Major depressive disorder (MDD) is increasingly recognized as involving both neuroinflammatory alterations and synaptic pathology. While (2R,6R)-hydroxynorketamine (HNK) exerts rapid antidepressant effects via synaptic modulation, memantine (MEM) shows complementary neuroprotective properties. However, whether their combination offers complementary benefits in inflammation-associated depressive-like phenotypes remains unclear. We investigated MEM combined with low-dose HNK (MEM + 1/2HNK) using an acute LPS-induced model of depressive-like behavior in male mice and primary cortical neuron cultures. Behavioral assessments included sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), and open field test (OFT). Proteomic profiling, western blotting, immunocytochemistry, and microelectrode array (MEA) recordings were performed. K252a, a broad-spectrum kinase inhibitor commonly used to interfere with Trk receptor-associated signaling, was used to assess the involvement of BDNF/TrkB-related signaling. MEM + 1/2HNK alleviated LPS-induced behavioral deficits in the SPT, FST, and TST, producing effects broadly comparable to full-dose HNK, whereas reduced-dose HNK and MEM alone showed limited efficacy. Proteomic profiling of the medial prefrontal cortex (mPFC) revealed upregulation of glutamatergic synapse and mTOR signaling proteins. MEM + 1/2HNK restored excitatory synapse density and activated the BDNF-TrkB-PI3K-AKT-mTOR signaling pathway in vivo and in vitro. MEA recordings demonstrated that MEM + 1/2HNK reversed LPS-induced disruptions in neuronal network firing rates and synchrony. K252a treatment attenuated the behavioral, synaptic, and electrophysiological improvements induced by MEM + 1/2HNK, supporting the involvement of Trk receptor-associated signaling. Together, these findings suggest that MEM and low-dose HNK counteract inflammation-associated neural dysfunction in association with Trk-related signaling. These proof-of-concept findings do not establish a safety or overall drug-burden advantage over full-dose HNK and require validation in both sexes before translational advantages can be inferred.
BACKGROUND:Dysregulation of microbiota-gut-brain axis has been implicated in depression, with immune and inflammatory signalling representing potential pathways linking gut microbial alterations to depressive symptoms. Short-chain fatty acids (SCFAs), namely acetate, propionate and butyrate are promising immunomodulating mediators of systemic inflammation and neuroplasticity. However, clinical trials of this pathway have given inconsistent results. The aim of this research was to conduct a synthesis of evidence for the therapeutic role of SCFAs using two approaches, to assess association between SCFA levels and depressive symptom severity, and to assess the efficacy of interventions targeting SCFA-related pathways for depressive symptoms. METHODS:PubMed, Scopus, PsycINFO, Cochrane Library, and Web of Science were searched from inception till 2 March 2025. Searches were updated on 13 November 2025. For intervention meta-analysis, randomized controlled trials (RCTs) evaluating interventions that have the potential to modulate SCFA production (probiotics, fecal microbiota transplantation (FMT), transcutaneous auricular vagus nerve stimulation (taVNS) and direct SCFA administration were included. For correlation meta-analysis, observational studies correlating the fecal SCFA levels with depression scores and RCT derived dataset were used. Here, correlation coefficients and Standardized Mean Differences (SMD) were pooled using random-effects models. Sensitivity and subgroup analyses were conducted to explore a moderating effect of the intervention type and the metabolic status (BMI). RESULTS:The review included eight randomized controlled trials (N = 430) of which 7 (N = 385) contributed to primary intervention meta-analysis and 7 observational studies (N = 369). Up to 6 datasets contributed to the faecal SCFA correlation meta-analyses. Among non-obese individuals, acetate (p < 0.001) and propionate (p = 0.004) depletion levels were significantly associated with increased severity of depression. SCFA-modulating interventions had a significant beneficial effect on depressive symptoms in comparison to controls (Overall SMD - 0.74, 95% CI - 1.10 to - 0.37; p < 0.0001; I^2 = 64%)), k = 7. Across intervention classes, point estimates were largest for FMT (SMD (-1.45), taVNS (SMD (-1.04), and direct sodium butyrate (SMD (-0.84) although formal subgroup differences were not statistically significant (p = 0.44). Exploratory sensitivity analyses suggested that obesity status may be a potential biological moderator of treatment response, although this finding should be considered hypothesis-generating. CONCLUSION:This meta-analysis provides preliminary evidence that targeting the immunometabolic gut-brain axis through SCFA-related pathways may represent a promising approach for depressive symptoms, with exploratory findings suggesting a potential role of metabolic phenotype. The findings support further investigation of phenotype-directed SCFA-related interventions, incorporating metabolic and inflammatory characteristics alongside clinical outcomes. Future precision psychiatry trials should be stratified by metabolic status to identify patient subgroups most likely to respond to this form of immunomodulation.
