Brain, Behavior, and Immunity最新文献

{"title":"Neuroprotective effects of Bifidobacterium animalis HN019 and Lactobacillus acidophilus NCFM in MPTP-induced Parkinson’s disease mice","authors":"Chengjun Mo ,&nbsp;Yiwei Qian ,&nbsp;Yi Zhang ,&nbsp;Xiaoqin He ,&nbsp;Yiqiu Lai ,&nbsp;Shaoqing Xu ,&nbsp;Penghui Ai ,&nbsp;Xiaodong Yang ,&nbsp;Qin Xiao","doi":"10.1016/j.bbi.2026.106257","DOIUrl":"10.1016/j.bbi.2026.106257","url":null,"abstract":"<div><div>Several studies have demonstrated that modulation of the gut microbiota represents a promising strategy to alleviate symptoms of Parkinson’s disease (PD). Our previous study revealed a depletion of <em>Lactobacillus</em> species in patients with PD and an association between <em>Bifidobacterium</em> abundance and improvement in non-motor symptoms. <em>Lactobacillus acidophilus</em> NCFM and <em>Bifidobacterium animalis</em> subsp. <em>lactis</em> HN019 are two well-characterised probiotic strains. In the present study, a probiotic cocktail containing these two strains exhibited protective effects on both the gastrointestinal tract and the substantia nigra (SN) in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Oral supplementation with the probiotics alleviated motor and non-motor dysfunctions in the PD mouse model. Furthermore, α-synuclein (α-Syn) overexpression was reduced in both the colon and SN. Inflammatory factors and the toll-like receptor 2/toll-like receptor 4-nuclear factor κ-light-chain-enhancer of activated B cells (TLR2/TLR4–NF-κB) signalling pathway in the colon and brain were downregulated following probiotic treatment. Alterations in the gut microbiota were further examined to identify potential regulatory factors of inflammation. The relative abundances of propionate- and butyrate-producing bacteria, their biosynthetic pathways, and the critical enzymes were all elevated in the gut microbiota of probiotic-treated mice. These findings suggest that the probiotic cocktail exerts strong anti-inflammatory effects in both the colon and SN by enhancing microbial production of propionate and butyrate and suppressing activation of the TLR2/TLR4–NF-κB pathway.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106257"},"PeriodicalIF":7.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adverse childhood experiences and physiological wear-and-tear in adolescence: Findings from the Generation XXI cohort","authors":"Armine Abrahamyan ,&nbsp;Milton Severo ,&nbsp;Michelle Kelly-Irving ,&nbsp;Liane Correia-Costa ,&nbsp;Mariana Amorim ,&nbsp;Sara Soares ,&nbsp;Sílvia Fraga","doi":"10.1016/j.bbi.2026.106260","DOIUrl":"10.1016/j.bbi.2026.106260","url":null,"abstract":"<div><h3>Background</h3><div>Adversity-induced stress may increase vulnerability to biological risk and contribute to cumulative physiological dysregulation, as reflected by elevated allostatic load (AL). We aimed to estimate the association between adverse childhood experiences (ACEs) and AL at two different time points in a pediatric population from the population-based Generation XXI birth cohort.</div></div><div><h3>Methods</h3><div>Total ACE scores were derived from prospectively collected data at ages 10 and 13. AL was assessed using nine biomarkers across four physiological systems: cardiovascular, metabolic, immune/inflammatory, and renal. We analyzed a sample of 3787 participants with data collected at baseline and two subsequent follow-up waves. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were obtained from linear and logistic regression analyses to estimate the associations between ACEs measured at ages 10 and 13and the AL index at age 13.</div></div><div><h3>Results</h3><div>We found a significant association between exposure to ACE at age 13 and an elevated AL index at the same age (β = 0.004; 95 % CI [0.001; 0.006]), but not at age 10 (β = 0.001; 95 %CI [-0.002; 0.004]). In the analysis of individual ACEs, we found that when ACEs occurred before age 10, parental separation or divorce (β = 0.024; 95 %CI [0.007; 0.042]) emerged as a significant factor contributing to increased AL index. When adversity occurred between ages 10 and 13, parental separation or divorce (β = 0.023; 95 %CI [0.007; 0.039]), difficulties in school (β = 0.021; 95 %CI [0.007; 0.035]), and household alcohol/drug use (β = 0.058; 95 %CI [0.011; 0.106]) during this period were associated with increased AL burden at age 13, after adjusting for adolescents’ age, sex, height, and maternal education. Biomarker-level analyses showed that, among the four physiological systems comprising AL, metabolic and immune systems appeared most responsive to ACEs.