Brain, Behavior, & Immunity - Health

Background: Early-life adversity (ELA) is one of the strongest predictors of poor mental and physical health later in life, increasing an individual's risk for disorders ranging from depression to metabolic syndrome. However, whether and how ELA shapes immune memory through adulthood, subsequently affecting susceptibility to immune-associated diseases such as autoimmunity, remains elusive. Methods: To address this question, we employed a translationally and ethologically relevant mouse model of resource deprivation, the limited bedding and nesting model, to study the long-term effects of ELA on the immune system. ELA was induced by limited bedding and nesting material in the cage during postnatal days (P)2-9, which provokes fragmented and unpredictable maternal behavior in the dams, and results in chronic stress in the pups. Nucleic acid Linked ImmunoSandwich Assay (NULISA) was used to survey the proteome of adult (~P90) mice of both sexes that experienced ELA vs. control conditions. Results: Using a novel proteomic method, we detected significant upregulation in the levels of IL-17A in the adult blood, primarily in females. Within females, ELA also upregulated IL-13 and CCL3. Three proteins, HGF, PDGFA, and WNT16, were significantly downregulated in ELA mice of both sexes. Conclusions: Being a hallmark proinflammatory cytokine, IL-17A is found to increase in patients with systemic lupus erythematosus (SLE), as well as in animals with lupus-like diseases in virtually all reports. Importantly, autoimmune diseases like SLE have a higher prevalence in women than men, and our data support this sex bias. Together, our data suggest that ELA shapes long-term immune function in a way that may increase risk for autoimmune diseases, with promise for the development of more targeted and personalized therapies for autoimmunity.

Stressors experienced during the postnatal period may increase vulnerability to mental health disorders, including postpartum depression and anxiety. In rodents, maternal separation (MS) has been shown to alter behaviours in dams, but these observations have been made almost exclusively in rats and thus robust mouse models of postpartum mental health disorders using this stressor remain limited. Here we first examined, in mice, the effects of MS on maternal caregiving and on anxiety- and depressive-like behaviours. As stress-induced inflammatory activation in the gut-brain axis has been associated with behavioural alterations in non-postpartum contexts, changes in pro-inflammatory cytokines and tight junction proteins in the brain and intestinal tract were also examined. Female C57BL/6N mice were assigned to a No Separation (NS) or a MS condition that consisted of 3-hour daily separation sessions from postnatal days (P) 2 to 14. Maternal care behaviours were assessed on P3 and P7, followed by anxiety- and depressive-like behaviours on P22 and P23, and the collection of the medial prefrontal cortex (mPFC) and colon on P24 to determine the expression of selected genes. Caregiving patterns in MS dams fluctuated throughout the early postnatal period. Although behaviours and gene expression outcomes remained unchanged by MS, grooming time in the splash test was correlated with the expression of different genes in the mPFC. These findings suggest that C57BL/6 mouse dams may be less sensitive to the actions of MS on behaviour and on brain and intestinal markers of inflammation and barrier permeability, at least when examined shortly after weaning.

Stressful experiences are a major risk factor for the development of neuropsychiatric disorders in vulnerable individuals. Identifying features that can distinguish stress-susceptible from resilient individuals remains a central goal in stress neurobiology. Due to the routine exclusion of female subjects from stress research or the use of male-defined criteria in behavioral characterization of subjects post-stress, female stress responses and vulnerability profiles remain poorly understood. This work aimed to gain a better understanding of sex-specific stress responses to social defeat stress. Here, we used a novel paired male-female social defeat paradigm and tracked subjects longitudinally in a ''two-hit'' design to evaluate responses to both acute social defeat stress (ASDS) and chronic social defeat stress (CSDS), and to determine how prior stress exposure influences subsequent vulnerability. We found that both ASDS and CSDS induces changes in social avoidance/approach behavior in males but not females, as measured by a classic social interaction ratio. Prior ASDS exposure enhanced susceptibility to subsequent CSDS most clearly in males, with females displaying specific changes in corner zone occupancy. Furthermore, we observed divergent anxiety profiles between males and females in a post-stress behavioral battery. Finally, females exhibited specific stress-related locomotor responses following ASDS. Together, these findings suggest that females may adopt distinct behavioral strategies following social defeat stress.