BACKGROUND:Inflammation in pregnancy induced by chronic disease, infection, or environmental exposures has been associated with neurodevelopmental conditions in observational study designs. OBJECTIVE:To investigate causal effects of pregnancy inflammation on offspring neurodevelopment in the Norwegian Mother, Father and Child Cohort Study (MoBa) using a genetically informed design. METHODS:In pre-registered analyses, we tested potential causal effects of increased C-reactive protein (CRP), interleukin-6 (IL-6), and glycoprotein acetyls (GlycA) in pregnancy on neurodevelopmental outcomes using trio polygenic score (PGS) and intergenerational Mendelian randomization (MR) analyses. PGS and MR genetic instruments were used to predict neurodevelopmental outcomes in the MoBa cohort, which included mother-reported neurodevelopmental traits registered from age 3 to 8 years and diagnoses of ADHD and autism. In both the trio PGS and intergenerational MR analyses, simultaneous inclusion of mothers', fathers', and children's genotypes allowed for effects consistent with the hypothesized causal pathway (maternal inflammation) to be estimated independent of familial confounding factors. RESULTS:Validation analyses of genetic instruments only showed strong predictive value for CRP. Trio PGS in 41,531 complete trios did not reveal maternal indirect effects of genetic liability to higher CRP on offspring neurodevelopmental outcomes. The results of the trio MR also failed to support a causal link between maternal inflammation, proxied by higher CRP, during pregnancy and offspring neurodevelopment. CONCLUSION:This study provided no evidence consistent with causal effects of higher CRP in pregnancy on offspring neurodevelopment. This may imply that observational links are driven by genetic confounding, though other factors - such as selective participation in MoBa - cannot be ruled out as alternative explanations for our null findings.
BACKGROUND AND AIMS:Post-traumatic stress disorder (PTSD) comorbid with depression is a prevalent, treatment-refractory clinical syndrome. Emerging evidence indicates shared microglial alterations in PTSD and depression, suggesting it may represent a common pathological substrate. However, the underlying neuroimmune mechanisms remain unclear. METHODS:PTSD- and depression-like behaviors were induced in rats by using single prolonged stress combined with foot shock (SPS&S). Cellular activity, spatial distribution, and morphology were assessed using qPCR, immunofluorescence, and Golgi-Cox staining. Microglial activity was inhibited using clodronate liposomes (CDSlip) and minocycline. Bulk RNA sequencing was performed to profile neuroimmune-related signaling molecules. RESULTS:Stress induced PTSD- and depression-like behaviors, accompanied by region-specific enhanced microglial activity in the anterior-medial NAC core (amNACc) and lateral NAC shell (LNACsh). Selective depletion of microglia in amNACc and LNACsh via CDSlip specifically alleviated stress induced PTSD- and depression-like behaviors, respectively. Morphological and functional analyses in each region revealed that microglia reshaped the spatial pattern of neuronal structure and function, manifested by enhanced in amNAC and inhibited in LNACsh, via differentially pruning adjacent inhibitory synapses in corresponding region. Further transcriptomic analysis of synaptic pruning relevant signaling pathway showed upregulated expression of "Eat me" signal molecules (particularly Mertk) in the amNAC and downregulated expression of "Find me" signal molecules (particularly Cx3cr1) in the LNACsh, consistent with the observed spatial synaptic pruning profiles. Minocycline administration reversed stress-induced PTSD and depression-like behaviors while normalizing the region-specific alterations in synaptic pruning signaling molecules. CONCLUSION:Stress may elicit two regionally heterogeneous microglial subpopulations within NAC: phagocytosis-enhanced and recognition-impaired, which remodel the structure and function of local neural networks by differential pruning of inhibitory synapses, thereby driving the manifestation of PTSD- and depression-like behaviors, separately. These findings deepen our understanding of the neuroinflammatory mechanisms underlying trauma-related psychiatric disorders and identify novel targets for immunomodulation-based targets for transdiagnostic interventions .
