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.

Chemotherapy-induced cognitive impairment (CICI), a frequent consequence of doxorubicin (DOX) treatment in patients with breast cancer, currently lacks effective preventive measures. This work explored whether administering basic fibroblast growth factor (bFGF)-encapsulated elastic nanoliposomes (bFGF-Els) administered intranasally could mitigate DOX-induced cognitive impairment in a mouse model of triple-negative breast cancer. The optimized bFGF-Els were spherical and uniform, with a mean size of 110.8 nm, a polydispersity index of 0.079, a zeta potential of -32.6 mV, an encapsulation efficiency of 87.5%, and favorable deformability. Compared with those receiving DOX alone, mice receiving intranasal bFGF-Els showed markedly better cognitive performance, as evidenced by reduced escape latency and increased platform crossing and target quadrant time (all P < 0.01). Histological and biochemical analyses revealed that bFGF-Els attenuated hippocampal CA1 neuronal damage, decreased reactive oxygen species and malondialdehyde levels, restored superoxide dismutase and glutathione peroxidase activity, and reduced pro‑inflammatory cytokines (interleukin‑1β, interleukin‑6, and tumor necrosis factor‑α) (all P < 0.01). At the mechanistic level, bFGF-Els increased the ratios of phosphorylated PI3K to total PI3K and phosphorylated AKT to total AKT and increased the levels of nuclear Nrf2 (nuclear factor erythroid 2‑related factor 2), heme oxygenase‑1(HO-1), NAD(P)H:quinone oxidoreductase‑1(NQO1), and B‑cell lymphoma 2 (Bcl-2), while reducing nuclear factor‑κB (NF-κB), Bcl‑2‑associated X protein (Bax), and cleaved caspase‑3 (all P < 0.01). bFGF-Els did not affect the anti-tumor efficacy of DOX, as the tumor volume and weight were similar among all the groups treated with DOX (P > 0.05). In conclusion, intranasal bFGF-Els enable efficient bFGF transport to the brain and relieves DOX-triggered CICI by curbing oxidative stress, neuroinflammation, and apoptosis through the PI3K/AKT axis, all while preserving the antitumor activity of chemotherapy.

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.

HIV-associated neurocognitive impairment (NCI) affects up to 50% of individuals living with HIV, causing cognitive, motor, and behavioral deficits, largely driven by brain inflammation. Activation of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor primarily involved in regulating lipid and glucose metabolism, has demonstrated anti-inflammatory effects in neurodegenerative diseases. However, its efficacy in addressing HIV-associated NCI remains unclear. We investigated whether INT131, a novel selective PPARγ agonist, could mitigate HIV-induced brain inflammation and neurocognitive deficits in male and female mice using the EcoHIV mouse model. Mice were intraperitoneally (IP) injected with either saline or EcoHIV and evaluated six weeks post-infection across four groups: (i) saline control, (ii) saline + INT131 (20 mg/kg/day, administered IP via osmotic pumps for 28 days), (iii) EcoHIV + saline, and (iv) EcoHIV + INT131 (n = 10-12/group). We analyzed the expression of viral genes, inflammatory, and oxidative stress markers in spleen and brain tissues, along with neuroprotective/apoptotic markers, p-NF-κB p65, PPARγ and blood-brain barrier (BBB) tight junction proteins. Behavioral assessment evaluated locomotion, learning, memory and anxiety. In EcoHIV infected male and female spleen and brain tissues, INT131 significantly reduced the expression of viral genes, viral p24, inflammatory cytokines/chemokines, and oxidative stress markers. Furthermore, INT131 mitigated expression of BBB tight junction proteins, PPARγ, and neuroprotective markers. Behavioral deficits induced by EcoHIV were reversed following INT131 treatment in both sexes. These findings suggest that PPARγ could serve as a novel molecular target for the treatment of HIV-associated NCI, with INT131 identified as a promising therapeutic candidate.

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.

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.

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.