Fig 5 - available from: Journal of Neuroinflammation
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IL-10 reversed LH-dependent recognition and spatial memory impairments. Male mice were subjected or not (NS) to the learned helplessness paradigm and separated into 2 groups: non-learned helpless (NLH) and learned helpless (LH) mice, according to their number of failures out of 30 escapable shock trials, and the next day, learning and memory was assessed. After the cognitive assessments, mice were treated with IL-10 (5 μg/mouse) i.n. and retreated 1 h before the learning and memory assessment on the next day as shown in (a). The percentage of a mouse's total object exploration time spent exploring the familiar (F) and novel (N) objects (b) and the total time (s) mice spent engaged in exploration of both the familiar and novel objects combined (c) in the novel object recognition test were reported. Each dot represents a mouse. Two-way ANOVA F(2,74) interaction = 0.6239, F(1,74) treatment = 102.8, F(2,74) condition = 4.298 × 10 −14 , Bonferroni post hoc test, *p < 0.05, compared to % time spent with familiar object, bars represent means ± SEM, n = 11-15 mice/group. d The percentage of a mouse's total maze exploration time spent exploring the start (S), familiar (F), and novel (N) arms in the two-trial Y-maze test was measured in a different cohort of mice than b. Each dot represents a mouse. Two-way ANOVA, F(4,57) interaction = 1.501, F(2,57) treatment = 46.50, F(2,57) condition = 4.036 × 10 −11 , Fisher's least significant difference test, *p < 0.05, bars represent means ± SEM, n = 5-12 mice/group
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Background:
Major depressive disorder is a widespread mood disorder. One of the most debilitating symptoms patients often experience is cognitive impairment. Recent findings suggest that inflammation is associated with depression and impaired cognition. Pro-inflammatory cytokines are elevated in the blood of depressed patients and impair learning...
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Context 1
... studies were conducted using male adult (8-12 weeks old) C57BL/6 wild-type, GSK3α/β 21A/21A/9A/9A knock-in, and Fmr1 −/− mice. Female mice were used in Suppl Fig 5. When indicated, mice were treated intranasally (i.n.) with phosphate-buffered saline (PBS) or murine recombinant IL-10 (5 μg/mouse, Peprotech) 24 h and 1 h prior to behavioral testing. When indicated, mice received 10 μg/mouse siRNA targeting STAT3 (69367, Ambion) or scrambled siRNA control (Silencer Negative Control #5 siRNA, Ambion) 24 h prior to subjecting mice to behavioral testing and every 24 h for the subsequent 3 days until the end of the experiment. ...
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... treatment with IL-10 ( Fig. 1 f, h-j) and microglial cells contributed to the impaired learning and memory in LH mice (Fig. 3 b-d), we tested if IL-10 administration reverses cognitive impairments in LH mice. Mice were subjected or not to the learned helplessness paradigm and treated with intranasal IL-10, 24 h and 1 h before cognitive assessment (Fig. 5 a). Administration of IL-10 blocked the impairments in novel object recognition and spatial memory in LH mice, whereas IL-10 treatment did not affect novel object recognition or spatial memory of NS and NLH mice (Fig. 5 b-d, Suppl Fig 3A). IL-10 did not seem to affect learned helpless behavior per se as the percent of learned helpless ...
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... of IL-10 blocked the impairments in novel object recognition and spatial memory in LH mice, whereas IL-10 treatment did not affect novel object recognition or spatial memory of NS and NLH mice (Fig. 5 b-d, Suppl Fig 3A). IL-10 did not seem to affect learned helpless behavior per se as the percent of learned helpless mice after IL-10 treatment was similar to the one of mice after vehicle treatment (Suppl Fig 5A). ...