Sleep disturbances can trigger peripheral inflammatory responses, and both poor sleep and inflammation have been linked to cognitive impairment. However, whether peripheral inflammation mediates the association between sleep quality and cognitive health remains insufficiently tested. We analyzed data from two independent cohorts: 259,817 non-demented participants (mean age 58 years, 55.39% female, mean follow-up 10.29 years) from the UK Biobank (UKB) and 1,107 participants (mean age 74 years, 56.82% female, mean follow-up 4.17 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). At baseline, sleep quality was assessed using self-reported or caregiver-reported information. Peripheral blood lymphocyte count (LYM), neutrophil count (NEU), neutrophil-to-lymphocyte ratio (NLR), and serum C-reactive protein (CRP) were used as pragmatic peripheral inflammatory markers. Causal mediation analyses tested whether peripheral inflammation mediated the associations of sleep quality with cognitive performance and risk of incident dementia. In both cohorts, poor sleep quality was associated with higher levels of LYM, NEU, NLR and CRP (p < 0.001), and with lower cognitive function (p < 0.001). Poor sleep quality was also associated with an increased risk of incident dementia in UKB (p < 0.001), whereas this association was not significant in ADNI (p = 0.33). Higher NEU, NLR, and CRP levels were associated with lower cognitive function (UKB, p < 0.001; ADNI, p < 0.05) and increased risk of dementia (p < 0.001). In UKB, selected markers mediated the associations of sleep quality with fluid intelligence (p < 0.001), numeric memory score (p < 0.05), and risk of incident all-cause dementia and Alzheimer's disease (p < 0.001). However, the mediation proportions were limited (< 10%). In ADNI, no significant mediation was observed. These findings suggest that peripheral inflammation provides a statistically significant but quantitatively limited explanation for the association between sleep and cognitive health. Future studies should investigate additional mechanisms and potential intervention targets in more diverse cohorts.
Dysregulated interactions between stress-sensitive neural circuits and immune signaling contribute to depression. We investigated whether the septohippocampal cholinergic pathway mediates the behavioral and neuroimmune effects of transcutaneous auricular vagus nerve stimulation (taVNS). Male mice were studied using chronic unpredictable mild stress (CUMS) and lipopolysaccharide (LPS) challenge models. Depression-related behaviors were assessed using the sucrose preference, forced swim, tail suspension, open field, and elevated plus maze tests. Cholinergic markers, hippocampal cytokines, microglial morphology, and α7 nicotinic acetylcholine receptor (α7nAChR) expression were examined by Western blotting and immunofluorescence. In a separate LPS cohort, hippocampal extracellular acetylcholine (ACh) was measured by microdialysis-HPLC during awake, freely moving recording. Cre-dependent excitatory DREADDs were used to activate medial septal ChAT neurons during taVNS treatment. CUMS increased medial septal ChAT expression and ChAT/c-Fos co-labeling, reduced hippocampal AChE and α7nAChR expression, and increased hippocampal TNF-α, IL-1β, IL-6, and microglial activation. Three weeks of taVNS improved depression-like behaviors and reversed these cholinergic and neuroimmune changes. In LPS-challenged mice, taVNS reduced hippocampal extracellular ACh and improved inflammation-associated anxiety/depression-related behavior. Chemogenetic activation of medial septal ChAT neurons attenuated the behavioral benefits of taVNS. These findings support septohippocampal cholinergic-microglial signaling as a neuroimmune mechanism through which taVNS improves depression-like behavior.