Microglial activation is a central component of neuroinflammatory responses in many brain pathologies. Increasing evidence indicates that microglial phenotype is tightly linked to cellular metabolism, with pro-inflammatory activation associated with enhanced glycolytic flux. Lactate, traditionally considered a metabolic substrate, has recently emerged as a signaling molecule capable of modulating immune responses. However, its direct impact on microglial inflammatory activation remains incompletely understood. In the present study, we investigated the effects of lactate on microglial phenotype under inflammatory conditions using primary rat microglial cultures stimulated with lipopolysaccharide (LPS). Microglial activation was assessed through the expression of phenotypic markers, cytokine production, and secreted chemokine profiles. LPS stimulation induced a strong pro-inflammatory response characterized by increased CD86 expression, elevated TNF-alpha secretion, and enhanced release of several pro-inflammatory chemokines. Post-treatment with sodium L-lactate significantly attenuated these inflammatory responses, reducing pro-inflammatory marker expression and cytokine secretion, while restoring the anti-inflammatory marker CD206. To explore the relevance of these findings in a pathological context, the effects of lactate were further examined in a neonatal rat model of hypoxia-ischemia. Sodium L-lactate administration after injury reduced microglial activation and promoted a shift toward an anti-inflammatory phenotype in cortical regions, whereas hippocampal microglia showed a more limited response. Together, these results demonstrate that lactate directly modulates microglial inflammatory activation and cytokine production in vitro and suggest that lactate-mediated metabolic signaling may contribute in vivo to the regulation of neuroinflammatory responses.

Anhedonia emerges in adolescence, has putative substrates in neural reward and dopamine systems, and is a hallmark of poor course in depression. Psychoneuroimmunology models suggest altered immune and reward systems may jointly underlie its development. When dopamine availability (rather than function) is considered, immune activation may be understood as a moderator amplifying how lower dopamine levels translate into motivational deficits. This cross-sectional study analyzed data from 55 youth with current depression (Mage=21.4 years; Female=75%). Plasma was assayed for relative quantification of 92 immune proteins, followed by dimensionality reduction via principal component (PC) analysis, forming five PC scores. Dopamine availability was indexed by basal ganglia tissue iron, quantified by MRI R2', a measure detectable in youth. Anhedonia was assessed using the Snaith-Hamilton Pleasure Scale (SHAPS), thought to capture overall anhedonia, and Positive Valence Systems Scale (PVSS), which provides overall, anticipatory, and consummatory anhedonia scores. PC1 scores--whose loadings indicated broad inflammatory activity, including cytokines, chemokines, and tissue remodeling/angiogenic markers--moderated the relationship between basal ganglia dopamine availability and anhedonia: At higher PC1 levels, lower dopamine availability was linked to greater overall anhedonia (as measured by SHAPS) and anticipatory anhedonia, but not to consummatory anhedonia. Exploratory analyses showed comparable effect patterns for PC4, reflecting T cell-related effector/apoptotic signaling. Analyses of individual basal ganglia regions suggest potential differences in dopaminergic-immune interactions across these regions, with effects most consistently observed in the putamen. Findings highlight nuanced neuroimmune pathways underlying anhedonia components in youth and support inflammation-based models of depression emphasizing dopaminergic-immune interplay.

Background: Major depressive disorder (MDD) is a heterogeneous condition characterized by neuro-immune-metabolic-oxidative stress (NIMETOX) pathways. A systems-biology approach may help elucidate how these interconnected NIMETOX disturbances relate to early-life adversity and multidimensional clinical phenomes in adolescent MDD. Objectives: This study aimed to define the peripheral metabolic, vascular, and acute-phase, oxidative, and lipid biomarker profiles of adolescent MDD and to investigate associations with ACEs and clinical phenotypes. Methods: This cross-sectional study recruited 80 adolescents with MDD and 53 matched healthy controls and assessed C-peptide and insulin, vascular tone markers, the acute-phase inflammatory axis, oxidative stress, and lipid profiles. Results: MDD adolescents exhibited significant reductions in C-peptide, NO, ApoE, ApoA1, HDL-C, albumin, and transferrin, together with increased ApoB/ApoA1 ratio. These biomarkers correlated significantly with family dysfunction, childhood trauma, bullying exposure, and maladaptive parenting. These biomarkers and stressors accounted for 46.2% to 61.2% of the variance in psychological resilience, and major affective, physiosomatic, self-injurious, suicidal, and self-regulation phenomes. ACEs and bullying exposure, together with relevant socio-demographic data, explained 10.5% to 28.4% of the variance in selected metabolic, vascular, and acute-phase biomarkers. Multivariable classification models showed adequate discrimination between MDD and healthy controls, achieving up to 88.5% classification accuracy and an AUC of 0.948. Conclusion: Adolescent MDD is characterized by coordinated reductions in negative acute-phase proteins, metabolic and lipoprotein protective factors, and endothelial NO, without overt CRP-defined inflammation or conventional dyslipidemia. These findings support a systems-biology model of impaired peripheral homeostatic protection associated with developmental adversity and multidimensional depressive phenomes.