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... ameliorative effects of intranasal IL-10 treatment on cognitive impairments in LH mice led us to test if IL-10 treatment was also effective in other mouse models that display impaired learning and memory, the mouse model of Fragile X syndrome [Fmrp1 −/− mice [20];] and mice expressing constitutively active glycogen synthase kinase-3 (GSK3) [GSK3 knock-in mice [38];]. IL-10 treatment reversed novel object recognition impairments in both Fmrp1 −/− mice (Suppl Fig 5C-F) and GSK3 knock-in mice (Suppl Fig 5G-J). We also tested if IL-10 treatment ameliorated cognitive impairments in female wild-type mice. ...
Context 5
... ameliorative effects of intranasal IL-10 treatment on cognitive impairments in LH mice led us to test if IL-10 treatment was also effective in other mouse models that display impaired learning and memory, the mouse model of Fragile X syndrome [Fmrp1 −/− mice [20];] and mice expressing constitutively active glycogen synthase kinase-3 (GSK3) [GSK3 knock-in mice [38];]. IL-10 treatment reversed novel object recognition impairments in both Fmrp1 −/− mice (Suppl Fig 5C-F) and GSK3 knock-in mice (Suppl Fig 5G-J). We also tested if IL-10 treatment ameliorated cognitive impairments in female wild-type mice. ...
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Rheumatoid Arthritis (RA) has been associated with depression by up to 46% (1)Within the universe of manifestations of depression is learned helplessness (LH)
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This study aims to ascertain the impact of academic life satisfaction on the development of achievement motivation of school-going adolescents. The research employs a descriptive survey method within a correlational research design. Data is collected through the Deo-Mohan (1985) Achievement Motivation Scale and the Multidimensional Student’s Life S...
Citations
... Finally, our data demonstrated the antidepressant role of IL-10. Research on IL-10 knockout mice found an increase in depressive-like behaviors that were reversed with IL-10 injection [41]. In addition, the drugs for depression treatment, such as Fluoxetine and Sertraline, have displayed anti-inflammatory properties, including IL-10 up-regulation [3]. ...
The dysregulation of pro- and anti-inflammatory processes in the brain has been linked to the pathogenesis of major depressive disorder (MDD), although the precise mechanisms remain unclear. In this study, we discovered that microglial conditional knockout of Pdcd4 conferred protection against LPS-induced hyperactivation of microglia and depressive-like behavior in mice. Mechanically, microglial Pdcd4 plays a role in promoting neuroinflammatory responses triggered by LPS by inhibiting Daxx-mediated PPARγ nucleus translocation, leading to the suppression of anti-inflammatory cytokine IL-10 expression. Finally, the antidepressant effect of microglial Pdcd4 knockout under LPS-challenged conditions was abolished by intracerebroventricular injection of the IL-10 neutralizing antibody IL-10Rα. Our study elucidates the distinct involvement of microglial Pdcd4 in neuroinflammation, suggesting its potential as a therapeutic target for neuroinflammation-related depression.
... CD44 is a well-established CSC biomarker 33 that confers tumorinitiating potential, effectuates metastasis, regulates the expression of MMPs, PDL1, and more. 34 As a proof of concept, we have employed anti-inflammatory cytokines 35,36 such as IL-13 37 to demonstrate the instigation of LTP and observed an increase in stemness. Conversely, chemically-induced LTD by PMA displayed a synergistic effect with metabolic therapy and led to the transcriptional repression of stemness genes. ...
Therapy resistance and recurrence are irrefutably ascribed to the unique attributes of the cancer stem cell (CSC) population. Therefore, discerning the underlying mechanism is imperative in arbitrating a strategic therapeutic approach. In this study, we have observed the coexistence of neuron‐like cell (NLC) subpopulations in different cancer cell lines. The NLC subset was further validated by transfection studies and was found to be positive for PSD‐95. As a proof of concept, we have also demonstrated the transpiration of neurological phenomena such as long‐term potentiation (LTP) and long‐term depression (LTD) in cancer. We have utilized PMA drug and IL‐13 cytokine to study LTD and LTP, respectively, and observed a correlation between the memory marker (GLUN2B) and stemness markers (CD95 and CD58). Moreover, the transcriptional protein pCREB, which plays a crucial role in memory formation, was found to influence CD44 protein levels. These findings suggest that the instigation of LTD can impair cellular memory and sensitize CSC to the metabolic inhibitor, 3Bromopyruvate. Furthermore, this study interfaces the neurobiology of cancer and nanomedicine, wherein we have used biomimetic nanocarriers for the active targeting of drugs and demonstrate their ability to augment therapeutic efficiency.
