Brain, Behavior, & Immunity - Health

Stress is a major risk factor for numerous neuropsychiatric disorders and induces enduring synaptic plasticity within the nucleus accumbens core (NAcore), a key brain region involved in reward and stress-related behaviors. Previous studies from our laboratory demonstrated that stress-induced plasticity depends on matrix metalloproteinase (MMP)-2/9-mediated extracellular matrix (ECM) remodeling; however, the upstream cellular mechanisms regulating MMP activation remain unclear. Because microglia regulate neuroimmune signaling, ECM dynamics, and synaptic plasticity, we tested the hypothesis that microglial colony-stimulating factor 1 receptor (CSF1R) signaling contributes to stress-induced MMP-2/9 activation within the NAcore. Male rats received the CSF1R inhibitor PLX3397 prior to acute restraint stress. In vivo fluorescent zymography, immunohistochemistry, and quantitative PCR were used to assess MMP activity, microglial signaling, and inflammatory gene expression. Acute stress increased MMP-2/9 activity enhanced microglial CD68-associated phagocytic signaling, and elevated expression of Csf1r, Tnfa, Cnr2, and Mmp16 within the NAcore. Importantly, CSF1R inhibition attenuated stress-induced increases in MMP-2/9 activity and CD68 immunoreactivity. Combined, these findings identify microglial CSF1R signaling as an upstream regulator of stress-induced ECM remodeling within the NAcore and provide mechanistic insight into how acute stress recruits neuroimmune pathways to remodel reward circuitry.

Although cannabinoids such as delta-9-tetrahydrocannabinol (THC) are generally immunosuppressive in preclinical models, chronic cannabis use in humans is paradoxically associated with increased infection risk and systemic inflammation. In this study, we demonstrate that THC directly strengthens intestinal epithelial barrier function in vitro by increasing trans-epithelial electrical resistance in a concentration-dependent manner in Caco-2 monolayers. In a cross-sectional study of chronic cannabis users via smoking or snorting compared with non-using controls, plasma lipopolysaccharide (LPS), and microbial translocation-driven inflammatory cytokines (IL-23, MCP-1, IL-8) were significantly reduced, while some cytokines (IL-6, IL-1{beta}, TNF-, IL-10) remained unchanged. Concurrently, users exhibited elevated macrophage-derived chemokine (MDC) and homeostatic cytokines IL-15 and IL-21, markedly suppressed IL-7 and IL-4. Plasma IL-15 and MDC levels correlated with consumption intensity, and IL-23, IL-7, and IP-10 correlated with age of first use or during heaviest use. These findings suggest that habitual cannabis use may protect gut barrier integrity and reduce microbial translocation and associated inflammation, while simultaneously disrupting systemic immune homeostasis through selective cytokine dysregulation. This dual, dose-dependent immunomodulatory profile highlights the complex balance between potential benefits and risks in both recreational and therapeutic cannabis use.

Introduction: Multidomain lifestyle interventions may slow down cognitive decline and dementia, but the brain mechanisms underlying these effects remain unclear. We investigated brain, inflammation, cardiometabolic, and gut health changes associated with a six-month multidomain lifestyle intervention in Dutch older adults at risk for cognitive decline and dementia. Method: Participants aged 60-75 years with [≥]2 lifestyle-modifiable cardiovascular risk factors (e.g., BMI [≥]25, physical inactivity) were recruited and randomised in a 1:1 ratio to a high-intensity intervention or active control group using stratified (2,4) block-randomisation. The multidomain lifestyle intervention included five lifestyle domains (diet, physical activity, stress management and mindfulness, cognitive training, and sleep). Primary outcomes were changes in cerebral perfusion levels, brain activity during working memory, working memory performance, inflammation profile, and microbiota diversity. Secondary outcomes included lifestyle factors and markers of neuroimaging, brain health, cardiovascular and gut health, and cognitive functioning. The effects of the lifestyle intervention were investigated using linear mixed-effect models. Results: A total of 102 participants were randomised into the intervention (n=53) or active control group (n=49), of which 86 participants completed the six-month multidomain lifestyle intervention. Baseline characteristics were similar between the groups. Within the intervention group, favourable reductions in lifestyle-modifiable cardiovascular risk factors, such as BMI and blood pressure, were observed, but these were not significantly different from changes in the active control group. The intervention resulted in improved diet and sleep scores in the intervention group compared to the active control group (Beta 1.67, 95% CI 0.61;2.73, PFDR=0.01, and Beta -1.80, 95% CI -2.79;-0.81, PFDR=0.005, respectively). The intervention did not result in significant changes over time between the intervention and control group in primary and secondary outcomes. Conclusion: The HELI multidomain lifestyle was able to reduce lifestyle-modifiable cardiovascular risk factors associated with dementia, although not significant compared to the active control group. We did not observe significant intervention effects on brain, cardiometabolic, inflammatory, and gut health outcomes. These results emphasize the complexity of exploring the role of lifestyle on neurobiological brain mechanisms associated with maintaining optimal cognitive functioning in aging and their underlying peripheral (to central) mechanisms.

