Brain, Behavior, and Immunity最新文献

{"title":"Developmental origins of immune function: Maternal prenatal mood is associated with infant immune cell gene expression","authors":"Gabrielle R. Rinne ,&nbsp;Christine Dunkel Schetter ,&nbsp;Susan Jackman ,&nbsp;Steve W. Cole","doi":"10.1016/j.bbi.2025.106230","DOIUrl":"10.1016/j.bbi.2025.106230","url":null,"abstract":"<div><div>The in-utero environment shapes offspring mental and physical health trajectories over the lifespan, likely through developmental adaptations to fetal biological systems. Offspring immune system development is a putative pathway through which the prenatal environment influences offspring health. The current study tested associations of maternal prenatal depressive and anxiety symptoms with infant pro-inflammatory and antiviral gene expression in a sample of 118 mother-infant pairs enrolled in a longitudinal study. Mothers reported on depressive and anxiety symptoms during interviews in early, mid, and late pregnancy. About one month after birth, trained research staff collected dried blood spots from infants during a heel stick procedure (<em>M</em> = 1.3 months, <em>SD</em> = 1.1 months). Infant dried blood spots were assayed for genome-wide transcriptional profiles using RNAseq. We evaluated associations of maternal prenatal depressive and anxiety symptoms with infant genome-wide transcriptional profiles and used bioinformatics analyses to identify upstream transcriptional pathways of differentially expressed genes. Higher maternal depressive symptom levels over the course of pregnancy were associated with upregulation of the pro-inflammatory NF-κB transcription control pathway and downregulation of the antiviral IRF control pathway in infants. In contrast, anxiety symptoms were associated with downregulation of the antiviral transcriptional control pathway in infants but were not associated with differences in the pro-inflammatory transcriptional control pathway. However, the association of anxiety symptoms with antiviral transcriptional control pathways was no longer significant with adjustment for depressive symptoms. These findings suggest that depressive symptoms during pregnancy may influence infant immune function via inflammatory and antiviral transcriptional control pathways, with potential implications for subsequent health.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106230"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803186","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":"Resistant starch improves Parkinson’s disease symptoms through restructuring of the gut microbiome and modulating inflammation","authors":"Viacheslav A. Petrov ,&nbsp;Sebastian Schade ,&nbsp;Cedric C. Laczny ,&nbsp;Jenny Hällqvist ,&nbsp;Patrick May ,&nbsp;Christian Jäger ,&nbsp;Velma T.E. Aho ,&nbsp;Oskar Hickl ,&nbsp;Rashi Halder ,&nbsp;Elisabeth Lang ,&nbsp;Jordan Caussin ,&nbsp;Laura A. Lebrun ,&nbsp;Janine Schulz ,&nbsp;Marcus Michael Unger ,&nbsp;Kevin Mills ,&nbsp;Brit Mollenhauer ,&nbsp;Paul Wilmes","doi":"10.1016/j.bbi.2025.106217","DOIUrl":"10.1016/j.bbi.2025.106217","url":null,"abstract":"<div><div>Alterations in the gut microbiome and a “leaky” gut are associated with Parkinson’s disease (PD), which implies the prospect of rebalancing via dietary intervention. Here, we investigate the impact of a diet rich in resistant starch on the gut microbiome through a multi-omics approach. We conducted a randomized, controlled trial with short-term and long-term phases involving 74 PD patients of three groups: conventional diet, supplementation with resistant starch, and high-fibre diet.</div><div>Our findings reveal associations between dietary patterns and changes in the gut microbiome’s taxonomic composition, functional potential, metabolic activity, and host inflammatory proteome response. Resistant starch supplementation led to an increase in <em>Faecalibacterium</em> species and short-chain fatty acids alongside a reduction in opportunistic pathogens. Long-term supplementation also increased blood APOA4 and HSPA5 and reduced symptoms of PD.</div><div>Our study highlights the potential of dietary interventions to modulate the gut microbiome and improve the quality of life for PD patients.