... Major depressive disorder (MDD) is a prevalent mood disorder with increasing numbers of patients globally each year, representing a significant public health challenge and an important economic burden [1]. Although several studies investigate the molecular and circuits pathophysiology of depression, the precise pathogenic mechanisms are still unclear. ...
... This latter encompasses difficulties in concentration, decision-making, and everyday functioning [6]. Notably, cognitive impairment in MDD predominantly affects learning and executive/working memory, which have been associated with reduced hippocampal dendritic spine density [3,1]. Multiple neurobiological mechanisms contribute to cognitive dysfunction in MDD, including neuroinflammatory pathways and domain-specific deficits in learning, memory, executive function, processing speed, and attention [7]. ...
... OS primarily results from the excessive buildup of ROS, leading to a variety of cellular abnormalities, including changes in lipid and protein function, DNA damage, and ultimately cell death [9]. Stress conditions induce proinflammatory cytokines release through microglial activation and alter neuronal plasticity in the hippocampus (HP), increasing the risk of depression [1,10]. Chronic stress may induce depressive-like behaviors by dysregulation of the glutamate -GABA cycle in the HP and striatum [11]. ...
This research aimed to investigate the possible anti-amnesic effects of a combined therapy involving melatonin and H2S in a rat model displaying Depressive-Like Behaviors caused by Chronic Unpredictable Mild Stress (CUMS). Our study aims to assess the efficacy of this treatment in mitigating
oxidative stress and neuroinflammation in the striatum and hippocampus. Furthermore, we seek to investigate its ability to restore BDNF levels within this specific rat model. The rats underwent a 4-week CUMS protocol and were administered sodium hydrosulfide (a H2S donor) at a dose of 5.6 μmol/100 g/day, as well as melatonin at a dose of 1 mg/100 g/day from
the first day of the CUMS protocol. Following the CUMS exposure, the rats were assessed through various behavioral tests. Subsequently, the rats were euthanized after the behavioral tests, and blood samples were collected for corticosterone analysis. Oxidative stress (OS) markers, BDNF and TNF-α levels were analyzed in both the striatum and HP. Concurrently administering H2S and melatonin in a rat model of CUMS-induced depression demonstrates antidepressant-like effects. Furthermore, this combined treatment effectively prevents the development of learning and memory impairments associated with CUMS. Additionally, it reduces Malondialdehyde and nitric oxide levels, enhances glutathione peroxidase and superoxide dismutase activity in the striatum and HP, and mitigates CUMS-induced elevations in TNF-α levels in both brain regions.
Significantly, long-term administration of this combination reverses the chronic stress-induced reduction of hippocampal BDNF levels. These findings suggest that the synergy between H2S and melatonin holds promise in alleviating cognitive impairments.
... It is known that IL-10 reduces the adverse effects of proinflammatory cytokines on neuroplasticity by blocking the detrimental effects of lipopolysaccharides (LPS) or IL-1β and IL-6. Furthermore, this cytokine might have a direct effect on microglia activation, decreasing neuroinflammation [43]. This is in agreement with the findings about a genetic predisposition to a lower inflammatory response that increases the risk for symptoms of depression [23]. ...