</div></div><div><h3>Conclusions</h3><div>These findings suggest that adolescents exposed to selected ACEs at age 10 showed increased AL burden, with cumulative ACEs by age 13 further amplifying this association.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106260"},"PeriodicalIF":7.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contribution of proneurotrophin-3 to nerve trauma-induced neuropathic pain through promoting TrkC-mediated increase of CCL2 in primary sensory neurons","authors":"Huijie Shang ,&nbsp;Xianglei Meng ,&nbsp;Bing Wang ,&nbsp;Xiaozhou Feng ,&nbsp;Ruining Ma ,&nbsp;Huijuan Hu ,&nbsp;Alex Bekker ,&nbsp;Yuan-Xiang Tao","doi":"10.1016/j.bbi.2026.106256","DOIUrl":"10.1016/j.bbi.2026.106256","url":null,"abstract":"<div><div>Neuropathic pain induced by nerve trauma remains a substantial and unresolved clinical challenge. Despite ongoing research, therapeutic options for this disorder remain inadequate. Here, we report that neurotrophin-3 (<em>Nt3</em>) mRNA and its encoded proneurotrophin-3 (proNT3) protein are upregulated in neurons of the injured dorsal root ganglion (DRG), but not in the spinal cord, following peripheral nerve trauma. Mature neurotrophin-3 (NT3) protein is undetectable in the DRG under both normal and nerve trauma conditions. Genetic blockage of <em>Nt3</em> mRNA/proNT3 protein upregulation in the injured DRG attenuates the development and maintenance of nerve trauma-induced neuropathic pain, without impacting acute/basal pain responses or locomotor function. Conversely, mimicking nerve trauma-induced upregulation of DRG <em>Nt3</em> mRNA/pro-NT3 produces neuropathic pain-like symptoms. These symptoms are mitigated by intrathecal injection of NT3 protein or by selective knockdown of tropomyosin receptor kinase C (TrkC), but not TrkA or TrkB, in the DRG. Notably, intrathecal injection of NT3 also alleviates nerve trauma-induced neuropathic pain. Mechanistically, upregulated proNT3 contributes to the nerve trauma-induced increases of C-C chemokine ligand 2 (<em>Ccl2</em>) mRNA and CCL2 protein through activating TrkC in the injured DRG. Given that CCL2 is a key driver in neuropathic pain genesis and that <em>Nt3</em> mRNA co-expresses with <em>TrkC</em> and <em>Ccl2</em> mRNA in DRG neurons, proNT3 likely participates in nerve trauma-induced neuropathic pain through promoting TrkC-mediated increase of CCL2 in DRG neurons, highlighting a potential therapeutic target for the treatment of this disorder.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106256"},"PeriodicalIF":7.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive comparison of specific depression symptoms for peripheral inflammation","authors":"Lennart Seizer","doi":"10.1016/j.bbi.2026.106258","DOIUrl":"10.1016/j.bbi.2026.106258","url":null,"abstract":"<div><div>Peripheral inflammation has been associated with depression but may not map uniformly onto all depression symptoms and rather be associated with specific neurovegetative symptoms. The current work aims to extend previous research by applying a benchmark comparison in a residualized random forest framework, which allows us to statistically compare depression sum scores with specific symptoms in their relation to inflammation. The analysis was run using data of 311,474 individuals from the UK Biobank. Circulating C-reactive protein, white blood cell counts, the neutrophil-to-lymphocyte ratio and the systemic immune inflammation index were used as markers of peripheral inflammation. Depressive symptoms were assessed with a self-report questionnaire. Across multiple analytic settings, we found lethargy to perform significantly better in predicting peripheral inflammation levels compared to depression sum scores. These findings point to a specific phenotype of depression in which fatigue-related symptoms are most closely tied to peripheral inflammation, underscoring the value of symptom-level approaches for biomarker discovery and precision intervention. However, overall model performance was poor, making the practical significance of these differences difficult to interpret.