Brain, Behavior, and Immunity

Exposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- duramater, arachnoid, and piamater - possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on duramater mast cell histology and expression of inflammatory markers in male and female C57Bl/6 mice. We found that mast cell number, activation level, and relative expression of pseudopodia differ across duramater regions, and that NMSEW exerts region-specific effects on mast cells in males and females. Using gene expression analyses, we next found that NMSEW increases the expression of inflammatory markers in the duramater of females but not males, and that this is prevented by pharmacological inhibition of mast cells with ketotifen. Together, our results show that ELA drives sex-specific, long-lasting effects on the duramater mast cell population and immune-related gene expression, suggesting that the long-lasting effects of ELA on disease susceptibility could be partly mediated by meningeal function.

Microglial activation is a common feature of neurological and inflammatory diseases and may contribute to some associated symptoms. However, methodological limitations have made it challenging to identify the specific symptoms and behavioral consequences of selective microglial activation. In this study, we examined the spectrum of symptoms elicited by acute chemogenetic activation of microglia in mice and compared them to those induced by endotoxin-driven systemic inflammation. Both interventions upregulated inflammatory gene expression in the brain, reduced voluntary wheel running, and decreased self-care. Systemic inflammation additionally caused anorexia, weight loss, reduced motivation to work for palatable food, and impaired motor performance in the rotarod test--effects not observed with chemogenetic microglial activation. By showing that acute microglial activation reproduces certain motivational aspects of the sickness response while sparing other functions, the findings might shed new light on the contribution of microglia to symptoms and behavioral alterations during disease.

BackgroundDepression is a leading cause of disability worldwide yet its underlying factors, particularly microbial associations, are poorly understood. MethodsWe examined the longitudinal interplay between the microbiome and immune system in the context of depression during an immersive psychosocial intervention. 142 multi-omics samples were collected from 52 well-characterized participants before, during, and three months after a nine-day inquiry-based stress reduction program. ResultsWe found 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. ConclusionsOur findings reveal a protective link between the Prevotella-dominant microbiome and depression, associated with a less inflammatory environment and moderated symptoms. These insights, coupled with observed improvements in neuroinflammatory markers and mental health from the intervention, highlight potential avenues for microbiome-targeted therapies in depression management.

There are multiple reports of elevated inflammation in patients with major depression. It is, however, unclear whether these reported perturbations in immune functions in depression affect the general functionality of the peripheral immune system. Here, using single-cell RNAsequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) extracted from blood samples collected prior to a flu vaccination administration/immunization (at baseline), we found downregulated T cell and B-cell-associated gene expression repertoire coupled with a selectively upregulated plasmablast, CD14 classical monocytes, and natural killer (NK) proliferating cell-associated gene expression in 9 depressed patients (6 females) compared to 5 healthy controls (5 females), as well as in association with depression ratings. Our cell type proportion analysis revealed shifts in immune cell populations, specifically reduced numbers of CD4+ T and CD8+ T proliferating cells, plasmablasts, and NK cells in individuals with depression compared with controls. In contrast, we found increased numbers of CD14 classical and CD16 monocytes as well as doublet cells in depressed individuals compared with controls. Although our baseline and flu vaccine challenge did not show marked differences in peripheral immune markers measured by a multiplex cytokine assay, our results suggest impaired innate and adaptive immune responses at the transcriptomic and cellular population levels in depressed patients.

Decreases in social behavior are a hallmark aspect of acute "sickness behavior" in response to infection. However, immune insults that occur during the perinatal period may have long-lasting consequences for adult social behavior by impacting the developmental organization of underlying neural circuits. Microglia, the resident immune cells of the central nervous system, are sensitive to immune stimulation and play a critical role in the developmental sculpting of neural circuits, making them likely mediators of this process. Here, we investigated the impact of a postnatal day (PND) 4 lipopolysaccharide (LPS) challenge on social behavior in adult mice. Somewhat surprisingly, neonatal LPS treatment decreased sociability in adult female, but not male mice. LPS-treated females also displayed reduced social interaction and social memory in a social discrimination task as compared to saline-treated females. Somatostatin (SST) interneurons within the anterior cingulate cortex (ACC) have recently been suggested to modulate a variety of social behaviors. Interestingly, the female-specific changes in social behavior observed here were accompanied by an increase in SST interneuron number in the ACC. Finally, these changes in social behavior and SST cell number do not appear to depend on microglial inflammatory signaling, because microglia-specific genetic knock-down of myeloid differentiation response protein 88 (MyD88; the removal of which prevents LPS from increasing proinflammatory cytokines such as TNF and IL-1{beta}) did not prevent these LPS-induced changes. This study provides novel evidence for enduring effects of neonatal immune activation on social behavior and SST interneurons in females, independent of microglial inflammatory signaling.