Hemodialysis deteriorates patients’ physical, metabolic, and mental status. Clinical outcomes derived from inflammation determine a worse status but are less frequently identified. The objective of the study was to identify inflammatory determinants and the effect of SNP-related serum IL-6 and IL-10 levels on associated morbidity in hemodialysis. A sample of hemodialysis patients at IMSS Regional Hospital No.46 in Guadalajara (n = 85) were tested using the Malnutrition Inflammation Score (MIS) and Patient Health Questionnaire-9 (PHQ-9) to assess the associated morbidity. Serum cytokine levels were quantified by enzyme-linked immunosorbent assay (ELISA). The restriction fragment length polymorphism (RFLP) technique was used for analysis of IL-6-572C/G and IL-10-1082A/G. Using data visualization methods, we identified relevant determinants of inflammation. A simple regression model was constructed between predictors and targets with genotypes as covariates. Results showed malnutrition in 85.9% of patients and depressive symptoms in 50.6%. IL-10 was the most relevant inflammatory determinant, with regression coefficients (R2) between 0.05 and 0.11. The GG genotype of IL-10-1082 A/G evinced small effect on both clinical outcomes (δ of 0.35 and 0.37, respectively). Hemodialysis increases the associated morbidity, cytokines act as inflammatory determinants, and genetic variability contributes to the severity of clinical outcomes. Further studies need to refine the causal relationship between inflammation and CKD.
... Targeting the T lymphocyte/IL-10 resolution pathway may promote recovery from MDD [172]. Further investigations are warranted to determine the efficacy and safety of IL-10 agonists for the treatment of PSD, as a study has reported that administration of IL-10 can ameliorate depression-related impairments in mice [213]. ...
Post-stroke depression (PSD) affects approximately one-third of stroke survivors, severely impacting general recovery and quality of life. Despite extensive studies, the exact mechanisms underlying PSD remain elusive. However, emerging evidence implicates proinflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-alpha, and interleukin-18, play critical roles in PSD development. These cytokines contribute to PSD through various mechanisms, including hypothalamic–pituitary–adrenal (HPA) axis dysfunction, neurotransmitter alterations, neurotrophic factor changes, gut microbiota imbalances, and genetic predispositions. This review is aimed at exploring the role of cytokines in stroke and PSD while identifying their potential as specific therapeutic targets for managing PSD. A more profound understanding of the mechanisms regulating inflammatory cytokine expression and anti-inflammatory cytokines like interleukin-10 in PSD may facilitate the development of innovative interventions to improve outcomes for stroke survivors experiencing depression.
... In addition, there is a wealth of literature recognizing an association between chronic inflammation (i.e., excessive cytokine levels) and cognitive impairment in animals and humans (Simen et al., 2011;Yirmiya and Goshen, 2011), which has been further supported by converging findings over the past decade (Bourgognon and Cavanagh, 2020). In particular, most studies address the cognitive domains of learning (Brombacher et al., 2017;Hoseth et al., 2016), working memory (Bora, 2019;Hua et al., 2021;Ohgidani et al., 2016;Simpson et al., 2013;Trevizol et al., 2019;Worthen et al., 2020), and attention (North et al., 2021;G. Ye et al., 2018). ...
... Complementing the previous findings, anti-inflammatory cytokines (e.g., IL-4, IL-13, and IL-10) may have protective properties for cognitive functioning, as a deficiency of IL-4 and IL-13 may affect the production of brain-derived neurotrophic factor (BDNF) (Brombacher et al., 2017(Brombacher et al., , 2020. Moreover, Worthen et al. (2020) demonstrated that IL-10 administration reverses deficits in spatial working memory in a mouse model of depression. ...