Although gut microbiota dysbiosis is associated with emotional disorders, the signaling pathways that mediate gut-to-brain neuroinflammation remain unclear. This study employed a human microbiota-associated (HMA) mouse model colonized with microbiota from individuals with emotional abnormalities (HMA-EA), combined with functional oligosaccharides intervention experiments and a human intervention trial, to elucidate the mechanisms by which gut microbiota drives neuroinflammation. HMA-EA mice exhibited anxiety- and depression-like behaviors and a gut microbiota dysbiosis characterized by reduced abundance of immune and barrier-protective bacteria (including Turicibacter, Ligilactobacillus, and Lachnoclostridium), which compromised intestinal barrier integrity, compromised blood-brain barrier (BBB) integrity and induced neuroinflammation. Transcriptomic analysis combined with mechanistic validation suggested the IL-22/STAT3 pathway as a potential linkbetween gut microbiota and neuroinflammation. Functional oligosaccharides (chitooligosaccharides, mannan oligosaccharides, and fructo-oligosaccharides) ameliorated behavioral abnormalities, modulated immune and barrier-protective microbes, repaired intestinal barrier damage, and attenuated excessive activation of IL-22/STAT3 pathway, concurrently with attenuated neuroinflammation and preserved BBB integrity. A 12-week human intervention in a stress-exposed population provided preliminary evidence that functional oligosaccharides supplementation was associated withenrichment of microbeslinked to immune and barrier protection and attenuate activity of this pathway. Collectively, these findings reveal an association between gut microbiota, activation of the IL-22/STAT3 pathway, neuroinflammation, providing evidence to support microbiota-targeted interventions for mood disorders.
Calcitonin gene-related peptide (CGRP) is a key therapeutic target for migraine, yet its dual role in central neuroimmune regulation remains incompletely understood. This study reveals a critical paradox: while CGRP directly promotes anti-inflammatory activation of microglia in vitro, treatment with the CGRP receptor antagonist BIBN4096BS in a chronic migraine mouse model rapidly alleviated pain but was not accompanied by an increase in microglial anti-inflammatory markers, including CD206 and p-STAT6. This finding suggests that complete CGRP blockade may inadvertently attenuate a masked endogenous pro-repair tone. To supplement this signaling, we introduced IL-4 intervention. IL-4 not only restored microglial anti-inflammatory function via STAT6 pathway activation but also produced synergistic analgesic effects when combined with the CGRP antagonist, superior to either monotherapy. STAT6 overexpression further enhanced the anti-inflammatory effect of the CGRP and IL-4 combination, while STAT6 knockdown completely reversed this protective effect. These findings demonstrate that CGRP antagonism, while providing rapid analgesia, may come at the cost of suppressing neuroimmune repair. Combining CGRP antagonism with STAT6 pathway activation may offer a strategy to simultaneously block vasogenic pain and support immune homeostasis, providing a new conceptual framework for migraine therapy.
BACKGROUND:Cardiovascular-Kidney-Metabolic (CKM) syndrome is a pioneering paradigm focused on multisystem homeostasis. Nevertheless, the long-term cerebral manifestations of CKM syndrome and its specific relationship with neuropsychiatric disorders remain poorly understood. METHODS:Data for the study were obtained from Health and Retirement Study, UK Biobank, China Health and Retirement Longitudinal Study, and National Health and Nutrition Examination Survey. The exposures are continuous CKM stages (stages 0-4). The main outcomes were dementia, Parkinson's disease, depression, anxiety, and sleep disorders. Models were adjusted for demographic characteristics, lifestyle factors, and history of cancer. Proteomic signatures, brain structure, epigenetic aging, and inflammatory markers provided clues to the underlying associations. RESULTS:A total of 321,107 participants aged ≥45 years were included in the analysis. Advanced CKM syndrome exhibited higher risks of five disorders (Stage 4 in UK Biobank: HR, 95%CI: 1.91, 1.79-2.04 in dementia; 1.62, 1.45-1.80 in Parkinson's disease; 1.75, 1.66-1.84 in depression; 2.33, 2.18-2.48 in sleep disorders; 1.48, 1.40-1.56 in anxiety). CKM syndrome was associated with accelerated phenotypic aging and reduced volumes in the parietal, temporal, and orbitofrontal lobes. Enrichment analysis identified the "Cytokine-cytokine receptor interaction" pathway as a top enriched pathway in both disease clusters, highlighting the central role of immune-inflammatory signaling. Inflammatory markers, phenotypic aging, and certain proteins (GDF15 and PLAUR) may partly mediate the associations of CKM syndrome with these outcomes. CONCLUSIONS:Results of this study revealing the robust and persistent association of CKM stages with neurological and psychiatric disorders suggest that early intervention may be important for cognitive performance and emotional well-being in middle-aged and older adults.