Background Observational studies have reported an association between inflammation and postoperative complications but it is unclear whether these associations are causal. It is also unknown whether postoperative outcomes share a causal architecture with chronic, all-cause disease. Methods We performed bi-directional two-sample Mendelian randomization to investigate potential causal effects of 19 genetically-proxied inflammatory markers on postoperative acute kidney injury, atrial fibrillation (AF), delirium, myocardial infarction, stroke and surgical site infection, and their all-cause equivalents. Genetic instruments for inflammatory markers were sourced from nine GWAS of up to 204,402 European participants with outcome data derived from UK Biobank. Results The primary postoperative analysis showed a protective effect of down-regulated IL-6 signalling on stroke risk (OR (95% CI) 0.27 (0.11--0.69), p=0.006). However, in the all-cause analysis a causal effect on stroke was not present (OR (95% CI) 1.14 (0.75--1.24), p=0.78), whilst a robust protective effect was seen for down-regulated IL-6 with AF across all three instruments studied (all p<0.009). In postoperative and all-cause analyses, genome-wide variants for CRP showed a protective effect on delirium that was not present in cis-restricted analyses. Conclusions We found evidence supporting a potential causal role for IL-6 signalling in perioperative stroke. However, the divergence in IL-6 effects between postoperative and all-cause outcomes suggests that the inflammatory architecture of acute postoperative complications may differ from chronic disease states. Furthermore, our findings suggest previously reported associations between CRP and delirium likely represent horizontal pleiotropy rather than direct causation. Future work should interrogate local tissue responses and the immediate perioperative period.

BackgroundThe human gut microbiome and its effect on brain function and mental health is emerging as an area of intensive research. Both animal and human research point towards adolescence as a sensitive period when the gut-brain axis is fine-tuned, and when we can use dietary intervention to change the microbiome, with long-lasting consequences for mental health. Here we report the results of a systematic review/meta-analysis of microbiota-targeted (psychobiotics) interventions on anxiety in youth, together with a summary of consultation work of youth with lived experience. MethodsSeven databases were searched (no date cut-offs), and controlled trials in clinical and healthy human samples (age range: 10-24) seeking to reduce anxiety were included. All data on between group-differences post intervention and outcomes were extracted as standard mean differences (SMDs) and pooled together based on a random-effects model. Findings5416 studies were identified, 14 were eligible for the qualitative summary, of which 10 were included in the meta-analyses (total of 324 experimental and 293 control subjects). The heterogeneity I2 was12% and the pooled SMD was -0.04 (95% CI: -0.21, 0.14). One study presented with low bias risk whereas 5 with high and 4 with uncertain risk, accounting for that, sensitivities analysis revealed a SMD of -0.16 (95%CI: -0.39, 0.06). InterpretationThere is currently limited evidence for use of psychobiotics to treat anxiety in youth. However, future progress will require a multidisciplinary research approach, which gives priority to specifying mechanisms in the human models, providing causal understanding and addressing the wider context.