Introduction Depression is highly prevalent among cancer survivors and may be biologically distinct, although clinical studies investigating these mechanisms remain limited. Thus, the aims of this study were to (1) identify perturbed biological pathways associated with depressive symptom severity in cancer survivors, and (2) investigate whether these pathways are common or distinct to those perturbed in an age-matched non-cancer cohort. Methods We analyzed cross-sectional self-reported and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (PHD #39341). Cancer survivors and an age-matched non-cancer cohort (target ratio 1:2) were identified. The 20-item Center for Epidemiologic Studies Depression Scale (CES-D) was used to split participants into low (CES-D<16) and high ([&ge;]16) depressive symptom groups. Analyses were conducted separately for survivor and non-cancer cohorts. Differential gene expression between depressive symptom groups was evaluated with adjustments for covariates significantly associated with depression (survivor cohort: BMI; non-cancer cohort: marital status), with pathway impact analysis identifying perturbed pathways (FDR < 0.025). Results Ninety-three cancer survivors (11.8% with high depressive symptoms) and 176 non-cancer participants (9.7% with high depressive symptoms) were included. Sixty-eight and 72 perturbed pathways were associated with depression among survivor and non-cancer cohorts, respectively. Twenty-one of these pathways were perturbed uniquely among cancer survivors, which were related to neurodegeneration, reward circuitry, proliferation, and secretion. Inflammatory pathways were consistently perturbed across both cohorts. Conclusions Distinct biological mechanisms related to neurodegeneration, reward circuitry, autonomic secretion, and proliferative signaling may underlie depression in cancer survivors. Inflammation was implicated as a shared mechanism of depression across cancer and non-cancer populations. This study identifies potential therapeutic targets and highlights the need for precision medicine in treating depression among cancer survivors.

Neurobiological mechanisms underlying child maltreatment perpetration remain poorly understood, and the role of immune dysregulation has rarely been examined. Here, we tested whether peripheral inflammatory signatures are linked to brain structural alterations in mothers who have perpetrated maltreatment, and whether such alterations mediate this link to perpetration. In this cross-sectional study integrating structural MRI and inflammatory proteomics, 16 mothers with histories of maltreatment perpetration and 145 age-matched control mothers underwent brain imaging; a subgroup (n = 52; 11 maltreatment, 41 control) also completed plasma proteomic profiling using the Olink Target 96 Inflammation panel. Whole-brain voxel-based morphometry revealed significantly reduced gray matter volume (GMV) in the right middle/inferior temporal gyri, a region implicated in social cognition and contextual interpretation, in the maltreatment group. Proteomic analysis identified 16 inflammation-related proteins differentially expressed between groups; among these, nine were significantly associated with GMV in this temporal region. Lower GMV was associated with higher levels of pro-inflammatory proteins (CCL20, IL-17C) and with lower levels of immune-regulatory and metabolic proteins (CXCL1, CXCL6, SIRT2, STAMBP, MCP-2, MCP-4, 4E-BP1). Mediation analyses revealed that both protein sets were indirectly associated with perpetration through this regional GMV, with opposing patterns of direct association. These findings suggest that peripheral immune imbalance, characterized by elevated inflammatory signaling and diminished immune-regulatory capacity, is linked to structural vulnerability in a temporal cortical region involved in social cognition, specifically in perpetrating mothers. This neuroimmune pathway may contribute to maladaptive interpretation of child signals during caregiving and represents a potential target for biomarker-informed preventive intervention.

