Brain, Behavior, and Immunity最新文献

To date, 770 million people worldwide have contracted COVID-19, with many reporting long-term "brain fog". Concerningly, young adults are both overrepresented in COVID-19 infection rates and may be especially vulnerable to prolonged cognitive impairments following infection. This calls for focused research on this population to better understand the mechanisms underlying cognitive impairment post-COVID-19. Addressing gaps in the literature, the current study investigated differences in neuropsychological performance and cerebral haemodynamic activity following COVID-19 infection in undergraduate students. 94 undergraduates (age in years: M = 20.58, SD = 3.33, range = 18 to 46; 89 % female) at the University of Otago reported their COVID-19 infection history before completing a neuropsychological battery while wearing a multichannel near-infrared spectroscopy (NIRS) device to record prefrontal haemodynamics. We observed that 40 % retrospectively self-reported cognitive impairment (brain fog) due to COVID-19 and 37 % exhibited objective evidence of cognitive impairment (assessed via computerised testing), with some suggestion that executive functioning may have been particularly affected; however, group-level analyses indicated preserved cognitive performance post COVID-19, which may in part reflect varying compensatory abilities. The NIRS data revealed novel evidence that previously infected students exhibited distinct prefrontal haemodynamic patterns during cognitive engagement, reminiscent of those observed in adults four decades older, and this appeared to be especially true if they reported experiencing brain fog due to COVID-19. These results provide new insights into the potential neuropathogenic mechanisms influencing cognitive impairment following COVID-19.

Chronic pain is a major global concern, with at least 1 in 5 people suffering from chronic pain worldwide. Mounting evidence indicates that neuroplasticity of the anterior cingulate cortex (ACC) is a critical step in the development of chronic pain. Previously, we found that chronic pain and fear learning are both associated with enhanced neuronal excitability and cause similar neuroplasticity-related gene expression changes in the ACC of male mice. However, neuroplasticity, imposes large metabolic demands. In the brain, neurons have the highest energy needs and interact with astrocytes, which extract glucose from blood, mobilize glycogen, and release lactate in response to neuronal activity. Here, we use chronic and continuous inflammatory pain models in female and male mice to investigate the involvement of astrocyte-neuronal lactate shuttling (ANLS) in the ACC of female and male mice experiencing inflammatory pain. We found that ANLS in the mouse ACC promotes the development of chronic inflammatory pain, and expresses sex specific patterns of activation. Specifically, whereas both male and female mice show similar levels of chronic pain hypersensitivity, only male mice show sustained increases in lactate levels. Accordingly, chronic pain alters the expression levels of proteins involved in lactate metabolism and shuttling in a sexually dimorphic manner. We found that disrupting astrocyte-neuronal lactate shuttling in the ACC prior to inflammatory injury prevents the development of pain hypersensitivity in female and male mice, but only reduces temporary pain in male mice. Furthermore, using a transgenic mouse model (itga1-null mice) that displays a naturally occurring form of spontaneous osteoarthritis (OA), a painful inflammatory pain condition, we found that whereas both female and male mice develop OA, only male mice show increases in mechanisms involved in astrocyte-neuronal lactate shuttling. Our findings thus indicate that there are sex differences in astrocyte-neuronal metabolic coupling in the mouse ACC during chronic pain development.

Alzheimer's disease (AD), characterized by cognitive and behavioral abnormalities, is the most prevalent neurodegenerative disease worldwide. Neuroinflammation, which is induced by microglial activation, resulting in the expression of a multitude of inflammatory factors, is one of the principal characteristics of AD. Herein, we found that Egln3 is differentially expressed in microglia in the brains of AD mice. Egln3 is a member of the Egln family of proline hydroxylases, which regulates a variety of biological processes, including transcription, the cell cycle, and apoptosis, through hydroxylation, ubiquitylation, and participation in glycolysis. To further observe the effects of Egln3 on cognitive function, we utilized APP/PS1 mice as a pathological model of AD to conduct behavioral experiments and assess the expression levels of Aβ and inflammatory factors. The specific mechanisms by which Egln3 affects microglial activation were analyzed using in vitro experiments and transcriptome sequencing. The results of these analyses demonstrated that Egln3 is highly expressed in microglia in AD. Inhibition of Egln3 expression in the brains of APP/PS1 mice improves neuroinflammatory responses and cognitive function, indicating that a high expression of Egln3 promotes AD progression. Furthermore, our findings indicate that Egln3 could activate the MAPK pathway, which in turn contributes to the aggravation of neuroinflammation. Inhibition of the MAPK pathway results in attenuation of the pro-inflammatory state of microglia. Consequently, Egln3 may exacerbate neuroinflammation and promote AD progression via the MAPK pathway in microglia, making it a promising target for AD-related therapies.