Low-grade inflammation has been linked to altered reward processing and risk for mood disorders in adults, yet it remains unclear whether genetic liability for inflammation is associated with reward circuitry function before the typical age of onset for depression and anhedonia. Using data from the Adolescent Brain and Cognitive Development Study, we examined whether a polygenic score for C-reactive protein (PGS-CRP) was associated with striatal activation during reward processing in 4,830 children of European ancestry (ages 9-10). Participants com pleted the Monetary Incentive Delay task during functional MRI. Linear mixed-effects models tested associations between high versus low PGS-CRP and activation in the nucleus accumbens, caudate, and putamen during reward and loss anticipation and feedback, adjusting for sociodemographic, anthropometric, scanner, and genetic ancestry covariates. Higher PGS-CRP was associated with attenuated activation across all three striatal regions (i.e., the nucleus accumbens, caudate, and putamen) during anticipation of large relative to small rewards at baseline (all pFDR < 0.05, beta coefficient range from -0.014 to -0.017). Associations were not observed for loss anticipation, average reward anticipation, or reward/loss feedback, suggesting altered reward-magnitude coding rather than generalized incentive hypoactivation. The caudate effect persisted across 6 years of longitudinal follow-up into mid-to-late adolescence and remained robust after adjustment for psychiatric diagnoses and psychotropic medication. These findings provide the earliest population-level evidence that genetic inflammatory liability is associated with attenuated striatal reward-value coding, identifying a candidate neuroimmune pathway preceding clinical risk.
Stress is a major risk factor for substance use disorders, promoting vulnerability to cocaine-related behaviors through neuroimmune-glutamatergic dysregulation in the nucleus accumbens core (NAcore). Previous evidence from our laboratory has identified nuclear factor kappa B (NF-κB) as a key transcriptional regulator that sustains stress-induced glial activation, proinflammatory signaling, and downregulation of the glutamate transporter (GLT-1) in this region. Although lentiviral inhibition of NF-κB within the NAcore prevents these alterations, it remains unclear whether this pathway can be effectively targeted pharmacologically to restore the disrupted inflammatory-glutamatergic balance associated with cocaine sensitization. Here, we investigated whether local pharmacological inhibition of NF-κB using pyrrolidine dithiocarbamate (PDTC) reverses stress-induced cocaine cross-sensitization and associated molecular adaptations. Rats were exposed to chronic restraint stress (2 h/day for 7 days). Fourteen days after the first stress exposure, guide cannulae were implanted into the NAcore. On day 21, stressed and non-stressed animals received intra-NAcore microinjections of PDTC (5-20 μM) or vehicle prior to a saline or cocaine challenge (15 mg/kg, i.p.), and locomotor activity was assessed. NF-κB signaling (p65 nuclear translocation, cytosolic p65 levels and IKK phosphorylation), protein levels of GLT-1 and TNF-α, and related gene expression of GLT-1, TNF-α, IL-6, and IL-10 were quantified. PDTC dose-dependently abolished behavioral sensitization, suppressed p65 nuclear translocation and IKK phosphorylation, reversed TNF-α upregulation, and increased GLT-1 expression, while not preventing IL-10 induction. These findings provide pharmacological evidence supporting a central role for NF-κB activation within the NAcore in stress-induced cocaine sensitization and associated neuroimmune-glutamatergic adaptations. Targeting this pathway with PDTC or related NF-κB inhibitors may represent a promising strategy to reduce stress-related vulnerability to substance use disorders.