Social isolation is commonly used to model social stress and is a known risk factor for depression, with impacts on hippocampal function and postnatal neurogenesis. However, most studies focus on social isolation in juvenile mice isolation during adolescence, leaving the effects of prolonged adult isolation less understood. Post-transcriptional regulation of gene expression by microRNAs (miRNAs) plays a role in hippocampal function, and altered miRNA, as well as gene expression, has been reported in the hippocampus of mice exposed to social isolation. A single-nucleotide polymorphism in miR-30e in humans is associated with increased expression of the mature miRNA, impaired cognition, electroencephalogram waveform latency, depression, and schizophrenia. We investigated whether adult isolation in mice alters gene regulation via microRNAs, particularly miR-30e-5p, and affects hippocampal function. In adult BALB/c male mice, 10 weeks of isolation increased miR-30e-5p expression in the ventral hippocampus, reduced its target gene Neurod1, and impaired hippocampal-dependent cognition (object pattern separation), without clear anxiety- or depression-like behaviours. Isolated mice also showed a blunted response to acute stress. These findings suggest that adult social isolation affects hippocampal function through post-transcriptional gene regulation, highlighting a role for miR-30e-5p in neurogenesis and cognition in response to psychological stress.

IntroductionEnvironmental factors are increasingly implicated in the etiology of autism spectrum disorder (ASD). Polybrominated diphenyl ethers (PBDEs) are anthropogenic toxicants added as flame retardants to consumer products that have become ubiquitous environmental contaminants and disrupt thyroid hormone (TH) and neuroendocrine systems. We have previously shown that developmental PBDE exposure produces ASD-like traits with involvement of oxytocin (OXT)-thyroid hormone signaling. Limosilactobacillus reuteri (LR), a widely used probiotic bacterium, has been shown to improve social functioning and increase TH and OXT levels in murine models. Therefore, we tested the hypothesis that LR supplementation (LR) prevents PBDE-induced deficits in socioemotional behavior with concomitant modulation of TH signaling genes on hypothalamic OXT neurons. MethodsC57BL/6N mouse offspring were exposed to a commercial penta-mixture of PBDE congeners, DE-71, at an environmentally realistic concentration, 0.1 mg/kg/d (DE-71), or to corn oil vehicle (VEH/CON) via their mothers during gestation and lactation. Offspring received supplementation with LR ATCC PTA 6475 (107-108 CFU/mL, po) indirectly via the dam or continuation directly through adulthood. Unsupplemented controls were given saline. ResultsFecal microbiome analysis in offspring confirmed colonization of LR at postnatal day (P) 40 and depletion by P104. LR treatment increased plasma total thyroxine in DE-71 and plasma OXT in VEH/CON dams. In DE-71 offspring of both sexes, LR normalized deficient scores on social novelty preference and emotional recognition in adult females and males and deficient long-term social recognition memory (SRM) in adult DE-71 females; DE-71 males were normal. Reduced olfactory dishabituation between two social odors may partly explain the compromised socioemotional behavior produced by DE-71 in an LR-dependent manner. Multiplex RNA in situ hybridization performed on immunoreactive OXT-ergic neurons in the paraventricular hypothalamic nucleus (PVH) revealed significant upregulation of TH transporter monocarboxylate transporter 8 (Mct8) and downregulation of iodothyronine deiodinase 3 (Dio3) in DE-71 relative to VEH/CON females. This toxicant-induced reprogramming was prevented by probiotic treatment. DE-71 males expressed reduction in Mct8 and Dio3 transcripts on OXT-ergic neurons with minimal LR protection. In the female supraoptic nucleus (SON), Mct8 and Dio3 were downregulated by DE-71 and normalized in DE-71+LR; there were no group effects on transcript levels in male SON. Results of fecal 16S rRNA sequencing indicated reduced -diversity and altered {beta}-diversity in the gut bacterial community of female but not male DE-71 exposed offspring; most changes were correctable by LR. Alterations in taxa-level abundance caused by DE-71 and reversed by LR were observed in both sexes. These involved Bifidobacterium, Coprococcus, Desulfovibrio, Oscillospira, and Peptococcaceae in females and Desulfovibrionaceae, Rikenella, and Turicibacter in males. Exposed dams showed no detriment in - and {beta}-diversity while showing reduced abundance of several Firmicutes and Proteobacteria taxa that could be rescued by LR. The relative abundance of Lactobacillus was upregulated in DE-71 males and DE-71+LR males and dams. ConclusionsThese results indicate that developmental probiotic supplementation effectively mitigated organohalogen-induced ASD-like deficits in socioemotional behavior and partially corrected dysbiosis of gut bacterial communities in exposed offspring of both sexes. Concomitantly, PBDEs altered the expression of TH regulatory genes Mct8 and Dio3 in PVH OXT neurons in a sex-dependent manner, suggesting that TH regulation of OXT neuroendocrine cells may modulate the emergence of toxicant-induced ASD-relevant behavior. While LR reinstated normal behavioral outcomes in PBDE-exposed offspring of both sexes, coincident normalization of hypothalamic TH signaling transcripts occurred more broadly in females, indicating the existence of unique parallel processes influencing the preventive effects of LR on ASD-relevant behavioral deficits in both sexes.