Introduction: Large social inequities have been repeatedly observed in physical disability. While inflammation has been identified as a potential underlying biological mechanism to proxy immune processes, the general inflammatory measures available in many population health studies lack specificity in capturing the complex nature of immune function. Therefore, we sought to examine whether specific biomarkers of immune function are associated with the prevalence of physical disability.

Methods: We leveraged data from 8,543 adults (mean age = 69 years, 54 % women) in the nationally-representative Health and Retirement Study and employed gender-stratified Poisson regression models to examine whether a more aged immune profile, indicated by higher values in each marker of immune aging (CD8+:CD4+, EMRA CD4+:Naïve CD4+, EMRA CD8+:Naïve CD8+, and CMV IgG), was associated with a higher prevalence of activities of daily living (ADL) disability.

Results: After adjustment, among women, one standard deviation (SD) increase in CMV IgG was associated with 12 % higher prevalence of ADL disability (PR: 1.12; 95 % CI: 1.04, 1.21). Similarly each 1-SD increase in the CD8 + CD4 + ratio was associated with a 9 % higher prevalence of ADL disability (PR: 1.09; 95 % CI: 1.03, 1.16). No associations were observed among men across any of the immune measures.

Discussion: Our findings provide initial support that biomarkers of immune aging may serve as an important mechanism in understanding physical disability, particularly among women.

Postoperative cognitive dysfunction (POCD) is common in the aged population and associated with poor clinical outcomes. Irisin, an endogenous molecule that mediates the beneficial effects of exercise, has shown neuroprotective potential in several models of neurological diseases. Here we show that preoperative serum level of irisin is reduced in dementia patients over the age of 70. Comprehensive proteomics analysis reveals that deletion of irisin affects the nervous and immune systems, and reduces the expression of complement proteins. Systemically administered irisin penetrates the blood-brain barrier in mice, targets the microglial integrin αVβ5 receptor, activates signal transducer and activator of transcription 6 (STAT6), induces microglia reprogramming to the M2 phenotype, and improves immune microenvironment in LPS-induced neuroinflammatory mice. Finally, prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction. Our findings provide new insights into the direct regulation of the immune microenvironment by irisin, and reveal that recombinant irisin holds great promise as a novel therapy for preventing POCD and other neuroinflammatory disorders. SUMMARY: Our findings reveal molecular and cellular mechanisms of irisin on neuroinflammation, and show that prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction.

In a letter critiquing our manuscript, Takefuji highlights general pitfalls in machine learning, without directly engaging with our study. The comments provide generic advice rather than a specific critique of our methods or findings. Despite raising important topics, the concerns reflect standard risks in machine learning, which we were aware of and explicitly addressed in our analyses. We applied rigorous methods, including nested cross-validation, stratified sampling, and comprehensive performance metrics, to mitigate overfitting, class imbalance, and potential biases. Traditional statistical methods, such as ANCOVA and Spearman correlations, were employed and supplemented our machine learning analysis to validate findings. Concerns about collinearity, causality, and data preprocessing were acknowledged and addressed as detailed in the manuscript and supplementary materials. Although the critique underscores critical issues in machine learning, it does not identify specific missteps in our study. We conclude that our analyses align with best practices and sufficiently address the potential pitfalls discussed in the commentary.

Background: Although depression is a leading cause of disability worldwide, the pathophysiological mechanisms underlying this disorder-particularly those involving the gut microbiome-are poorly understood.

Method: To investigate, we conducted a community-based observational study to explore complex associations between changes in the gut microbiome, cytokine levels, and depression symptoms in 52 participants (M_age = 49.56, SD = 13.31) receiving an immersive psychosocial intervention. A total of 142 multi-omics samples were collected from participants before, during, and three months after the nine-day inquiry-based stress reduction program.

Results: Results revealed that depression was associated with both an increased presence of putatively pathogenic bacteria and reduced microbial beta-diversity. Following the intervention, we observed reductions in neuroinflammatory cytokines and improvements in several mental health indicators. Interestingly, participants with a Prevotella-dominant microbiome showed milder symptoms when depressed, along with a more resilient microbiome and more favorable inflammatory cytokine profile, including reduced levels of CXCL-1.

Conclusions: These findings reveal a potentially protective link between the Prevotella-dominant microbiome and depression, as evidenced by a reduced pro-inflammatory environment and fewer depressive symptoms. These insights, coupled with observed improvements in neuroinflammatory markers and mental health from the intervention, may highlight potential avenues for microbiome-targeted therapies for managing depression.