BackgroundObservational studies have linked high adherence to the "Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay" (MIND) diet to improved cognitive functions in older adults. The underlying peripheral and central mechanisms of this association remain poorly understood, although multiple nutrients in the MIND diet are known for their anti-inflammatory effects. Therefore, we explored the cross-sectional relation between MIND diet adherence (Dutch version), systemic inflammation, neuroinflammation, and cognitive functioning in older adults. In addition, we examined the role of intestinal barrier permeability in MIND diet associations with (neuro)inflammation. MethodsWe included 88 older adults (60-75 year) at risk of cognitive decline. MIND-NL diet adherence was assessed using a food frequency questionnaire. Systemic inflammation (C-reactive protein levels, white blood cell-counts and neutrophil-to-lymphocyte ratio) and intestinal barrier permeability (lipopolysaccharide-binding protein, zonulin, and lipopolysaccharide) markers were measured in blood. Neuroinflammation-associated metabolites (myo-inositol, choline and creatine) were measured in the dorsolateral prefrontal cortex with proton magnetic resonance spectroscopy (1H-MRS). Cognitive functioning was assessed with a neuropsychological test battery. ResultsLinear models showed that both MIND diet adherence and systemic inflammation did not predict neuroinflammation or cognition independently. However, MIND diet adherence significantly moderated the relation between systemic inflammation and neuroinflammation ({beta}=-0.11, p=0.04) as well as between systemic inflammation and cognition ({beta}=0.044, p=0.02). Specifically, in individuals with lower MIND diet adherence (identified as scores [&le;]7), systemic inflammation was positively related to neuroinflammation, and negatively to cognition. Similarly, MIND diet adherence significantly moderated the relation between intestinal barrier permeability and neuroinflammation ({beta}=-0.17, p=0.05). Finally, within participants with lower MIND adherence (median split at [&le;]8.75), systemic inflammation mediated the relation between the intestinal barrier permeability and neuroinflammation ({beta}=0.427 [0.072; 0.891], p=0.04). ConclusionOur findings suggest that higher MIND diet adherence might protect against the detrimental effect of systemic inflammation on neuroinflammation and cognitive functioning. Moreover, we demonstrated that greater adherence to the MIND diet may specifically protect against the systemic inflammation-mediated relationship between intestinal barrier permeability and neuroinflammation. These findings should be confirmed in randomised controlled trials.

BackgroundSickness behavior comprises a coordinated constellation of motivational, cognitive, and social alterations that emerge during systemic inflammation. Although reductions in locomotion, feeding, and social engagement have been extensively characterized, how inflammation affects ultrasonic vocal communication--an ethologically relevant index of social motivation in rodents--remains insufficiently understood. Here, we investigated how systemic immune activation alters male-female social communication in mice by jointly assessing ultrasonic vocalizations (USVs) and approach behavior. MethodsSexually experienced male mice received an intraperitoneal injection of lipopolysaccharide (LPS), and their interactions with a novel estrous female were evaluated 24 h later by quantifying USVs and approach behavior. ResultsLPS administration robustly suppressed both the total number of USVs and the duration of male approach behavior, indicating a pronounced reduction in social motivation. Beyond this quantitative suppression, LPS also induced qualitative changes in vocal output, including shifts in the proportional use of specific USV subtypes and alterations in acoustic features such as sound pressure. ConclusionsThese findings demonstrate that USVs capture multiple dimensions of inflammation-induced disruption of social communication, reflecting not only diminished motivation to engage socially but also changes in the structure of communicative signals themselves. By revealing that systemic immune activation reshapes both social approach behavior and vocal communication patterns, this study establishes USV analysis as a sensitive and translationally relevant behavioral readout for probing neuroimmune mechanisms underlying the social and communicative disturbances characteristic of sickness behavior. More broadly, our results highlight the utility of vocal communication analyses for elucidating how inflammatory processes perturb social circuits and communicative function in health and disease.