Introduction: Mast cells are central effectors of IgE-mediated allergic responses and reside in barrier tissues, where they encounter diverse environmental compounds. How naturally occurring bioactive compounds influence mast cell function under resting versus allergic conditions remains poorly defined. Methods: We compared the effects of cholera toxin, aconitine, and sennoside A on viability, degranulation, and cytokine production in murine bone marrow-derived mast cells. We then examined the acute physiological effects of oral sennoside A in an ovalbumin-induced mouse model of food allergy. Results: None of the compounds reduced mast cell viability at the concentrations tested. Sennoside A, but not cholera toxin or aconitine, induced modest degranulation in resting mast cells without increasing TNF- or IL-6 secretion. In contrast, sennoside A markedly suppressed IgE-dependent antigen-induced degranulation, TNF- and IL-6 secretion, and Il1b expression. Acute oral sennoside A induced dose-dependent diarrhea and hypothermia and increased colonic Tnfa, Il1b, Il33, and Hdc expression. In allergic mice, sennoside A attenuated allergen-induced hypothermia, reduced duodenal Tpsab1 expression, and decreased circulating total IgE, OVA-specific IgE, and OVA-specific IgG1, while increasing Il5 expression. Conclusion: Sennoside A differentially regulates mast cell responses according to activation state and attenuates features of experimental food allergy. These findings identify a previously unrecognized immunomodulatory effect of sennoside A on IgE-driven mast cell activation. However, the mechanisms and the contribution of mast cells to the in vivo phenotype remain to be defined.

Preterm birth is strongly linked to systemic inflammation and encephalopathy of prematurity, which underlies subsequent cognitive impairment. T-cell immunity contributes to brain-immune crosstalk across the life course but its role in the pathogenesis of encephalopathy of prematurity is unknown. Protein epigenetic scores are DNA methylation (DNAm)-based proxies of circulating proteins. We tested the hypothesis that T-cell dysregulation has a specific role in child neurodevelopment following preterm birth. Multimodal data were collected from 144 preterm infants (median gestational age at birth 29+5 weeks [range 23+3 to 32+6]) recruited to a prospective cohort study: saliva DNAm for protein epigenetic score derivation and brain MRI, both at term-equivalent age, and the Mullen Scales of Early Learning Composite score at 5 years from a subset. We investigated associations of the epigenetic scores for cytotoxic and regulatory T cell-associated molecule (DNAm CRTAM) and C-reactive protein (DNAm CRP; a non-specific marker of inflammation) with MRI metrics of encephalopathy of prematurity: global and regional brain volumes, and general factors of diffusion tensor imaging and neurite orientation dispersion and density imaging metrics averaged across 42 white matter tracts. We tested whether DNAm CRTAM explains more variance than DNAm CRP in MRI metrics of the encephalopathy of prematurity and cognitive scores in childhood. Higher neonatal DNAm CRTAM was associated with lower general factor of fractional anisotropy ({beta} = -0.252, q = 0.011) and higher general factors of radial diffusivity ({beta} = 0.215, q = 0.039), mean diffusivity ({beta} = 0.198, q = 0.047) and orientation dispersion index ({beta} = 0.201, q = 0.048), independent of inflammatory morbidities and other biological covariates after false discovery rate correction. DNAm CRTAM explained more variance than DNAm CRP (maximum incremental R2 = 4.2% vs 1.5%) in diffusion MRI metrics. Higher neonatal DNAm CRTAM was associated with lower cognitive scores at 5 years, independent of DNAm CRP and other covariates ({beta} = -0.332, P = 0.008), and explained more variance in cognitive scores than DNAm CRP (incremental R2 = 9.4% vs 1.2%). An epigenetic proxy of CRTAM in preterm infants is associated with both encephalopathy of prematurity in the neonatal period and lower cognitive performance at 5 years, explaining greater incremental variance than a non-specific marker of inflammation. The data implicate T-cell dysregulation in the pathophysiology of atypical neurodevelopment following preterm birth.