Introduction: Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a debilitating condition characterised by severe fatigue and post-exertional malaise (PEM). Reported neuropsychophysiological abnormalities suggest ME/CFS is multifactorial, but current knowledge remains fragmented. This study protocol outlines a multimodal investigation designed to (1) compare neuropsychophysiological mechanisms between ME/CFS patients and healthy participants, (2) test an integrative model of ME/CFS, (3) identify neuropsychophysiological subgroups within the patient population, and (4) identify predictors of symptom response during rehabilitation. Methods and analysis: This study will enroll 115 ME/CFS patients and 55 healthy participants. Groups will be comparable in age, sex, and education level, with a larger patient sample enabling subgroup and longitudinal analyses. A cross-sectional assessment at baseline will be carried out in both groups. Patients will then be evaluated longitudinally throughout a standardized cognitive-behavioral therapy rehabilitation program delivered as routine care. Baseline measures include systemic inflammation and general health biomarkers, measures of autonomic and central nervous system function, neuroinflammation (magnetic resonance spectroscopy, [18F]DPA714 PET in a subsample), serum short-chain fatty acid levels, gut microbiota composition and function, and neuroendocrine and self-reported responses to psychosocial stress. Fatigue severity (physical and cognitive) and PEM will be assessed through validated questionnaires, ecological momentary assessment, and laboratory tasks. These will be re-evaluated during therapy, and all non-neuroimaging measures will be repeated after the rehabilitation program. Statistical analyses will comprise multivariate analysis of variance, general linear models, classification algorithms, structural equation models, least absolute shrinkage selection operator principal component regression (LASSO-PCR), cluster analysis and latent class growth analysis (LCGA).

The SARS-CoV-2 S1 protein is associated with immune cell activation and persistent neurological symptoms, yet the underlying mechanisms remain unclear, posing a major challenge in elucidating Long COVID pathophysiology. To investigate how circulating S1 contributes to long-term neurological alterations, we intravenously injected hACE2 mice with varying doses of S1 (5, 10, and 20 {micro}g) and observed temporally dysregulated systemic inflammatory responses accompanied by sub-acute CD4+ T cell infiltration into central limbic regions. This immune response induced mild sustained increases in cFos+ cells in the amygdala and mild neuroinflammation in the hippocampal CA1 region, resulting in both acute and long-term anxiety-like behaviors, while working memory remained unaffected. Together, these findings suggest that systemic S1 protein induces a sustained proinflammatory response that promotes lasting neurological alterations through immune-to-brain signaling pathways. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/733010v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@10982caorg.highwire.dtl.DTLVardef@169a275org.highwire.dtl.DTLVardef@28e66aorg.highwire.dtl.DTLVardef@12f6c85_HPS_FORMAT_FIGEXP M_FIG C_FIG