Inflammatory biomarkers like C-reactive protein (CRP) are elevated in a subset of patients with depression and have been associated with lower functional connectivity (FC) in a ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) reward circuit and symptoms of anhedonia. Evidence linking these relationships to the effects of inflammation on dopamine is consistent with our recent findings that acute levodopa (L-DOPA) increased VS-vmPFC FC in association with deceased anhedonia in depressed patients with higher but not lower CRP (>2 versus ≤ 2 mg/L). To determine whether repeated L-DOPA administration caused sustained effects on FC and behavior in these patients, medically stable depressed outpatients with CRP > 2 mg/L and anhedonia (n = 18) received one week of three doses of L-DOPA (150-450 mg/day/week with carbidopa) or placebo in a randomized order. Resting-state (rs) and task-based (tb; monetary incentive delay) fMRI, effort-based motivation, and exploratory measures of anhedonia and depression severity were assessed at baseline and after one week of placebo and each dose of L-DOPA. Responses to individual doses of L-DOPA varied across outcomes. For example, VS-vmPFC rs-FC was significantly increased by L-DOPA at 150 and 450 mg/day/week (p < 0.01), whereby approximately half of patients responded optimally to 150 mg/day L-DOPA and approximately half required higher doses for maximum effect. While effort-based motivation was only significantly increased by L-DOPA at 150 mg/day (p < 0.05), it correlated with VS-vmPFC rs-FC at this dose (r = 0.64, p = 0.024), and all L-DOPA doses met a clinically significant threshold of ≥ 10 % increase versus placebo. When comparing the maximum response at any L-DOPA dose to placebo, high effect sizes were observed for these primary outcomes and tb-FC during reward anticipation (d_z = 0.82-0.98, p < 0.01), as well as secondary and exploratory measures of anhedonia and depression severity (d_z = 0.48-0.97, p < 0.05). Sustained effects on reward circuitry, effort-based motivation, and anhedonia by repeated L-DOPA administration support the therapeutic potential of agents that increase dopamine in depressed patients with higher inflammation.

Adolescence is a crucial period marked by profound changes in the brain. Exposure to psychological stressors such as bullying, abuse or maltreatment during this developmental period may increase the risk of developing depression, anxiety and comorbid cardiometabolic conditions. Chronic psychological stress is associated with behavioral changes and disruption of the hypothalamic-pituitary-adrenal axis, leading to corticosterone overproduction in rodents and changes in both the immune system and the gut microbiome. Here, we demonstrate the ability of Bifidobacterium longum CECT 30763 (B. longum) to ameliorate adolescent depressive and anxiety-like behaviors in a chronic social defeat (CSD) mouse model. The mechanisms underlying this beneficial effect are related to the ability of B. longum to attenuate the inflammation and immune cell changes induced by CSD after the initial stress exposure through the induction of T regulatory cells with enduring effects that may prevent and mitigate the adverse consequences of repeated stress exposure on mental and cardiometabolic health. B. longum administration also normalized dopamine release, metabolism and signaling at the end of the intervention, which may secondarily contribute to the reversal of behavioral changes. The anti-inflammatory effects of B. longum could also explain its cardioprotective effects, which were reflected in an amelioration of the oxidative stress-induced damage in the heart and improved lipid metabolism in the liver. Overall, our findings suggest that B. longum regulates the links between the immune and dopaminergic systems from the gut to the brain, potentially underpinning its beneficial psychobiotic and physiological effects in CSD.

Poor sleep quality is a major issue for many adolescents and is associated with fatigue, poor academic performance, and depression. Adolescence is a crucial neurodevelopmental stage where multiple neuropsychiatric illnesses often emerge, suggesting increased central nervous system vulnerability, specifically at this age, which could be exacerbated by poor sleep. Studies on adolescent mice show that sleep deprivation or sleep disturbance (SD) induces structural and functional brain changes, indicating that SD affects the adolescent brain. The long-term consequences of such changes are poorly understood. We hypothesize that SD during adolescence increases vulnerability to future depression triggers in adulthood, such as social isolation or inflammation. To test this, female adolescent mice (post-natal day (P)36) were subjected to SD for seven days, 4 h per day during the light phase (zeitgeber time 2-6). We demonstrate that this SD protocol acutely leads to changes in the expression of Cx3Cr1, and Dnmt3b in the hippocampus and of Htr1a in the prefrontal cortex. To examine the long-term consequences of the SD protocol during adulthood (P77-84), the mice were then either exposed to single housing or received a single injection of lipopolysaccharide (LPS) to mimic known triggers of depression. Behavioral changes were examined using digital ventilated cages to track home-cage activity and the open field and tail suspension tests to assess anxiety- and despair-like behavior, respectively. In contrast to our hypothesis, we did not observe any changes in home-cage activity, anxiety- or despair-like behavior as a result of combining SD in adolescent female mice with a depression trigger in adulthood. We conclude that the adolescent brain is sensitive to SD, but SD during adolescence in mice does not lead to an exacerbated depression-like response to social isolation or inflammation during adulthood.