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106258"},"PeriodicalIF":7.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimulant use disorder indicative of increased serum soluble intercellular adhesion molecule-1 concentrations with altered brain reward and interoceptive processing","authors":"Kaiping Burrows ,&nbsp;Breanna A. McNaughton-Long ,&nbsp;Angela K. Yakshin ,&nbsp;Valerio Coussa ,&nbsp;Rayus Kuplicki ,&nbsp;Robin L. Aupperle ,&nbsp;Jonathan B. Savitz ,&nbsp;Martin P. Paulus ,&nbsp;Jennifer L. Stewart ,&nbsp;Leandra K. Figueroa-Hall","doi":"10.1016/j.bbi.2026.106261","DOIUrl":"10.1016/j.bbi.2026.106261","url":null,"abstract":"<div><div>Stimulant use disorders (STIM): (1) elicit compulsive behaviors that can lead to altered brain structure and function; and (2) trigger inflammatory responses by inducing the release of immune molecules, suggesting potential adverse effects. Our previous findings show that amphetamine use disorder is associated with altered neural processing during reward, interoception, and inhibitory control tasks. To extend these findings, we investigated links between neural processing and inflammation that may contribute to STIM. Participants from the first half of the Tulsa-1000 (T1000) study (<em>n</em> = 500) met criteria for either group: (1) stim+ (<em>n</em> = 49) reported methamphetamines/amphetamines as their current drug of choice and met criteria for past-year STIM; or (2) stim- (<em>n</em> = 90) endorsed no past-year diagnosis other than nicotine use disorder. Immunoassays were used to measure six inflammatory analytes. We examined blood oxygen-level-dependent (BOLD) responses to monetary incentive delay (MID), visceral interoceptive awareness (VIA), and inhibitory control with the stop signal task (SST) performed during functional magnetic resonance imaging. The stim+ group exhibited higher serum soluble intercellular adhesion molecule-1 (sICAM-1) concentrations than the stim- group, no significant differences or associations were found with the other inflammatory factors. Within the stim+ group, greater sICAM-1 levels were associated with: (1) lower right nucleus accumbens (NAc) BOLD signal during MID reward anticipation; and (2) higher right amygdala BOLD signal during interoceptive attention. No significant sICAM-1 associations emerged for the SST in stim+ . Inflammation may play a central role in stimulant use as indicated by increased sICAM-1, which may point to central mechanisms. The association between high inflammation and reduced NAc reward activation or higher interoceptive signals in STIM may reflect an STIM-sICAM-1 feedback loop mechanism.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106261"},"PeriodicalIF":7.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered gut microbiome function in ADHD: More Prevotella, less vitamin B12 biosynthesis, and beneficial modulation by synbiotic treatment","authors":"Miranda Stiernborg ,&nbsp;Liu L. Yang ,&nbsp;Elin Skott ,&nbsp;MaiBritt Giacobini ,&nbsp;Philippe A. Melas ,&nbsp;Justine W Debelius ,&nbsp;Catharina Lavebratt","doi":"10.1016/j.bbi.2026.106259","DOIUrl":"10.1016/j.bbi.2026.106259","url":null,"abstract":"<div><div>The effect of psychostimulant medication in ADHD on the gut microbiome remains unknown. Oral Synbiotic 2000, comprising multiple lactic acid bacteria and dietary fibers, reduces psychiatric symptoms and plasma immune markers in ADHD, but its impact on the gut microbiome is unexplored. This study aimed to (i) study the fecal bacterial microbiome, focusing on species and bacterial gene modules, in ADHD patients and neurotypical controls, and (ii) examine microbiome changes attributable to Synbiotic 2000. Fecal samples were collected from 147 participants at baseline, and 106 completers at follow-up from a randomized placebo-controlled trial of Synbiotic 2000 conducted in children and adults with ADHD. At