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106217"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751664","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 infant gut microbiome and the intergenerational transmission of psychiatric risk","authors":"Ellen Jopling ,&nbsp;Avril Metcalfe-Roach ,&nbsp;Stuart E. Turvey ,&nbsp;Piushkumar Mandhane ,&nbsp;the CHILD Study investigators ,&nbsp;B. Brett Finlay ,&nbsp;Joelle LeMoult","doi":"10.1016/j.bbi.2025.106232","DOIUrl":"10.1016/j.bbi.2025.106232","url":null,"abstract":"<div><div>Elevated stress during the prenatal period is associated with increased psychiatric risk among children. However, less is known about the mechanisms through which this intergenerational transmission of risk occurs. The early life microbiome is one candidate mechanism through which maternal stress during the prenatal period could impact offspring mental health, with a growing body of literature highlighting the importance of the early life microbiome in mental health across the lifespan. This study leverages Canada’s largest deeply phenotyped birth cohort to elucidate the mechanistic associations between maternal prenatal stress, dynamic changes in the microbiome across the first year of life, and child internalizing symptoms. Analytic sample size with use of full information maximum likelihood methodology was 2,985. Analyses indicated that early diversification of the early life microbiome significantly mediated the relation between higher maternal perceived stress during pregnancy and increased internalizing symptoms among offspring at 5 years of age. Crucially, microbial taxa impacted by early diversification of the microbiome implicated the immune system. This work supports maturational dynamics of the microbiome as one mechanism through which prenatal stress is biologically embedded to impact offspring’s later mental health. By linking several burgeoning areas of research, this study lays the groundwork for future multidisciplinary work examining the intergenerational transmission of psychiatric risk through the microbiome.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106232"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809642","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":"Social stress worsens colitis through β-adrenergic–driven oxidative stress in intestinal mucosal compartments","authors":"Maria Elisa Caetano-Silva ,&nbsp;Miranda E. Hilt ,&nbsp;Ivan Valishev ,&nbsp;Casey Lim ,&nbsp;Mikaela Kasperek ,&nbsp;Akriti Shrestha ,&nbsp;Helen Fu ,&nbsp;Eleanor Eck ,&nbsp;Robert McCusker ,&nbsp;Heather Armstrong ,&nbsp;Brett Loman ,&nbsp;Michael T. Bailey ,&nbsp;Jacob M. Allen","doi":"10.1016/j.bbi.2025.106222","DOIUrl":"10.1016/j.bbi.2025.106222","url":null,"abstract":"<div><div>Psychological stress is a known risk factor for inflammatory bowel disease (IBD), but the mechanisms linking stress to worsened disease remain unclear. Because distinct stress paradigms activate different neuroimmune circuits, it is critical to investigate model-specific effects. We examined how social stress primes the gut for heightened inflammation and whether this is mediated by specific neuroendocrine pathways, including α2-/β-adrenergic (sympathetic) or glucocorticoid/ corticotropin-releasing hormone receptor (CRHR1) (HPA axis) signaling. Mice were exposed to social disruption (SDR) stress and pre-treated with pharmacological antagonists targeting α2-adrenergic receptors (idazoxan), β-adrenergic receptor (β-AR) (propranolol), glucocorticoid receptor (mifepristone), or CRHR1 (antalarmin). Intestinal epithelial cell (IEC) gene expression and microbiota composition were assessed following SDR. To determine disease impact, SDR was combined with either <em>Citrobacter rodentium</em> infection or dextran sulfate sodium (DSS)-induced colitis, with interventions including the β-AR inhibitors and the NADPH oxidase inhibitor apocynin. SDR significantly upregulated expression of Dual oxidase 2 (<em>Duox2</em>), Dual oxidase maturation factor 2 (<em>Duoxa2</em>), and inducible nitric oxide synthase 2 (<em>Nos2</em>) in IECs (2- to 8-fold, <em>p</em> &lt; 0.0001), effects reversed by β-AR blockade but not α2-adrenergic, CRH, or glucocorticoid inhibition. SDR also induced microbial dysbiosis, characterized by reduced α −diversity and compositional shifts, which was rescued by propranolol. Stress exacerbated disease severity in both infectious (<em>C. rodentium</em>) and chemically induced (DSS) colitis, amplifying colonic expression of <em>Duox2</em>, <em>Nos2</em>, and <em>Ccl2</em>, especially. Apocynin mitigated stress-induced ROS/RNS production and body weight loss even prior to colitis onset, reduced colonic expression of key oxidative enzymes, especially DUOX2, and alleviated both chemically and infectious colitis severity. These findings provide strong evidence that social stress sensitizes the gut to inflammation through β-adrenergic and NADPH oxidase–driven oxidative stress, highlighting potential therapeutic targets for mitigating stress-exacerbated IBD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106222"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793402","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 paradoxical protective effect of chronic stress on advanced Alzheimer’s disease pathology","authors":"Yoel Shor ,&nbsp;Reut Said ,&nbsp;Nina Fainstein ,&nbsp;Gilly Wolf ,&nbsp;Lihi Sofer Stepanov ,&nbsp;Marva Lachish ,&nbsp;Tal Ganz ,&nbsp;Yara Shwaiky ,&nbsp;Hadar Benyamini ,&nbsp;Yuval