ImportanceInsomnia has been associated with reduced immune function and increased risk of infections and sepsis in observational studies. These studies are prone to bias, such as residual confounding. To further understand the causal relation between insomnia and sepsis risk we used a two-sample Mendelian randomization (MR) approach. ObjectiveIs genetically predicted insomnia associated with risk of sepsis? DesignTwo-sample MR was performed to estimate the causal effect of genetically predicted insomnia on sepsis risk. Data was obtained from a genome-wide association study (GWAS) identifying 556 independent genetic variants (R2<0.01) strongly associated with insomnia (P < 5e-8). We conducted sensitivity analyses to address bias due to pleiotropy and sample overlap, along with mediation analyses. SettingObservational study using genetic variants as instrumental variables in large populations. ParticipantsFor insomnia, 2.4 million subjects of European ancestry from the UK Biobank and 23andMe. For sepsis, 462,918 subjects of European ancestry from the UK Biobank. ExposureGenetically predicted insomnia. Main Outcome and MeasureSepsis. ResultsA doubling in the population prevalence of genetically predicted insomnia was associated with an odds ratio of 1.42 (95% CI 1.23-1.63, P = 9.1e-7) for sepsis. Sensitivity analyses supported this observation. Three quarters of the effect was mediated through body mass index. Conclusions and RelevanceThe concordance between our findings and previous observational studies support of a causal role of genetically predicted insomnia in the risk of sepsis.

Withdrawal StatementThe authors have withdrawn this manuscript because of updates to the original manuscript. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Inflammatory pathways are implicated in depression, but the specific immune proteins and causal variants involved remain unclear. This study investigated potential causal relationships between 91 immune-related plasma proteins and depression using generalized summary Mendelian randomisation. We identified a robust association between CD40 protein levels and depression (OR: 0.95, 95% CI: 0.94 - 0.97, p = 1.71 x 10-{superscript 1}{superscript 1}), primarily driven by cis-acting variants. However, pairwise statistical colocalisation analyses of the CD40 locus indicated that CD40 protein and depression had distinct - though not independent - lead variants, suggesting the Mendelian randomisation signal was confounded by linkage disequilibrium. Analyses using expression quantitative trait locus data from the Genotype-Tissue Expression project prioritised SLC12A5, not CD40, as the most likely effector gene for depression risk at the locus. SLC12A5 encodes a potassium chloride co-transporter preferentially expressed in brain tissue, consistent with a role in depression. A phenome-wide association study showed the CD40 protein lead variant was primarily associated with inflammatory disorders, while the depression lead variant was more strongly linked to psychiatric conditions. Our results emphasise the importance of combining Mendelian randomisation with colocalisation analyses to disentangle pleiotropic effects at loci with complex genetic architecture, such as CD40/SLC12A5. While plasma CD40 protein levels are unlikely to play a causal role in depression, SLC12A5-mediated effects may contribute to its pathophysiology. These findings highlight the need for further functional and multi-omic studies to clarify immune-brain interactions and identify therapeutic targets for depression.

BackgroundAdverse life events and psychosocial stressors contribute to a range of neuropsychiatric disorders. However, the role of inflammatory dynamics around stress exposure remains unclear. Using TriNetX, a large international electronic health records database, we examined how systemic inflammatory activity and its temporal dynamics relate to subsequent risk of mental illness and somatic symptoms. MethodsWe compared 36,772 individuals with records of adverse life events and leukocytosis in the surrounding period with matched individuals with normal leukocyte counts, and performed an analogous comparison for socioeconomic and psychosocial stressors in cohorts of 87,936 individuals with leukocytosis and matched controls. To contrast dynamic with static inflammatory responses, we compared cohorts exhibiting leukocyte count changes with those maintaining persistently normal or persistently elevated leukocyte counts around stressor exposure. Outcomes, including new mental health and somatic symptom presentations, were evaluated within two years of the stressor. ResultsFollowing acute stressors, leukocytosis (compared with normal leukocyte counts) was associated with lower rates of subsequent anxiety disorders, cognitive symptoms and several somatic symptom diagnoses, with similar reductions in anxiety observed after chronic stressors. A dynamic inflammatory response was associated with the most favourable outcomes, with lower rates of anxiety, depression, functional neurological disorder, cognitive and sleep difficulties, fatigue, and multiple pain-related and other somatic symptoms than persistently low or high inflammation. ConclusionOur findings suggest that a well-regulated inflammatory response to stressors is associated with a reduced risk of diverse mental health and somatic outcomes, and that a transient immune activation may support recovery rather than confer risk.