baseline, adult samples were compared to those of 52 adult controls, and patients on psychostimulants were compared to those not on psychostimulants in adults and children separately. The fecal microbiome was sequenced using shallow shotgun sequencing and analyzed for diversity and differential abundance using machine learning. Plasma short-chain fatty acids (SCFAs) and serum vitamin B12 levels were measured. At baseline, adult ADHD patients had significantly different abundances of four species compared to controls. In children, those on psychostimulants exhibited a higher abundance of species from the genus <em>Prevotella</em>, alongside a lower abundance of the vitamin B12-synthesis module, M00122, than those not on such medication. The lower M00122 abundance was associated with a looser stool consistency, implicating a shorter colonic transit time. Synbiotic 2000 did not affect taxonomic or functional α-diversity in adults or children. However, looser baseline stool consistency was linked to greater increases in evenness in the Synbiotic group over time. There was a significant Synbiotic-specific effect on taxonomic and functional β-diversity, not only the increased abundance of the Synbiotic 2000 species<em>.</em> Plasma levels of formic acid and propionic acid increased towards control levels in the Synbiotic group. In conclusion, distinct species were differently abundant in adults with ADHD compared to controls. The implications of the lower abundance of the vitamin B12-synthesis module, in children on psychostimulant medication, for the gut ecosystem and host intestine remain to be elucidated. Synbiotic 2000 influenced the taxonomy and functionality of the fecal microbiome and increased plasma SCFA levels towards normal. Further research is warranted to explore the clinical implications of microbiome modulation in the treatment of ADHD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106259"},"PeriodicalIF":7.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LRRC4 enhances synaptic function and alleviates neuronal injury in high-fat diet mice","authors":"Suping Qin ,&nbsp;Jiaxin Deng ,&nbsp;Bin Hu ,&nbsp;Xuejiao Zhang ,&nbsp;Yi Ding ,&nbsp;Tianxin Zhang ,&nbsp;Bohui Yuan ,&nbsp;Dexu Sun ,&nbsp;Xiaotian Wang ,&nbsp;Feng Zhou ,&nbsp;Xiaomei Liu","doi":"10.1016/j.bbi.2026.106254","DOIUrl":"10.1016/j.bbi.2026.106254","url":null,"abstract":"<div><div>Obesity, a chronic metabolic disease, increases the risk of neurodegenerative disorders and cognitive impairments. Cumulative evidence reveal obesity impairs hippocampal synaptic plasticity and induces neuronal apoptosis. Leucine rich repeat containing 4 (LRRC4) is a member of the Netrin G ligand (NGL) family, and plays a crucial role in maintaining neuronal morphology, function, and structure of synapses. However, it remains unclear whether LRRC4 affects obesity-induced cognitive impairment or its underlying mechanism. Herein, we showed that a high-fat diet (HFD) led to cognitive deficits in obese mice, as assessed by the Morris water maze and Nest building tests. The expression of LRRC4 and postsynaptic dense protein 95 (PSD-95) was downregulated in the hippocampus of mice with HFD-fed obesity. Furthermore, the effects of LRRC4 overexpression (AAV-LRRC4) and knockout (<em>Lrrc4^−/−</em>, deletion location: 28,831,753–28,828,926) on neurological function and synapses were investigated. Data from behavioral and electrophysiological studies demonstrated that LRRC4 knockout impaired synaptic plasticity and resulted in cognitive impairment in mice. Moreover, the expression level of PSD-95 was further decreased in <em>Lrrc4^−/−</em>mice fed by HFD. Meanwhile, the expression of the anti-apoptotic protein Bcl-2 was decreased, whereas the levels of the pro-apoptotic proteins cleaved-caspase 3 and BAX were increased in the hippocampus of HFD <em>Lrrc4^−/−</em> mice. This indicated that <em>Lrrc4</em> knockout exacerbated neuronal injury and apoptosis. Overexpression of LRRC4 in the hippocampus of HFD mice, ameliorated the behavioral abnormalities of HFD mice and strengthened synaptic transmission. In parallel, Golgi staining displayed a significant increase in the length and number of dendritic branches of neurons. Additionally, LRRC4 overexpression promoted PSD-95 expression and exerted an anti-apoptotic effect, as evidenced by the upregulation of Bcl-2 and downregulation of cleaved caspase-3 and BAX in the hippocampus. These findings suggest that LRRC4 enhances synaptic function and alleviates neuronal injury in HFD mice. Targeting LRRC4 may have therapeutic potentiality for neurodegenerative disorders and cognitive deficits.