Perceived everyday discrimination is a psychosocial stressor that is adversely associated with biological health. These associations may be partly mediated by the modulation of leukocyte gene expression through stress-related neuroendocrine pathways. The Conserved Transcriptional Response to Adversity (CTRA) provides a framework for examining how everyday discrimination may alter molecular signaling pathways through coordinated changes in gene expression. This study quantified associations between perceived everyday discrimination and CTRA patterns in a diverse, nationally representative sample of U.S. adults. Data were drawn from Wave 5 (2016-2017) of the National Longitudinal Study of Adolescent to Adult Health (Add Health). Perceived everyday discrimination was assessed using the validated Everyday Discrimination Scale and standardized using z-scores. CTRA gene expression was evaluated using an a priori-defined set of 52 genes. Weighted regression models tested associations between everyday discrimination and CTRA, sequentially adjusting for sociodemographic, behavioral, clinical, and technical covariates. We found no evidence of a linear association between discrimination and CTRA. However, exploratory analyses suggested a non-linear (inverted-U) relationship (b = -0.023, 95% CI: -0.044, -0.001, p = 0.036); the association was directionally positive at lower exposure but reached significance only at the highest levels, where CTRA expression declined as discrimination increased.. This pattern indicates that the relationships of discrimination with gene expression may not follow a straightforward dose-response pattern, instead reaching a threshold beyond which additional exposure elicits reduced biological reactivity, possibly reflecting adaptation or coping among those exposed to chronic discrimination.
Regular physical exercise promotes brain plasticity and cognitive functions; however, many individuals with neurological or neuropsychiatric impairments face barriers that limit adherence to exercise-based interventions. Exercise-induced microRNAs (miRNAs) have emerged as potential regulators of activity-dependent signaling pathways associated with brain health. Using a voluntary wheel-running mouse model, we identified hippocampal miRNAs responsive to five weeks of exercise in both male and female mice. Small RNA sequencing detected 698 hippocampal miRNAs. Although overall hippocampal miRNA expression profiles were not significantly separated by exercise status, differential expression analysis identified miR-212-3p, miR-212-5p, and miR-466d-3p as significantly upregulated following exercise after adjustment for sex. KEGG pathway analysis of 285 predicted target genes revealed enrichment in pathways related to synaptic function, neurogenesis, inflammation regulation, and tissue remodeling. To determine whether exercise-responsive miRNAs remain inducible under neuropathological conditions, we evaluated their expression in a chronic methamphetamine (METH) and EcoHIV co-exposure mouse model. Voluntary exercise significantly increased hippocampal expression of miR-212-3p, miR-212-5p, and the co-transcribed miR-132-3p in both female and male mice, whereas miR-466d-3p was no longer responsive. Exercise was also associated with reduced astrocyte activation in the caudate putamen and partial recovery of neuronal integrity, as reflected by increased NeuN immunoreactivity in the hippocampal CA1 region, although recognition memory was not significantly restored during the intervention period. Together, these findings identify the miR-212/132 cluster as a robust exercise-responsive miRNA signature that remains inducible in a chronic METH/EcoHIV mouse model and may represent a promising candidate for future studies of exercise-mimetic strategies aimed at promoting brain resilience.