Neurofilaments (NFs) are not only important for axonal integrity and nerve conduction in large myelinated axons but they are also thought to be crucial for receptor and synaptic functioning. Therefore, NFs may play a critical role in cognitive functions, as cognitive processes are known to depend on synaptic integrity and are modulated by dopaminergic signaling. Here, we present a theory-driven interdisciplinary approach that NFs may link inflammation, neurodegeneration, and cognitive functions. We base our hypothesis on a wealth of evidence suggesting a causal link between inflammation and neurodegeneration and between these two and cognitive decline (see Figure 1), also taking dopaminergic signaling into account. We conclude that NFs may not only serve as biomarkers for inflammatory, neurodegenerative, and cognitive processes but also represent a potential mechanical hinge between them, moreover, they may even have predictive power regarding future cognitive decline. In addition, we advocate the use of both NFs and MRI parameters, as their synthesis offers the opportunity to individualize medical treatment by providing a comprehensive view of underlying disease activity in neurological diseases. Since our society will become significantly older in the upcoming years and decades, maintaining cognitive functions and healthy aging will play an important role. Thanks to technological advances in recent decades, NFs could serve as a rapid, noninvasive, and relatively inexpensive early warning system to identify individuals at increased risk for cognitive decline and could facilitate the management of cognitive dysfunctions across the lifespan.
... The severity of depressive symptoms for all patients was assessed by authors SG and SM at baseline, two weeks, four weeks, and eight weeks using the HAM-D. Severity scoring was rated as mild (8)(9)(10)(11)(12)(13)(14)(15)(16) moderate (17)(18)(19)(20)(21)(22)(23), and severe (>24). Treatment adherence was assessed by obtaining a history from patients and cross-checking it with their caregivers. ...
... Still, the levels were high at baseline, as in the study by Zou et al. and Dahl et al. which showed a declining trend over time [8,17]. This is inconsistent with earlier animal and human studies which found a lack of expression of the IL-10 gene or low levels of IL-10 was associated with depression and administration of IL-10 reverses depression [5,18,19]. ...
Patients with major depressive disorder have varying response rates to treatment. Multiple factors such as non-adherence, comorbidity, chronic stressors, and biological factors may be responsible for this variation. Inflammatory (pro and anti) markers have been well studied as a cause for depression, predisposing factors, and a consequence of depression. Among these, interleukins (ILs), interferons, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) have been studied repeatedly. We conducted a pilot study to assess the levels of these inflammatory markers in patients with major depressive disorder. The specific objectives of this study were to compare and correlate changes in pro- and anti-inflammatory markers throughout different phases of depression, including pretreatment and posttreatment periods, and to evaluate the pattern of pro- and anti-inflammatory markers in patients who experienced remission or showed a positive response to treatment.
... However, several other factors may also contribute to this outcome (Bardo and Bevins, 2000;Huston et al., 2013;Tzschentke, 1998). Previous literature has indicated that IL-10 modulates both habituation and memory for previously encountered objects (Harvey et al., 2006;Worthen et al., 2020), and depression-and anxiety-like behaviors (Bluthe et al., 1999;Harvey et al., 2006;Mesquita et al., 2008;Munshi et al., 2019;Patel et al., 2021;Yang et al., 2021). The relationship between IL-10 and anxiety may be of particular relevance to the current findings. ...
... The relationship between IL-10 and anxiety may be of particular relevance to the current findings. Some studies have reported reduced IL-10 expression accompanied by increased depression and anxiety-like behavior, an effect which can be reversed by repeated injection or viral overexpression of IL-10 (Patel et al., 2021;Worthen et al., 2020;Yang et al., 2021). However, others have noted that acute injections of IL-10 induced anxiety-like behavior in non-pathological animals (Harvey et al., 2006;Munshi et al., 2019). ...
Dopamine transmission from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) regulates important aspects of motivation and is influenced by the neuroimmune system. The neuroimmune system is a complex network of leukocytes, microglia and astrocytes that detect and remove foreign threats like bacteria or viruses and communicate with each other to regulate non-immune (e.g neuronal) cell activity through cytokine signaling. Inflammation is a key regulator of motivational states, though the effects of specific cytokines on VTA circuitry and motivation are largely unknown. Therefore, electrophysiology, neurochemical, immunohistochemical and behavioral studies were performed to determine the effects of the anti-inflammatory cytokine interleukin-10 (IL-10) on mesolimbic activity, dopamine transmission and conditioned behavior. IL-10 enhanced VTA dopamine activity and NAc dopamine levels via decreased VTA GABA currents in dopamine neurons. The IL-10 receptor was localized on VTA dopamine and non-dopamine cells. The IL-10 effects on dopamine neurons required post-synaptic phosphoinositide 3-kinase activity, and IL-10 appeared to have little-to-no efficacy on presynaptic GABA terminals. Intracranial IL-10 enhanced NAc dopamine levels in vivo and produced conditioned place aversion. Together, these studies identify the IL-10R on VTA dopamine neurons as a potential regulator of motivational states.