Sickness is an organismal response to inflammation, yet its immune, metabolic, neural, and behavioral components are often studied separately and predominantly in male C57BL/6 mice. In this study, we characterized these responses to systemic lipopolysaccharide (LPS) in female BALB/c mice. Mice received intraperitoneal LPS at moderate concentrations and outcomes were assessed during the acute and resolving phases of endotoxemia. LPS caused rapid disappearance of resident peritoneal macrophages, followed by neutrophil accumulation and increased circulating TNF- and IL-6. In the liver, LPS induced inflammatory, acute-phase, and anti-inflammatory transcripts while suppressing genes involved in lipid, cholesterol, and xenobiotic metabolism. Hepatic glutathione was reduced, whereas total superoxide dismutase activity was unchanged. These peripheral responses were followed by transient hypothermia, reduced food intake, and body weight loss. Regional brain mapping showed increased c-Fos labeling in the area postrema, nucleus of the solitary tract, external lateral parabrachial nucleus, paraventricular nucleus of the hypothalamus, and arcuate nucleus. In parallel, LPS selectively promoted IBA1-positive area in the median eminence and arcuate nucleus, whereas several other regions showed no changes, indicating that neuronal and microglial responses are regionally distinct. Behaviorally, LPS reduced locomotion and exploration, increased freezing, and increased forced-swim immobility. Changes in spatial exploration were most pronounced during the acute phase, whereas locomotor suppression and passive stress-coping persisted longer and varied in magnitude with the timing of inflammatory challenge. Together, these findings show that systemic LPS produces a coordinated sickness state in female BALB/c mice that links peripheral inflammation and hepatic metabolic and redox changes with region-specific neuronal and microglial responses, altered thermoregulation and feeding, and behavioral suppression.

Prenatal and early postnatal life is a period of rapid brain growth, making the developing brain particularly susceptible to external influences. Adapting the biopsychosocial model of mental health and illness, this review provides a systematic overview of how biological, psychological, and social exposures from conception to age three critically converge to shape brain development and neurodevelopmental outcomes. Following a pre-registered protocol and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, 55 studies were included, primarily published in the past 15 years. Earlier studies focused predominantly on biological exposures, while more recent work has increasingly examined psychological exposures and, more rarely, social exposures. While each exposure exhibited its own pattern of brain alterations and neurodevelopmental changes, an overarching pattern emerged across the different components of the biopsychosocial model. Adverse biological exposures were consistently associated with delayed brain maturation as reflected by brain imaging measures. Adverse psychosocial exposures showed a more complex pattern of associations with both delayed and accelerated brain maturation. Crucially, adverse exposures, whether associated with delayed or accelerated brain maturation, were consistently associated with poorer neurodevelopmental outcomes, underscoring the necessity of considering both brain and behavior when estimating the impact of early exposures. We conclude that research into early-life exposures on brain maturation and neurodevelopmental outcomes is on the rise, but there is a great need for further investigation, in particular of psychological and social exposures. The interactions between exposures, the brain, and outcomes are highly complex, requiring assessment of both brain development and behavior together, ideally in within-subject longitudinal designs in future studies.

Objectives Increased risk of childhood obesity up to age six years has been linked to higher maternal allostatic load (AL), the physical manifestation of repeated stress exposure. However, associations are less evident when using psychological stress indicators, and data mainly come from higher income countries. Using psychological and physiological stress markers, this study evaluates maternal stress exposures and child risk of obesity in Peruvian women and their children, ages 5 to 15 years, living in a disadvantaged urban area. Methods Maternal stress exposures included mental distress (12-item General Health Questionnaire scores of 5+ for moderate/high and <5 for no/low distress) and AL (lower/moderate/higher AL assessed from Latent Profile Analysis of hair cortisol, BMI, waist circumference, systolic and diastolic blood pressure). Child outcomes included BMI-for-age and waist circumference-for-age z scores (BAZ and WCAZ). Linear regression analyses were conducted, adjusting for confounders and reported as coefficients and 95% confidence intervals (95% CI). Results Versus mothers with no/low distress, those with moderate/high distress had children with 0.40 (95% CI: -0.66,-0.13) and 0.32 lower (-0.53,-0.11) child BAZ and WCAZ respectively. Versus lower AL mothers, moderate AL mothers had children with 1.15 (0.41,1.88) and 0.74 (0.20,1.28) greater BAZ and WCAZ while higher AL mothers had children with 1.43 (0.95,1.92) and 0.91 (0.50,1.32) greater BAZ and WCAZ respectively. Conclusions Children of mothers with higher AL were at greater risk of overweight or obesity, which may add to the rising burdens of non-communicable diseases in resource-constrained settings as well as the related social, economic, and public health costs.