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106254"},"PeriodicalIF":7.6,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of lipopolysaccharide on energy metabolism and immune cell activation in different microglia model systems","authors":"Susanne Michels ,&nbsp;Johanna Eichberg ,&nbsp;Fahd Alhamdan ,&nbsp;Micha Engeser ,&nbsp;Rafael Leite Dantas ,&nbsp;Felix SR Picard ,&nbsp;Mona Mathews-Ajendra ,&nbsp;Oliver Brüstle ,&nbsp;Martin K-H Schäfer ,&nbsp;Judith Alferink ,&nbsp;Holger Garn ,&nbsp;Markus Wöhr ,&nbsp;Carsten Culmsee","doi":"10.1016/j.bbi.2026.106255","DOIUrl":"10.1016/j.bbi.2026.106255","url":null,"abstract":"<div><div>Microglia, the brain’s resident immune cells, constantly monitor their environment for signs of tissue damage or pathogens. Upon activation by stimuli like lipopolysaccharide (LPS), microglia undergo metabolic changes and release pro-inflammatory mediators. However, variations between human and rodent microglia, as well as differences between in vitro and in vivo conditions, likely influence microglial cellular functions and their responses to stimulation. In the present study, we compared several rodent and human model systems, including cell lines, primary cultures, induced pluripotent stem cell (iPSC)-derived cultures, and acutely isolated microglia, and revealed striking differences in LPS-induced metabolic changes and nitric oxide (NO) production. Using the murine microglial cell line BV-2, we demonstrated that NO was critical for restricting metabolism to glycolysis by blocking oxidative phosphorylation. In contrast, human iPSC-derived microglia and acutely isolated microglia from intraperitoneally injected rats maintained mitochondrial respiration upon LPS activation and did not show significant NO production and inducible nitric oxide synthase (iNOS) expression, respectively. Furthermore, we found that NO was not required for the increase in glycolysis rate or the release of pro-inflammatory cytokines upon LPS stimulation. Our results suggest that glycolysis is essential for microglial activation and cytokine production irrespective of NO production. However, the specific metabolic pathways involved may differ between species and experimental conditions. Understanding these differences is crucial for developing effective therapeutic strategies targeting microglial dysfunction in neurological diseases.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106255"},"PeriodicalIF":7.6,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term NRF2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy","authors":"Lucía Viqueira ,&nbsp;Elisa Navarro ,&nbsp;Pilar Negredo ,&nbsp;Juan Antonio Bernal ,&nbsp;María Isabel Rodríguez-Franco ,&nbsp;Elena Tortosa ,&nbsp;Manuela G. López","doi":"10.1016/j.bbi.2026.106253","DOIUrl":"10.1016/j.bbi.2026.106253","url":null,"abstract":"<div><div>Tauopathies, including Alzheimer’s disease, feature chronic microglial reactivity that drives neuroinflammation and disease progression. Pharmacological microglial depletion and subsequent repopulation using colony-stimulating factor 1 receptor inhibitors have emerged as a potential therapeutic strategy to reprogram dysfunctional microglia. Despite promising short-term results, the long-term efficacy and pharmacological modulation of repopulated microglia remain poorly understood. Here, we investigated the long-term effects of microglial repopulation alone and in combination with the activation of the cytoprotective nuclear factor erythroid 2 p45–related factor 2 (NRF2) in an <em>in vivo</em> AAV-hTau^P301L induced model. Integrating different behavioural, immunohistological and transcriptomic analysis, we evaluated cognitive function, tau pathology, neuronal survival and glial reactivity. We found