Abstract Background The neuropsychiatric sequelae (cognitive deficits, anxiety and depression) post-COVID-19 exist as part of the spectrum of the multisystemic long COVID. People with these symptoms have been shown to have worse functional outcomes. Hence, this significantly impacts the economy, primarily due to productivity losses. Yet, the precise underlying pathogenesis remains unknown, as do any diagnostic or prognostic biomarkers. Aim This study aims to identify functionally impacted brain regions in those with post-COVID-19 neurological sequelae and to evaluate how alterations in brain function relate to acute serum inflammatory mediators and brain injury biomarkers. Methods The study will utilise data from the COVID-19 Clinical Neuroscience Study (CNS), a large UK multicentre study conducted during the pandemic. This sub-study will be a secondary analysis of the COVID-19 CNS, a prospective observational study that compared COVID-19-positive participants with negative controls. Participants had an MRI, blood tested for acute serum inflammatory mediators and brain injury biomarkers, and neuropsychiatric assessment (cognitron test, PHQ-9 and GAD-7) post-acutely and at follow-up. The DPABI (Data Processing & Analysis for Brain Imaging) toolbox will be used for pre-processing and analysis of the neuroimaging data (resting state functional MRI) to obtain regional homogeneity (ReHo). The association between ReHO and neuropsychiatric symptoms, acute inflammatory mediators and brain injury biomarkers will be explored. Regression models would be used to determine the risk and protective factors for developing these symptoms. Conclusion It is anticipated that the study will provide new insights into the functional basis of post-acute COVID-19 neuropsychiatric manifestations and identify new diagnostic biomarkers. Key words: Regional Homogeneity, COVID-19, functional MRI, neuropsychiatry, biomarkers

Importance: Phosphorylated tau at threonine 217 (p-tau217) and brain-derived tau (BD-tau) are increasingly used as blood biomarkers of Alzheimer's disease (AD) and related neurological disorders. However, the distributions and biological correlates of elevated plasma p-tau217 and BD-tau in plasma from individuals eligible for blood donation remain unclear. Objective: To estimate the proportions of plasma p-tau217 and BD-tau exceeding exploratory study-specific thresholds, and examine associated inflammatory and transcriptomic features. Design: Cross-sectional study. Setting: Hospital blood bank. Participants: 257 de-identified donor samples were obtained between September 2025 and June 2026. Plasma samples from 30 population reference participants and 20 AD patients were used to derive study-specific thresholds. Complementary transcriptomic analyses were performed in 29 fresh whole blood samples. Main Outcomes and Measures: The primary outcome was the proportion of donor samples exceeding the study-specific ROC-derived Youden threshold. The proportion exceeding the prespecified published p-tau217 threshold was the secondary outcome. Other measures included plasma concentrations of BD-tau, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6); correlations among plasma p-tau217, BD-tau and inflammatory cytokines; and associated transcriptomic alterations. Results: Plasma p-tau217 concentrations exceeded the study-specific ROC-derived Youden threshold in 53 of 256 donor samples (21%; 95% CI, 16%-26%) and the published threshold, used for a secondary comparison, in 99 of 256 samples (39%; 95% CI, 33%-45%). Plasma BD-tau concentrations exceeded the study-specific threshold in 89 of 257 samples (35%; 95% CI, 29%-41%). Plasma p-tau217 concentrations were positively associated with plasma TNF-alpha (Kendall's tau = 0.339; P < .001) and IL-6 (Kendall's tau = 0.310; P < .001) concentrations. Exploratory transcriptomic analyses identified gene expression patterns associated with p-tau217 concentrations. Measurement using a second p-tau217 antibody showed the similar findings. Conclusions and Relevance: Plasma p-tau217 and BD-tau concentrations exceeded exploratory study-specific thresholds in a subset of blood-donor samples, and higher p-tau217 concentrations were associated with inflammatory biomarkers and exploratory transcriptomic differences. These findings raise the possibility of elevated circulating tau species in some blood donors, but their clinical significance requires confirmation. Whether elevated circulating p-tau217 in donated blood has biological consequences for transfusion recipients is unknown, but deserves investigation.