Infection with SARS-CoV-2 can lead to long COVID, a chronic multisystemic condition estimated to affect approximately 400 million people worldwide. Although underlying mechanisms remain elusive, aberrant ongoing inflammation driven by Epstein-Barr virus (EBV) reactivation and persistent SARS-CoV-2 viral reservoirs have been hypothesized. We compared cellular and humoral immune responses to SARS-CoV-2 and EBV between participants with neuropsychiatric long COVID and recovered individuals. Peripheral blood mononuclear cells (PBMCs) and sera were collected from 27 long COVID individuals with [&ge;]2 neuropsychiatric symptoms and 27 matched recovered participants at 3-6 months post-COVID-19 symptom onset (PSO). PBMCs were assessed for IFN-{gamma}, IL-2, TNF, and granzyme B T-cell responses against SARS-CoV-2, EBV, and human cytomegalovirus (HCMV). Sera were evaluated for neutralizing activity against live ancestral SARS-CoV-2 and EBV, and EBV reactivation was assessed by early antigen-diffuse IgG. We observed no significant differences in SARS-CoV-2-, EBV-, or HCMV-specific T-cell responses or live virus neutralization between long COVID and recovered groups at 3-6 months PSO. EBV reactivation was additionally only detected in one neuropsychiatric long COVID participant. However, reduced EBV neutralizing capacity at 3-6 months significantly associated with fatigue at 12 months PSO. Anti-EBV viral capsid antigen IgG levels were also significantly diminished in long COVID participants and similarly trended lower in those reporting fatigue at 12 months PSO. We therefore detected no differences in SARS-CoV-2- or EBV-specific T-cell responses or serological neutralizing capacity between neuropsychiatric long COVID and recovered participants; however, diminished EBV-specific humoral immunity may serve as a prognostic marker for neuropsychiatric long COVID development. IMPORTANCEWe performed a comprehensive analysis of cellular and humoral immune responses to SARS-CoV-2, Epstein-Barr virus, and human cytomegalovirus in individuals with neuropsychiatric long COVID, a subgroup that remains poorly characterized. Although no differences in virus-specific T-cell immunity were observed between long COVID and recovered individuals, diminished Epstein-Barr virus neutralization at 3-6 months was associated with persistent or relapsing fatigue at 12 months post-COVID-19 symptom onset. Anti-viral capsid antigen IgG antibody levels were also significantly lower in neuropsychiatric long COVID participants at 3-6 months and similarly trended lower in those reporting fatigue at 12 months post-symptom onset. Together, these findings suggest that impaired humoral immunity to Epstein-Barr virus may contribute to the development or persistence of neuropsychiatric long COVID and highlight a promising future direction for mechanistic studies.

BackgroundPostoperative delirium (POD) is a common neurocognitive complication following major surgery, particularly in older adults and those undergoing liver resections. Neuroinflammatory mechanisms are considered central to its pathophysiology, yet molecular mediators remain poorly defined. Autoantibodies (aABs) targeting G protein-coupled receptors (GPCRs)--especially those relevant to neurotransmission--may contribute to POD by disrupting neuroimmune homeostasis. This study explored the perioperative dynamics of GPCR-specific aABs and their association with POD incidence. MethodsIn this secondary analysis of the PHYDELIO randomized controlled trial (ISRCTN18978802), we evaluated serum aAB levels targeting five GPCRs (M3R, M4R, {beta}2AR, D2R, and 5-HT2AR) in 142 patients undergoing liver surgery. Samples were collected preoperatively and on postoperative days 1, 2, and 7. POD was diagnosed using a comprehensive clinical assessment integrating validated screening tools and chart reviews. Repeated-measures ANOVAs examined time x group interactions, with additional post hoc and nonparametric tests applied as appropriate. ResultsSerum levels of four GPCR aABs (M3R, M4R, D2R, and 5-HT2AR) declined significantly following surgery and returned near baseline by day 7. {beta}2AR aAB levels remained stable. Patients who developed POD (45.8%) exhibited consistently lower aAB levels, reaching statistical significance for M3R (p = .029). No significant time x delirium interaction was found for any antibody. DiscussionMajor abdominal surgery transiently alters GPCR aAB levels, suggesting perioperative immune modulation or adsorption to tissue following disrupted barriers. Lower M3R aAB concentrations were associated with POD, aligning with proposed cholinergic involvement in its pathogenesis. While only M3R-specific effects reached significance, the consistent trend across aABs supports further investigation into their role as biomarkers or mediators of POD. Future studies should assess their functional activity and potential utility in risk stratification and therapeutic targeting.