that, whereas microglial repopulation alone did not significantly affect disease progression, NRF2-driven microglial replenishment sustained cognitive function, prevented hippocampal neuronal loss and restored microglial phenotype. Transcriptomic analyses further revealed that the combined treatment modulated tau- associated mitochondrial gene expression changes. These results highlight the importance of shaping the fate of self-renewed microglia and propose NRF2-mediated microglial repopulation as a potential pharmacological strategy for the treatment of tauopathies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106253"},"PeriodicalIF":7.6,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The COVID generation: the neurodevelopmental consequences of in-utero COVID-19 exposure","authors":"Susan Weiner ,&nbsp;Yao Wu ,&nbsp;Jacob Jenhao Cheng ,&nbsp;Melissa Liggett ,&nbsp;Cassianna McCants ,&nbsp;Esther Adegbulugbe ,&nbsp;Anna Mears ,&nbsp;Diedtra Henderson ,&nbsp;Nickie Andescavage ,&nbsp;Catherine Limperopoulos","doi":"10.1016/j.bbi.2025.106238","DOIUrl":"10.1016/j.bbi.2025.106238","url":null,"abstract":"<div><h3>Background</h3><div>In historical viral epidemics, such as the H1N1 influenza and Zika viruses, prenatal exposures were correlated with risk for neuropsychiatric conditions in offspring. However, the long-term effects of prenatal COVID-19 viral exposure on offspring neurodevelopment are still being discovered.</div></div><div><h3>Methods</h3><div>We prospectively recruited mother-baby dyads during the COVID-19 pandemic, who had been exposed to the SARS-CoV-2 virus during pregnancy (2020–2022) into a longitudinal infant brain development study and compared them to a low-risk normative pre-pandemic cohort (2016–2019). Quantitative 3-D volumetric magnetic resonance imaging (qMRI) was conducted at a neonatal visit when the infant was approximately 2 weeks of corrected age. Behavioral development was assessed using the Bayley Scales of Infant and Toddler Developmental, Third Edition (BSID-III) and the Infant-Toddler Social and Emotional Assessment (ITSEA), when the child was approximately 2 years old. An ordinary least squares regression model was used to determine the neurodevelopment of toddlers relative to their exposure to the SARS-CoV-2 virus. Mediation analyses were performed to assess how in utero exposure to SARS-CoV-2 affected the newborn brain and toddler developmental outcomes. Analyses were adjusted for maternal age and educational level, infant sex, and total brain volume on qMRI.</div></div><div><h3>Findings</h3><div>This study prospectively recruited 142 mother baby dyads, 103 from a normative prepandemic cohort and 39 pairs who had been exposed to the SARS-CoV-2 virus during pregnancy. In utero viral exposure was associated with altered newborn regional brain volumes in the cortical gray matter (<em>q</em> = 0.001), subcortical gray matter (<em>q</em> &lt; 0.001), cerebral white matter (<em>q</em> = 0.005), and left hippocampus (<em>q</em> = 0.008). Viral exposure additionally was associated with lower cognition (<em>q</em> = 0.010) and social emotional (<em>q</em> = 0.001) scores on the BSID-III and higher scores on the internalizing domain (<em>q</em> = 0.040) of the ITSEA. The lower cognition scores on the BSID-III following SARS-CoV-2 exposure were mediated in part by the altered cortical gray matter volumes (21.9 % mediated, <em>p</em> = 0.034). These lower cognition scores further mediated the relationship between the SARS-CoV-2 viral exposure and increased internalizing behavior scores on the ITSEA (61.0 % mediated, <em>p</em> = 0.040).</div></div><div><h3>Conclusions</h3><div>This study reports that in utero SARS-CoV-2 viral exposure was associated with decreased cognitive skills in toddlers at age 2, and this association was mediated by cortical gray matter volumes in the newborn brain. In addition, toddler cognitive scores further mediated an increase in toddler internalizing behaviors. These findings highlight the need for ongoing assessments for children born during the COVID-era.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106238"},"PeriodicalIF":7.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}