Microglia, the tissue resident immune cells of the central nervous system, are critical regulators of postnatal neural circuit refinement. Innate immune receptors on microglia such as toll-like receptor 4 (TLR4) are best characterized in the context of inflammation, however, endogenous TLR4 ligands are generated during typical developmental processes. Here, we investigated whether TLR4 signaling in CX3CR1-expressing myeloid cells contributes to microglial morphology, synaptic engulfment, and behavioral development in mice under basal conditions. TLR4 conditional knockout altered maternal separation-induced ultrasonic vocalizations without impacting social preference or anxiety-like behaviors. Conditional TLR4 knockout in CX3CR1-expressing myeloid cells markedly increased microglial ramification and cell volume within the paraventricular nucleus (PVN) of the hypothalamus. TLR4 conditional knockout also reduced microglial engulfment of vGlut2-positive presynaptic material, while overall excitatory synapse numbers remained unchanged. Together, these findings demonstrate that TLR4 signaling in CX3CR1-expressing myeloid cells contributes to microglial morphology, presynaptic engulfment, and neonatal communicative behavior under basal conditions.

Introduction: Pesticide exposure has been associated with poorer mental health, yet little is known about whether seasonal fluctuations in agricultural pesticide use are associated with cyclical changes in mood among people living in agricultural communities. We evaluated associations between 10 peak and off-peak pesticide spray seasons and ecological momentary assessment (EMA)-derived mood in a floricultural region in Ecuador. Methods: 496 participants completed repeated EMA surveys across 10 assessment administrations over 2.5 years (2022-2024), including one single-assessment administration and nine 10-day bursts (Nobservations=14,332). Mood outcomes included negative affect (sadness, anxiety, stress, anger, tiredness, difficulty concentrating; overall mean=2.79, Standard Deviation [SD]=1.32), positive affect (happiness, motivation; overall mean=4.21, SD=1.60), and behavioral dysregulation (aggression and impulsivity, overall mean=1.86, SD=1.29). Generalized linear mixed models estimated pooled, between-person and within-person associations between peak pesticide spray seasons and mood, adjusting for demographic and longitudinal factors Effect modification by sex, floricultural occupation, and cohabitation with a floricultural worker was assessed. Results: Peak spray seasons were associated with higher negative affect ({beta}=0.11 [0.06, 0.16]) and behavioral dysregulation ({beta}=0.10 [0.05, 0.15]) but not positive affect ({beta}=0.01 [-0.05, 0.07]). Associations were driven by within-person changes. Sex modified associations with negative affect, which were stronger in males than females. Floricultural occupation modified associations, with poorer mood, greater behavioral dysregulation and lower positive affect among floricultural workers than non-workers. Discussion: Peak pesticide spray seasons were associated with worsening of negative affect and behavioral dysregulation. EMA may provide a sensitive approach for detecting short-term neurobehavioral changes associated with seasonal pesticide exposure.

