to early life stress.

This study aimed to evaluate the effects of ketamine, on behavioral parameters, oxidative stress, and inflammation in the brain of male and female rats submitted to the animal model of maternal deprivation (MD). Wistar rats were deprived of maternal care in the first 10 days of life (three hours daily). As adults, male and female rats were divided: control + saline deprived + saline and deprived + ketamine (15 mg/kg). The behavior was evaluated through the open field and forced swimming tests. Then brain was removed for analysis of oxidative damage, the activity of superoxide dismutase (SOD), catalase (CAT), and myeloperoxidase (MPO) activity, and levels of interleukin-6 (IL-6). MD induced depressive behavior in males and ketamine reversed these changes. MD induced an increase in lipid peroxidation in males and females; ketamine reversed these effects in males. Protein carbonylation was increased in males and females, with ketamine decreasing such effects. The concentration of nitrite/nitrate increased in males and females, whereas ketamine decreased this in the PFC of males. SOD and CAT activities were decreased in male and female deprived groups and deprived groups treated with ketamine. MPO activity and IL-6 levels increased in males subjected to MD and ketamine reversed this effect. The results suggest that stressful events in early life can induce behavioral, neuroimmune changes, and oxidative stress, however, such effects depend on sex and brain area. Ketamine presents anti-inflammatory and antioxidant properties and could be considered an alternative for individuals who are resistant to classical treatments.

Sex-related patterns of the gut-microbiota-brain axis in the neuropsychiatric conditions.

Sex differences are often observed in psychiatric patients, especially major depressive disorders (MDD), schizophrenia, and developmental disorders, including autism spectrum disorders (ASDs). The prevalence rates between males and females seem variate according to the clinical condition. Although the findings are still incipient, it is suggested that these differences can involve neuroanatomical, neurochemical, and physiological sex differences. In this context, the microbiota-gut-brain axis hypothesis arises to explain some aspects of the complex pathophysiology of neuropsychiatric disorders. The microbiota composition is host-specific and can change conforming to age, sex, diet, medication, exercise, and others. The communication between the brain and the gut is bidirectional and may impact the entire system homeostasis. Many pathways appear to be involved, including neuroanatomic communication, neuroendocrine pathways, immune system, bacteria-derived metabolites, hormones, neurotransmitters, and neurotrophic factors. Although the clinical and preclinical studies are sparse and not very consistent, they suggest that sex differences in the gut microbiota may play an essential role in some neuropsychiatric conditions. Thus, this narrative review has as a mainly aim to show the points sex-related patterns associated to the gut-microbiota-brain axis in the MDD, ASDs, and schizophrenia.

Environmental enrichment improves lifelong persistent behavioral and epigenetic changes induced by early-life stress.

This study aimed to evaluate the effects of environmental enrichment (EE) in Wistar rats subjected to maternal deprivation (MD). MD was performed in the first post-natal days (PND) ten for 3 h/day. The groups were: control; deprived without EE; and deprived with EE. The EE was applied for 3 h/day. Forced swimming test (FST) and open field test were performed, and histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities in the prefrontal cortex (PFC) and hippocampus were evaluated on 31, 41, and 61 PND. MD altered spontaneous locomotor activity and immobility time in FST, but the effects were sex- and developmental period dependent. In deprived females at PND 31, 41, and 61, HDAC and DNMT increased in the PFC and hippocampus. In females exposed to EE for 20 days, there was a decrease of HDAC in the hippocampus and DNMT in the PFC and hippocampus. Exposure of females to EE for 40 days can reverse HDAC and DNMT increase in all brain areas. In deprived males at PND 31, 41, and 61, HDAC and DNMT increased in the hippocampus, and in the group exposed to EE for 40 days, there was a decrease in hippocampal activity. In PFC of male deprived rats at PND 61 and EE for 40 days, there was a reduction of HDAC and DNMT. MD induced lifelong persistent behavioral and epigenetic changes, and such effects were more evident in female than male rats. EE can be considered an essential non-pharmacological strategy to treat long-term trauma-induced early life changes.

The impact of early life stress and immune challenge on behavior and glia cells alteration in late adolescent rats.

Maternal deprivation (MD) is known to be related to long-term changes that could influence the onset of psychiatric disorders. Studies have demonstrated that early life stress makes the cells in the brain more susceptible to subsequent stressors. To test it, we used an animal model of MD conducted from postnatal day (PND) 1 to 10. Deprived and non-deprived rats (control) were randomized to receive or not lipopolysaccharide (LPS) at 5 mg/kg on PND 50. The behavior and glial cells activation were evaluated in all groups from 51 to 53 PND. There was an increase in the immobility time in the MD and MD+LPS groups. The spontaneous locomotor activity was not changed between groups. We found elevated ionized calcium-binding adapter molecule 1 (Iba-1)-positive cells levels in the control+LPS and MD+LPS groups. In the MD+LPS group, it was found an increase in Iba-positive cells compared to the MD+sal group. The glial fibrillary acidic protein (GFAP)-positive cells were also increased in the MD+LPS, compared to control+sal, control+LPS, and MD+sal groups. Immune challenge by LPS in late adolescence, which was subjected to MD, did not influence the depressive-like behavior but exerted a pronounced effect in the microglial activation and astrocyte atrophy.