Long COVID (LC) is a broad label encompassing the heterogeneous long-term consequences of SARSCoV2 infection that persist for at least 3 months post-infection. Despite its substantial global burden, there is still a lack of reliable biomarkers or panels capable of distinguishing individuals with Long COVID from healthy individuals or from those who have recovered from acute COVID-19. We previously characterized a biomarker panel comparing 85 adults with WHO-defined Long COVID against 85 age- and sex-matched controls who had recovered within three months of acute COVID-19 in 2020, at between 12 and 24 months post-infection. That initial profile evaluated blood cell counts, coagulation status, routine SARS-CoV-2 serology, immune cell populations, and basic cytokine levels based on Luminex assays. We have enhanced our biomarker panel by incorporating more precise cytokine quantification using the high-precision ELLA automated immunoassay system. To assess potential ongoing peripheral systemic inflammation, we measured classical inflammatory markers in blood, including C-reactive protein (CRP), tumor necrosis factor alpha (TNFalpha), interleukin (IL)1beta, and IL6. In this manuscript, we present data that confirm age- and gender-matching between the LC and control group; and compared differences in cytokine levels and comorbidities.

IntroductionBipolar disorder (BD) is characterized by recurring episodes of mania and depression. Despite extensive research, the pathophysiology underlying these mood swings remains elusive. Emerging evidence indicates a potential role for neuroinflammation and microglial activation in the pathophysiology of BD. MethodsWe employed a reverse-translational approach to generate directly induced microglia-like (iMG) cells from peripheral blood monocytes of a single patient with BD, repeatedly sampled across depressive, manic, and subsequent depressive phases. RNA sequencing was performed on iMG cells at each time point to identify differentially expressed genes related to mood state transitions. ResultsA thorough analysis of longitudinal gene expression data has led to the identification of three functional gene categories: "state-dependent genes", "depression-to-mania transition genes (named: firing genes)", and "mania-to-depression transition genes (named: extinguishing genes)". A total of 168 firing, 59 extinguishing, and 77 state-dependent genes were identified. Notably, functional annotation revealed that, compared to the extinction gene set, the firing gene set was enriched in immune and inflammatory response pathways, particularly early-response cytokines such as IL1B and TNF. ConclusionsBased on these findings, we propose that inflammatory immunomodulation by microglia contributes to mood switching in BD, especially in the process of depression-to-mania transition. The classification of genes by their relationship to state transitions offers a novel framework for understanding the molecular mechanisms underlying this complex disorder and may identify potential therapeutic targets to stabilize mood. Further validation with larger cohorts is warranted.

Disruptions in excitatory-inhibitory (E/I) balance during neurodevelopment have been implicated in a range of psychiatric conditions, yet the neurochemical alterations associated to early-life insults and their potential contribution to E/I imbalance remain poorly understood. Using a "two-hit" rat model combining maternal immune activation (MIA; lipopolysaccharide -LPS- on gestational days 15-16) and peripubertal unpredictable stress (PUS; postnatal days 28-38), we examined the long-term effects of these insults, alone and in combination, on the adult dorsal hippocampus. Assessments included gene and/or protein expression of glutamatergic and GABAergic markers, endocannabinoid system enzymes, neuromodulatory amino acid level and prepulse inhibition (PPI) of the acoustic startle response. MIA increased GluN1 protein expression, while PUS reduced the Grin2a/Grin2b mRNA ratio, indicating incomplete NMDA receptor subunit maturation. GABA levels and GABA-A{gamma}2 expression were unchanged, suggesting deficient inhibitory compensation in the face of heightened excitatory tone. PUS increased Mgll gene expression, whereas a trend towards reduced Dagla expression was observed exclusively in non-stressed LPS-exposed animals, suggesting that MIA may suppress 2-AG synthesis only in the absence of subsequent stress. MIA and PUS displayed interactive effects on taurine levels, with elevation observed only in the double-hit condition; glycine was elevated by MIA independently of PUS. These findings support a model in which MIA and PUS converge on hippocampal E/I balance through complementary adaptations -- excitatory upregulation, incomplete synaptic maturation, and reduced endocannabinoid tone -- inadequately counterbalanced by inhibitory systems. Taurine and glycine emerge as potential markers of homeostatic compensation in response to early neurochemical dysregulation.