OBJECTIVE: Sepsis-associated encephalopathy (SAE) and sepsis-associated delirium (SAD) lack confirmatory laboratory tests or biomarkers. We evaluated whether the Th17/interleukin (IL)-17 axis or neuroglial-injury biomarkers reflect acute brain dysfunction beyond systemic inflammation and whether biomarker profiles differ between these phenotypes. DATA SOURCES: EMBASE, MEDLINE/PubMed, and the Cochrane Library from inception to August 1, 2026, supplemented by backward and forward citation searching, following PRISMA 2020. STUDY SELECTION: Observational studies of adults with sepsis classified by SAE or SAD status and reporting circulating biomarker concentrations by neurological group or biomarker-outcome associations. Eighteen studies (2,388 participants; 1,863 with sepsis) were included. DATA EXTRACTION: Two reviewers independently extracted study, phenotype, assay, and outcome data. Risk of bias was assessed with the Newcastle-Ottawa Scale and certainty with GRADE. DATA SYNTHESIS: Random-effects models pooled standardized mean differences (SMDs) separately against non-septic and septic controls and odds ratios (ORs) for biomarker-outcome associations. IL-6 was the only mediator elevated in both comparative frameworks and associated with outcomes (non-septic controls: SMD, 0.54 [0.25-0.82]; septic controls: SMD, 1.05 [0.51-1.59]; OR, 1.85 [1.50-2.29]). S100B, neuron-specific enolase, IL-10, tumor necrosis factor; and interferon-gamma; were elevated versus septic controls, whereas IL-17 was modestly elevated only versus non-septic controls (SMD, 0.37 [0.01-0.73]). The IL-6 septic-control effect was concentrated in SAE (p<0.0001) and remained robust in leave-one-out and risk-of-bias sensitivity analyses. Certainty was low to very low, and all 14 computable prediction intervals included the null. CONCLUSIONS: IL-6 emerges as the leading circulating candidate biomarker of sepsis-associated brain dysfunction, while S100B and NSE capture neuroglial injury beyond sepsis. Current evidence does not establish a discriminating role for the Th17 axis. Future studies require standardized neurological phenotyping and appropriately matched septic controls to establish diagnostic value.

Introduction: Neuroinflammation is a known pathophysiologic mechanism in multiple sclerosis and a proposed mechanism in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Positron Emission Tomography (PET) imaging of the translocator protein (TSPO) has been widely used to measure neuroinflammation, though second-generation ligands are highly sensitive to a single nucleotide polymorphism, rs6971, resulting in high, mixed, and low affinity binders. It is unknown whether this polymorphism is associated with neuroinflammatory disorders. Materials and Methods: Eighty-six total participant genotypes for TSPO binding affinity were identified through Sanger sequencing (30 fibromyalgia, 21 ME/CFS, 11 multiple sclerosis, and 24 healthy controls). Associations between patient group and genotype were assessed with Fishers Exact test. Associations between genotype and symptom severity from self-report questionnaires were assessed with Kruskal-Wallis tests. Results: In the present study individuals with fibromyalgia, (ME/CFS), or multiple sclerosis were more likely to have a mixed- or low-affinity genotypes compared to healthy controls. Presence of the low or mixed genotypes were also associated with greater self-reported fatigue severity and depressive symptoms. Discussion: These findings should be confirmed in larger samples but suggest functional consequences of rs6971 polymorphism that may be related to the pathophysiology of pain and fatigue illnesses.

BACKGROUND: One in three adolescents with a concussion history report experiencing long-lasting somatic, sleep, emotional, and/or cognitive disturbances (persisting symptoms after concussion (PSaC)). Cognitive difficulties, such as attentional problems, are common symptoms and can interfere with ongoing development. Clinically, psychiatric symptoms also present in youth with PSaC. A concussion causes diffuse functional and microstructural alterations to neural networks. To develop targeted treatments for PSaC (e.g., neurostimulation), we need to understand how and where structural alterations and neural dysfunction intersect to cause long-lasting symptoms. OBJECTIVES: 1) Identify functional and microstructural properties in intrinsic connectivity networks, as well as neuropsychological outcomes, that differentiate adolescents with concussion with PSaC from those who do not have PSaC. 2) Determine whether neural activity within intrinsic connectivity networks mediates the relationship between network microstructure and specific neuropsychological features in adolescents with concussion. METHODS: CAMBY is a prospective study of adolescents aged 12 to 18 years with a history of concussion. Participants are allocated based on recovery status (PSaC vs. No-PSaC (recovered controls)). Advanced structural (magnetic resonance imaging; MRI) and functional (magnetoencephalography; MEG) neuroimaging and neuropsychological measures will be collected one month or more after concussion. Microstructural and functional features will be computed within intrinsic connectivity networks, then compared between PSaC and recovered control groups and related to symptom domains and neuropsychological profiles. IMPACT: This will be the first study to integrate MRI, MEG, and neuropsychology in adolescents with PSaC to identify disrupted networks underlying PSaC. This observational study is a necessary step towards future clinical trials that accurately target promising therapeutic neurostimulation protocols.