Immunity impacts all aspects of Alzheimer's disease (AD) pathology. Previously, we found improved pathology and cognition in the amyloid-focused 5XFAD mouse model deficient in the innate immune cell axis consisting of the innate-like mucosal-associated invariant T (MAIT) cells and the MHC class I-like antigen-presenting molecule they recognize, MR1. However, little is known about how a lack of the MR1/MAIT cell axis impacts cognition and whether an increased abundance of MAIT cells impacts pathology and cognition in the tau-focused PS19 mouse model. We crossed PS19 mice onto an MR1 KO background, resulting in a lack of both MR1 and MAIT cells, and alternatively, onto MAITCAST mice, that have ∼7× more MAIT cells. Using immunofluorescent microscopy, flow cytometry, and cognitive tests including Barnes maze and Novel Object Recognition, we analyzed the impact of MAIT cell numbers on tau pathology. Although an elevation in MAIT cell frequency was found that expressed higher levels of CD69 in PS19 mice on the MAITCAST vs. wildtype background, overall MAIT cell numbers in the brain did not differ between these groups. Interestingly, increased MR1 expression was detected on microglia only in PS19 mice, whereas MR1 was higher in PS19 and PS19/MAITCAST mouse astrocytes. Increased MAIT cell numbers did not alter tau accumulation or cognitive performance, whereas the lack of the MR1/MAIT cell axis did not affect tau burden, but was associated with reduced neuronal density and impaired recognition memory. Together, these findings suggest that the MR1/MAIT cell axis does not substantially influence the early development of tau pathology.
Psychological stress is a risk factor for cognitive impairment, yet the molecular mechanisms linking stress exposure to hippocampal dysfunction remain incompletely understood. β-Endorphin (β-EP), an endogenous opioid peptide, has been implicated in stress-related processes; however, its contribution to stress-associated cognitive impairment remains unclear. Using a chronic psychological stress model, we found that stressed rats exhibited anxiety- and depression-like behaviors, impaired learning and memory, reduced hippocampal neuronal plasticity, and altered microglial morphology and functional responses. These changes were accompanied by elevated β-EP levels in serum and hippocampal tissue and elevated hippocampal μ-opioid receptor (MOR) and δ-opioid receptor (DOR) expression. In vivo pharmacological studies showed that β-EP administration recapitulated several stress-associated alterations, whereas naloxone partially attenuated these alterations in stressed rats. Using BV2 cells as an exploratory model, β-EP exposure induced cellular alterations, including increased cell proliferation and phagocytic activity, and these changes were partially attenuated by naloxone and the selective MOR and DOR antagonists CTOP and NTI. Transcriptomic analysis and subsequent validation revealed increased NLRP3 inflammasome-related signaling in β-EP-treated BV2 cells, while pharmacological inhibition with the selective NLRP3 inhibitor MCC950 attenuated β-EP-associated cellular alterations. Collectively, these findings suggest that β-EP contributes to psychological stress-associated cognitive deficits in association with opioid receptor signaling and microglial alterations, and suggest NLRP3 inflammasome-related signaling as a potential pathway involved in β-EP-associated cellular responses.
A consequence of neuroinflammation after traumatic brain injury (TBI) is microglial priming and increased sensitivity to secondary challenges including stressors and infections. We investigated whether diffuse TBI was associated with hypothalamic microglial morphological remodeling and altered inflammatory and neuroendocrine responses to a stressor, acute social defeat (ASD). Adult male mice were subjected to diffuse TBI (midline fluid percussion injury) and then were exposed to acute stress (ASD for 2 h) 14 days later. Mice that received both TBI and ASD had increased mRNA expression of several cytokines and chemokines (Il1b, Il6 and Ccl2), receptors (Tlr4 and Itgax) and inflammatory pathways (Nfkb1) in periventricular hypothalamus and the pituitary gland. In addition, neurohormones (Avp and Oxt) were increased by ASD in the TBI mice. CRH immunoreactivity in the hypothalamic paraventricular nucleus (PVN) increased 20 h after ASD in mice with TBI. In behavioral testing, ASD provoked aversion to new objects in the TBI mice. PVN microglial morphological analysis revealed decreased cell size and complexity in mice exposed to TBI and ASD, indicating that ASD and TBI converged to increase microglial morphological remodeling in the hypothalamus. Although these results do not demonstrate that TBI induces microglial priming and sensitization of the hypothalamic stress response, they support that diffuse TBI is associated with changes in the hypothalamus that contribute to an altered response to acute stress, including an amplified neuroinflammatory response, microglial morphological remodeling, alterations in hypothalamic neuroendocrine markers and avoidance-like/anxiety-like behavior. Thus, TBI represents a risk factor for disrupted responses to acute stressors.