Black carbon (BC), a combustion-derived component of fine particulate matter, has been linked to depressive symptoms, but controlled experimental evidence remains limited. We established a controlled BC inhalation model combined with chronic restraint stress (CRS) to determine whether inhaled BC alone induces depressive-like behavior and whether concurrent stress enhances behavioral and molecular vulnerability. Male C57BL/6J mice were assigned to Control, CRS, BC, or BC+CRS groups and exposed for 21 consecutive days, followed by behavioral testing and molecular analyses of plasma-depleted whole blood and stress-related brain regions. BC exposure alone induced depressive-like behavior, and the combined BC+CRS condition showed the most pronounced phenotype. These findings indicate that inhaled BC is sufficient to influence stress-relevant behavior and may heighten vulnerability under chronic stress. At the molecular level, BC shifted peripheral responses toward a stress- and inflammation-associated state with reduced plasticity-related signaling, whereas CRS preferentially engaged glucocorticoid-responsive regulation. Combined BC+CRS exposure further altered plasticity- and transcription-related regulatory programs in blood and stress-related brain regions, with prominent changes in the nucleus accumbens. These condition-dependent molecular patterns suggest that BC engages blood-brain stress-related pathways in a context- and region-specific manner. Together, these findings identify inhaled BC as a neurobehaviorally relevant environmental hazard.

Chronic cocaine use is associated with neuroinflammation and cognitive dysfunction, but the underlying mechanisms remain unclear. We previously identified oral enrichment of Streptococcus parasanguinis (SP) and other species in individuals with cocaine use disorder (CUD), and here demonstrate that cocaine selectively enhanced SP growth in vitro. To investigate causality, antibiotic-pretreated wild-type C57BL/6 mice received chronic oral inoculation of SP, S. salivarius, Neisseria flavescens, or vehicle. SP-treated mice exhibited spatial memory impairment, increased brain IL-1{beta}, and non-region-specific microglial activation, without detectable bacterial translocation into the brain. While amyloid-associated signaling changes were observed across all bacterial treatment groups, only SP induced cognitive deficits and neuroinflammation. Untargeted metabolomics identified distinct SP-associated oral-to-brain metabolite signatures, including cysteine S-sulfate (CSS) and altered histamine-associated metabolites. CSS and histamine induced neuroinflammatory and amyloid-associated responses in vitro. Together, these findings identify a cocaine-associated oral pathobiont that promotes neuroinflammation and neurodegeneration, suggesting a novel oral microbiome-brain axis in CUD.

Early life stress (ELS), modeled in rodents through neonatal maternal separation (NMS), induces lasting behavioral and molecular alterations including pain hypersensitivity, anxiety-like behaviors, and cognitive deficits. While NMS disrupts the oxytocinergic system, the specific contribution of oxytocin receptor (OTR) dysfunction during critical neurodevelopmental periods remains unclear. Here, we investigated whether neonatal OTR blockade alone could recapitulate key features of the NMS phenotype. Control rats received daily injections of the selective OTR antagonist d(CH2)5-Tyr(Me)-[Orn8]-vasotocin (dOVT) during postnatal days 2-12, matching the NMS period. At adulthood, behavioral assessments revealed that control+dOVT animals exhibited mechanical and cold thermal hypersensitivity similar to NMS rats, though hot thermal sensitivity was unaffected. Anxiety-like behaviors observed in NMS animals were not reproduced by dOVT treatment. Notably, sex-specific spatial memory deficits emerged: male NMS and female control+dOVT rats showed impaired object location recognition, while females and males in their respective opposite groups remained unaffected. Molecular analyses of spinal cord tissue revealed significant downregulation of GAD65, BDNF, and CD11b in control+dOVT animals. Chloride cotransporters NKCC1 and KCC2 exhibited sexual dimorphism with opposite changes in NMS males versus females and different responses to dOVT. These expressions yet converged on an elevated NKCC1/KCC2 ratio in both sexes, indicating compromised chloride homeostasis despite sex-divergent molecular pathways. These findings demonstrate that developmental OTR dysfunction likely contributes to nociceptive and cognitive consequences of ELS, while anxiety-like phenotypes probably involve additional mechanisms. This work highlights OTR as a critical mediator of neurodevelopmental programming and a potential therapeutic target for mitigating ELS-related disorders.