Adverse childhood experiences like social isolation (SI) contribute to long term negative health outcomes and the development of severe psychiatric disorder. Adolescence is a unique period of coordinated social and motivational system development driven by dopamine (DA) signaling. Microglia, immune cells of the brain, may play a unique role in regulating SI-induced DA system changes and associated behavioral dysfunction. Male microglia refine dopamine D1 receptors (D1rs) in the nucleus accumbens (NAc) of adolescent male rats shaping play behavior. Here we characterized the molecular developmental impacts of postweaning SI from P21-P38, with a resocialization period to P54. We tested the role of microglial engulfment of D1rs in mediating behavioral consequences of SI using neutrophil inhibitory factor (NIF) to block complement-mediated engulfment required for D1r pruning. We found sex specific impacts of SI on brain development and the DA system. In SI males, microglia engulf more NAc D1rs than group housed (GH) controls. Within GH animals, NAc D1r density is positively correlated to play and allogrooming. In SI animals, NAc D1r density is negatively correlated to biting behavior, and is not correlated to play or allogrooming. Pharmacologically inhibiting microglial engulfment of D1r via bilateral NAc NIF injection prevents observed D1r:behavior correlations in GH and SI animals. NIF treatment interacts with SI, exaggerating aggressive-like behavior, showing a role for microglia in regulating aggressive-like behavior via complement pruning in adolescence. Microglia may play a unique role in regulating behavior that drive negative health outcomes in the face of developmental stress, including SI.

Objective To examine whether prospectively recorded maternal BMI in early pregnancy is associated with offspring multiple sclerosis (MS) risk, including childhood-onset and adult-onset MS. Design Nationwide population-based cohort study. Setting Swedish national health and demographic registers. Participants 1,524,863 singleton children born in Sweden from 1992 to 2007 and followed through 2025. Exposures Maternal BMI recorded at the first antenatal visit, categorised as underweight (<18.5), normal weight (18.5-24.9), overweight (25.0-29.9), and obesity ([&ge;]30.0), and also modelled continuously. Main outcome measures MS in offspring, identified as at least three ICD-10 G35 codes recorded on separate dates. Cox models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) adjusting for confounders. Results During follow-up, 1539 offspring (0.1%) were diagnosed with MS at a median age of 24 years (interquartile range, 20-27 years). MS incidence rates by maternal BMI category were 0.37 per 10,000 person-years for both underweight, and normal weight, 0.42 for overweight, and 0.45 for obesity. Compared with normal weight women, maternal overweight and obesity were associated with higher hazards of offspring MS, with adjusted HRs of 1.20 (95% CI, 1.05 to 1.37) and 1.35 (95% CI, 1.11 to 1.64), respectively. Onset-specific analyses showed similar findings for adult-onset MS and less precise but directionally consistent estimates for paediatric-onset MS. Each 1-unit increase in maternal BMI was associated with a 3%, 4%, and 3% higher hazard of overall, paediatric-onset, and adult-onset offspring MS, respectively. Conclusions In this population-based cohort study, higher maternal BMI were associated with an increased rate of MS in offspring. The findings provide large-scale prospective evidence that maternal adiposity may be related to offspring MS risk and support further investigation of the prenatal metabolic environment in the early-life origins of MS.

Maternal depression and psychosocial adversity during pregnancy are associated with altered offspring neurodevelopment, yet the molecular processes linking maternal state to the developing fetus remain incompletely understood. The placenta is positioned to sense and respond to maternal physiological signals, but how placental molecular responses relate to those in the developing brain is unclear. Here, we used a mouse model of prolonged social isolation initiated before conception and maintained throughout pregnancy to investigate inflammatory and transcriptional alterations across matched placenta and fetal-brain samples at gestational day 18. Maternal social isolation altered cytokine profiles in both tissues and induced extensive transcriptional changes in the placenta, with a more restricted response in the fetal brain. Functional analyses identified alterations in placental immune, metabolic and transport-related programmes and fetal-brain immune, neuronal and proliferative processes. Although sex-stratified analyses revealed different transcriptional profiles in male and female tissues, formal maternal housing x fetal-sex interaction testing did not identify significant gene-level interaction effects. Cross-tissue co-expression analysis initially identified extensive covariation between social-isolation-responsive placental and fetal-brain modules; however, most associations were attenuated after accounting for their shared relationship with maternal housing. An exposure-independent network analysis nevertheless identified an inverse pregnancy-level association between a placental module enriched for immune and interferon-related signalling and a fetal-brain module enriched for cell-cycle and proliferative processes. Together, these findings show that prolonged maternal social adversity is associated with coordinated but tissue-distinct molecular alterations across the placenta-fetal brain axis and demonstrate the importance of distinguishing parallel responses to a common maternal environment from direct cross-tissue molecular coupling.