Neuroinflammation contributes to psychiatric disorders, but preventive strategies targeting brain immune cells remain unexplored. Here we demonstrate that low-dose lipopolysaccharide (LPS) preconditioning prevents systemic inflammation-induced behavioral abnormalities through microglia-dependent mechanisms in male mice. Mice received preconditioning with 0.2 mg/kg LPS or saline for two consecutive days, followed by high-dose LPS challenge (5 mg/kg) or saline seven days later. Behavioral assessment revealed that preconditioning specifically prevented social preference deficits induced by systemic inflammation (preference score: -0.49{+/-}0.19 vs 0.14{+/-}0.10, p<0.01), while showing limited effects on locomotor activity and depression-like behaviors. Additionally, LPS preconditioning prevented anxiety-like behavior in a chronic corticosterone model and attenuated hippocampal inflammatory gene expression. Immunohistochemical analysis demonstrated that preconditioning suppressed microglial activation in hippocampal CA1 region, particularly reducing PBR/IBA1 ratio (37.5{+/-}2.4% vs 27.6{+/-}2.8%, p<0.01), with less pronounced effects in CA3. Critically, pharmacological microglial depletion using PLX3397 during the preconditioning period completely abolished these protective effects, establishing the causal role of microglia. Flow cytometric analysis revealed preconditioning-induced shifts in brain macrophage subpopulations defined by TMEM119 and CD45 expression patterns. Transcriptomic profiling identified subpopulation-specific responses, with one subset showing LPS-response pathway enrichment despite minimal gene expression changes, while another displayed extensive but functionally non-specific transcriptional alterations. These findings establish microglial preconditioning as a novel preventive strategy for neuroinflammation-induced social behavioral deficits and suggest potential therapeutic applications for psychiatric disorders involving neuroinflammatory components.

Recent studies have highlighted the crosstalk between neuroendocrine responses and the immune system but the mechanisms underlying this cooperation are still not well understood. The stress response is associated with peripheral inflammation suggesting that stress hormones including glucocorticoids and catecholamines could modulate the function of innate immune cells like neutrophils. Likewise, inflammatory mediators produced by immune cells are known to contribute to psychiatric diseases like major depressive disorder. Here we investigated the dynamic relationship between stress hormones and neutrophils and their contribution to mood disorders. We found that chronic restraint stress leads to plasma elevation of neutrophil extracellular traps (NETs) and increased NET formation in mice. Interestingly, the stress hormones, cortisol and epinephrine induce NET formation in human neutrophils ex vivo. Activation of neutrophils to form NETs leads to their increased expression of adrenergic and glucocorticoid receptors and neutrophil production of both cortisol and epinephrine indicating an autocrine/paracrine mechanism for the regulation of neutrophil inflammatory response by stress hormones. Strikingly, administration of NET components to mice induces depressive-like behavior. Moreover, activation of the glucocorticoid receptor in human volunteers leads to increase in gene expression of NET proteins. Furthermore, patients with major depressive disorder show gene upregulation of NET proteins. Our data highlights the bi-directional relationship between neuroendocrine processes and neutrophils that contribute to stress-induced increase in inflammation and the role of neutrophil inflammatory responses in propagation of behavioral changes following stress.