... Depression is associated with adverse interpersonal, educational, and financial outcomes [5,6], and has a substantial societal impact [7]. In addition to psychological impairment, depression is also associated with executive function (EF) deficits [8]. Furthermore, epidemiological studies and biological mechanism-informed research has linked cognitive impairment in depression with Alzheimer's disease and dementia [9]. ...
Background
Exercise is a promising nonpharmacological intervention to improve executive function (EF). However, results from randomized trials and meta-analyses examining the effects of exercise on working memory in adults with depression are mixed, and the influence of exercise on EF, as well as the key moderators of the relationship, remain inconclusive.
Objective
The present systematic review with meta-analysis examined the influence of exercise interventions on EF in adults with depression, and the influence of key moderating variables.
Methods
Electronic searches were conducted using Embase, Cochrane Central, Scopus, Ovid MEDLINE, PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang Database, and Weipu Database up to 25 June 2022, and updated on 16 January 2023. Randomized controlled trials (RCTs) examining the effects of exercise training on EF in adults with depression were included. A three-level meta-analysis based on a random-effects model was applied in R. Study quality was assessed using the Physiotherapy Evidence Database (PEDro) scale.
Results
A total of 14 RCTs that evaluated 1201 adults with depression were included. The results indicated that exercise significantly improved global EF [g = 0.180; 95% confidence intervals (CI) = 0.038, 0.323], and the subdomains of working memory (g = 0.182; 95% CI = 0.015, 0.350), cognitive flexibility (g = 0.222; 95% CI = 0.048, 0.395), and reasoning/planning (g = 0.889; 95% CI = 0.571, 1.206). In subgroup analyses, significant improvements in EF were only observed for aerobic exercise (g = 0.203; 95% CI = 0.023, 0.382), moderate-to-vigorous intensity exercise (g = 0.200; 95% CI = 0.022, 0.379), exercise performed three or more times per week (g = 0.207; 95% CI = 0.026, 0.388), in sessions ≤ 60 min (g = 0.173; 95% CI = 0.003, 0.343), and in program durations lasting at least 13 weeks (g = 0. 248; 95% CI = 0.034, 0.462).
Conclusions
This meta-analysis demonstrates the benefits of exercise training for improving EF and the subdomains of working memory, cognitive flexibility, and reasoning/planning in adults with depression. Future randomized clinical trials are warranted to determine the therapeutic effects of exercise training on EF and cognitive symptoms in depressed patients.
... However, recent studies have provided insights into the specific mechanisms through which microglia enhance memory by regulating synaptic pruning and neuronal remodeling. This suggests that microglia play a positive role in memory formation and consolidation (Mohammadi et al., 2020;Worthen et al., 2020;Liao et al., 2021). Microglia play a vital role in regulating the quality of memory by removing the ECM, which is involved in neuronal plasticity, learning, and memory (Vainchtein et al., 2018). ...
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by protein aggregation in the brain. Recent studies have revealed the critical role of microglia in AD pathogenesis. This review provides a comprehensive summary of the current understanding of microglial involvement in AD, focusing on genetic determinants, phenotypic state, phagocytic capacity, neuroinflammatory response, and impact on synaptic plasticity and neuronal regulation. Furthermore, recent developments in drug discovery targeting microglia in AD are reviewed, highlighting potential avenues for therapeutic intervention. This review emphasizes the essential role of microglia in AD and provides insights into potential treatments.