Background: The C-reactive protein-albumin-lymphocyte (CALLY) index integrates systemic inflammation, nutritional status, and immune function. We evaluated its association with survival in primary lung malignancies. Methods: Embase, PubMed, Scopus, and Web of Science were searched from inception to 18 September 2026. Risk of bias was assessed using the Quality In Prognosis Studies tool. Hazard ratios (HRs) were synthesized using random-effects models with restricted maximum likelihood estimation and Hartung-Knapp adjustment. Sensitivity analyses, subgroup analyses, and meta-regression examined robustness and heterogeneity. Results: Eleven studies contributed 13 cohorts to the overall survival (OS) analysis and 8 cohorts from seven studies to a combined recurrence/progression-free survival (RFS/PFS) analysis. Lower CALLY was associated with poorer OS (HR 1.78, 95% CI 1.49-2.12; I2=71.6%) and poorer RFS/PFS (HR 1.60, 95% CI 1.40-1.84; I2=0%). Associations persisted in leave-one-out analyses. No statistically significant subgroup differences were detected. Funnel-plot asymmetry suggested small-study effects for OS and RFS/PFS. Seven studies had moderate and four had high overall risk of bias. The certainty of evidence was rated as low for both OS and RFS/PFS, primarily due to risk of bias, heterogeneity, and endpoint indirectness. Conclusion: Lower CALLY was associated with adverse survival outcomes in the current synthesis. Methodological limitations and variation in biomarker measurement and endpoint definitions restrict interpretation. Prospective validation using standardized measurements and clinically coherent outcomes is needed to establish incremental prognostic value and clinical utility. Keywords: CALLY index; lung cancer; prognosis; overall survival; systematic review; meta-analysis

Introduction: Preterm birth is often associated with fetal membrane (FM) inflammation. Opioid-use disorder during pregnancy is a major public health issue as all opioids carry a risk for preterm birth. While maintenance therapy with methadone improves maternal outcomes, it also elevates the risk of preterm birth. We previously reported that the opioid, buprenorphine, induced human FM sterile inflammation. The goal of this study was to investigate if methadone also induced FM inflammation and to determine the mechanisms involved. Methods: Human FM explants were treated with or without methadone in the presence or absence of inhibitors to TLR4/MD2, TLR7, TLR8, NLRP3, the -opioid receptor, p65 NF{kappa}B, p38 MAPK, ERK or JNK. Supernatants were measured for cytokines/chemokines by ELISA. Tissues were analyzed by Western blot for NF{kappa}B and MAPK activity, and by RT-qPCR for the TLR7/8-activating miRs: miR-21a, miR-29a, miR-146a-3p, Let-7b. Pregnant C57BL/6 mice were injected with PBS or methadone on E15.5 and 6hrs later FMs were analyzed by RT-qPCR. Results: Methadone elevated human FM explant secretion of IL-1{beta}, TNF, MIP-1, GM-CSF, and PGE2, and expression of miR-21a. In vivo, methadone elevated mouse FM expression of MIP1A, KC, and COX2. TLR4/MD2 inhibition had no effect on human FM inflammation in response to methadone. NLRP3 inhibition reduced methadone-induced FM IL-1{beta}, TLR7 inhibition reduced methadone-induced FM TNF, and inhibition of either TLR8 or the -opioid receptor reduced methadone-induced secretion of TNF, MIP-1, GM-CSF, and PGE2, but not IL-1{beta} Methadone increased human FM activity of p65 NF{kappa}B, p38 MAPK, JNK, and ERK and inhibition of these signaling pathways collectively reduced methadone-triggered FM inflammation. Finally, naloxone reduced most of the methadone-induced FM inflammatory response. Conclusion: Methadone induces sterile inflammation in human and mouse FMs. In human FMs this inflammation is mediated through activation of innate immune TLR7, TLR8, and NLRP3; the -opioid receptor; and NF{kappa}B/MAPK signaling. These findings provide further insight into the mechanisms underlying the association between opioid use during pregnancy and preterm birth.