BackgroundFatigue and depressive mood is inherent to acute disease, but a substantial group of people report persisting disabling fatigue and depressive symptoms long after a COVID infection. Acute infections have shown to change decisions to engage in effortful and rewarding activities, but it is currently unclear whether fatigue and depressive symptoms similarly affect decision making during acute and persistent phases of a COVID infection. Here, we investigated whether fatigue and depressive mood are associated with altered weighting of effort and reward in decision-making during different timepoints after COVID infection. MethodsWe conducted an online cross-sectional study between March 2021 and March 2022. 242 Participants (18-65 years) with COVID <4 weeks ago (n=62), COVID >12 weeks ago (n=81), or no prior COVID (self-reported) (n=90) performed an effort-based decision-making task, in which they decided whether they wanted to exert physical effort (ticking boxes on screen, 5 levels) for reward (money to be gained in a voucher-lottery, 5 levels). State fatigue and depressive mood was measured by the Profile of Mood States (POMS) prior to the task. We used multilevel binomial regression analysis to test whether fatigue and depressive mood were related to acceptance rates for effort and reward levels and whether this differed between the groups. ResultsCompared with no COVID and COVID <4 weeks groups, the COVID >12 weeks group reported higher state fatigue scores (mean{+/-}SD: 20{+/-}7 vs. 14{+/-}7 and 12{+/-}6 POMS-score, respectively; both p<0.001) and was less sensitive to rewards (Reward*Group: OR: 0.35 (95%CI 0.20, 0.62), p<0.001 and OR: 0.38 (95%CI 0.20, 0.72), p=0.003). In the COVID >12 weeks group, fatigue was more negatively associated with reward sensitivity compared with the COVID <4 weeks group (Reward*Fatigue*Group: OR 0.47 (95%CI 0.25, 1.13), p=0.022) and the no COVID group (Reward*Fatigue*Group: OR 0.48 (95%CI 4.01, 0.92), p=0.029). No group differences were observed for the relationship between fatigue and effort sensitivity. No group differences were observed for the relationship between depressive mood and effort or reward sensitivity. Higher age, lower BMI, unhealthy lifestyle, and worrying during the acute phase of COVID each predicted decreased reward sensitivity in the >12 weeks group (Age*Reward: OR 0.30 (95%CI 0.19, 0.48), p<0.001; BMI*Reward: OR 1.43 (95%CI 1.01, 2.00), p=0.047); Lifestyle*Reward: OR 1.50 (95%CI 1.06, 2.14), p=0.022; Worrying*Reward: OR 0.59 (95%CI 0.38, 0.94), p=0.025, respectively). ConclusionThe finding that fatigue is related to lower reward sensitivity >12 weeks after COVID, suggesting potential reward deficits in post-covid fatigue. These findings are in line with previous observations that long-term inflammation can induce dysregulations in neural reward processing, which should be further investigated in future studies. HighlightsO_LIWe tested if fatigue and mood were related to altered decision making post-COVID C_LIO_LIParticipants post-COVID >12wks ago were more fatigued and less reward sensitive C_LIO_LIPost-COVID-related fatigue was associated with reduced reward sensitivity C_LIO_LIPost-COVID-related depressive mood was not associated with altered decision making C_LIO_LIHigher age, unhealthy lifestyle, and worrying predicted reward deficits C_LI

Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, is unknown. Here, we determined the effects of ELS induced by limited bedding and nesting material during the first week of life (postnatal days [P]2 - 9) on microglial i) morphology; ii) hippocampal gene expression; and iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice. The hippocampus of ELS-exposed adult mice displayed altered proportions of morphological subtypes of microglia, as well as microglial transcriptomic changes related to the tumor necrosis factor response and protein ubiquitination. ELS exposure leads to distinct gene expression profiles during microglial development from P9 to P200 and in response to an LPS challenge at P200. Functionally, synaptosomes from ELS-exposed mice were phagocytosed less by age-matched microglia. At P200, but not P9, ELS microglia showed reduced synaptosome phagocytic capacity when compared to CTRL microglia. Lastly, we confirmed the ELS-induced increased expression of the phagocytosis-related gene GAS6 that we observed in mice, in the dentate gyrus of individuals with a history of child abuse using in situ hybridization. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.

Surgical patients over 70 experience postoperative delirium (POD) complications in up to 50% of procedures. Sleep/circadian disruption has emerged as a potential risk factor for POD in epidemiological studies. However, the relationship remains unclear in a clinical setting. This protocol presents a single-site, prospective, noninvasive observational study designed to examine the relationship between sleep/circadian regulation and POD and how this association is influenced by AD pathology and genetic risk for AD. This novel approach for understanding modifiable risk factors of POD and cognitive decline after surgery could assist with establishing treatments and preventative measures for POD in the future.