Background Multimorbidity is increasingly prevalent, and associated with worse clinical and psychosocial burdens. Interoception, the brain's ability to sense and interpret internal bodily signals, may contribute to multimorbidity, through its link with health behaviors, stress regulation, and mental health. This study examines whether self-reported interoceptive accuracy and attention is associated with multimorbidity, by identifying multimorbid subgroups and their interoceptive profiles. Methods Morbidity classes were identified through latent class analyses in two Dutch survey datasets, focusing on depression and alexithymia (DA-dataset; N = 671) and lifestyle factors (L-dataset; N = 1022). Linear regression analyses were used to assess interoceptive accuracy and attention (by the Interoceptive Accuracy Scale and Interoceptive Attention Scale respectively) among different subgroups. Results Multimorbid subgroups were characterized by older age, low socioeconomic position, and elevated physical, psychological, and behavioral problems. Multimorbid classes exhibited lower interoceptive accuracy (DA-dataset: B = -1.14, 95% CI = [-2.89, 0.62]; L-dataset: B = -2.36, 95% CI = [-3.83, -0.89]) and higher attention (DA-dataset: B = 3.62, 95% CI = [0.97, 6.27]; L-dataset: B = 1.07, 95% CI = [-1.42, 3.56]) compared to healthier classes. Conclusion Multimorbid populations demonstrated lower interoceptive accuracy and higher interoceptive attention. This highlights the psychosocial complexity of multimorbid populations which may impact their self-management and health behavior. These findings underscore the need to expand treatments to include psychosocial domains for multimorbid patients.

The prevalence of neurodevelopmental disorders (NDDs) has increased dramatically, with growing evidence linking prenatal maternal stress exposure to NDDs. Across diverse maternal stressors, immune dysregulation emerges as a common feature, suggesting that fetal microglia may detect changes in the intrauterine environment and influence neurodevelopment. Accordingly, we utilized a mouse model of prenatal maternal cold stress to investigate the impact of maternal stress during pregnancy on fetal microglia morphology, cellular interactions, and phagocytic behaviors. Pregnant mice were exposed to cold stress from embryonic day 11.5 (E11.5) to E15.5 and fetal hypothalamic tissue was assessed from both male and female embryos. By adapting the morphology analysis toolset MicrogliaMorphology to assess fetal microglia, we demonstrate regional differences in microglial morphology in the fetal hypothalamus at baseline, with hypothalamic nuclei such as the paraventricular nucleus (PVN) containing fewer rod-like microglia compared to the broader hypothalamus. Interestingly, prenatal maternal cold stress induced a male-specific shift in microglial morphology from ameboid to ramified within the E15.5 PVN. Male embryos also displayed increased microglial-arginine vasopressin (AVP) neuronal interactions and microglial phagocytosis within the E15.5 PVN, but these changes were unique to microglia with a ramified morphology and were not observed when microglia with an ameboid or rod-like morphology were assessed. Using pHrodo bioparticles and flow cytometry, we further illustrate that prenatal maternal cold stress drives increased phagocytic activity in the E15.5 hypothalamus of male embryos, but not females. Together, these data demonstrate that prenatal maternal cold stress alters microglia morphology and drives morphology-dependent microglial interactions and phagocytic behaviors in male embryos which are unique to the hypothalamic PVN--a nuclei critical for social behaviors. Our findings also suggest that specific hypothalamic nuclei such as the PVN may be more sensitive to prenatal maternal stress, which has the potential to provide a cellular basis underlying the sex differences in microglia-dependent social deficits that were previously reported for this model.