Nevo ,&nbsp;Yarden Brock ,&nbsp;Jonathan Gurevitz ,&nbsp;Tzuri Lifschytz ,&nbsp;Amit Lotan ,&nbsp;Tamir Ben-Hur","doi":"10.1016/j.bbi.2025.106224","DOIUrl":"10.1016/j.bbi.2025.106224","url":null,"abstract":"<div><h3>Background</h3><div>Core pathology in Alzheimer’s disease (AD) includes amyloid-β (Aβ) deposition, gliosis, and eventual neuronal loss. Depression during midlife increases the risk of developing AD at late life. Late-life depression is highly prevalent among AD patients, but its role in AD pathogenesis is unclear, and specifically whether it pushes the brain with established AD pathology towards degeneration. CNS myeloid cells (Microglia and CNS-associated macrophages) clear Aβ early on; however, in advanced disease stages, they adopt a neurotoxic phenotype that exacerbates neurodegeneration. It is unclear whether and how stress and depression influence CNS myeloid cells’ dysfunction in AD and the neurodegenerative process.</div></div><div><h3>Methods</h3><div>To investigate the impact of chronic stress on microglial function and on neurodegeneration, we utilized the 5xFAD mouse model, which exhibits extensive Aβ pathology but no neuronal loss at age 7 months, representing a late preclinical AD stage. We used a six-week chronic mild stress (CMS) paradigm to induce depressive behavior, after which CNS myeloid cell activation state was evaluated by transcriptomic analysis, activation marker expression and oxidation function. Neuronal and microglial densities were assessed histologically.</div></div><div><h3>Results</h3><div>Transcriptomic analysis of freshly isolated CNS myeloid cells showed a basal hyper-activated state in non-stressed 5xFAD mice, whereas CMS suppressed multiple immunologic and metabolic pathways. CMS reduced CD68 expression and reduced oxidative function in CNS myeloid cells. CMS did not induce neurodegeneration in the (behaviorally-relevant) pre-frontal, primary motor, hippocampal and Amygdalar cortices in 5xFAD mice. Rather, CMS protected these regions from microglia-mediated neurodegeneration, caused by a microbial TLR2 agonist.</div></div><div><h3>Conclusion</h3><div>Chronic stress and depression attenuate CNS myeloid cells. While this has been shown to promote amyloid pathology at early stages, similar attenuation of CNS myeloid cells at the stage of established AD pathology may interfere with their transition into fully neurotoxic microglia, which cause neurodegeneration. These findings highlight the importance of tailoring microglial-targeted therapies to the stage-dependent roles of these cells during AD progression.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106224"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800391","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":"From skin to spinal Cord: How IL-17a Drives psoriatic chronic itch","authors":"Xin Liu ,&nbsp;Jian Jiang ,&nbsp;Shiying Lin ,&nbsp;Wenqiang Ge ,&nbsp;Qingxiao Tao ,&nbsp;Suwen Liu ,&nbsp;Ouyang Zhanmu ,&nbsp;Yang Yang ,&nbsp;Bao Chai ,&nbsp;Jingyu Zhang ,&nbsp;Man Li ,&nbsp;Hongxiang Chen","doi":"10.1016/j.bbi.2025.106218","DOIUrl":"10.1016/j.bbi.2025.106218","url":null,"abstract":"<div><div>Interleukin-17a (IL-17a) has been established as a master regulator of inflammatory cascades in psoriasis pathogenesis. Monoclonal antibodies targeting IL-17a have demonstrated significant efficacy in relieving psoriasis-related symptoms, including the rapid alleviation of chronic itching. However, whether IL-17a is involved in chronic psoriatic pruritus and the specific mechanisms of its action remain poorly understood. In this study, we demonstrate that IL-17a significantly exacerbates chronic itch in a murine model of psoriasis. Mechanistically, IL-17a upregulation in psoriatic skin tissues activated the IL-17a receptor (IL-17Ra) in sensory neurons, subsequently promoting the expression of IL-6 in dorsal root ganglion (DRG) neurons. This neuron-derived IL-6 is transported via sensory nerve fibers to the spinal dorsal horn (SDH), where it triggers astrocyte activation and subsequent IL-1β secretion to potentiates chronic itch signaling in psoriasis. Our findings uncover a neuroimmune circuit in which IL-17a-IL-17Ra signaling on sensory neurons mediates the propagation of pruritic signals from peripheral skin to the central nervous system, with spinal IL-6-astrocyte-IL-1β axis serving as an amplifier of psoriatic pruritus.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106218"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741056","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 aged amygdala’s unique sensitivity to refined diets, independent of fat or sugar content: A brain region and cell type-specific analysis","authors":"Michael J. Butler ,&nbsp;Jade A. Blackwell ,&nbsp;Andrew A. Sanchez ,&nbsp;Hannah F. Sanders ,&nbsp;Dominic W. Kolonay ,&nbsp;Jeferson Jantsch ,&nbsp;Stephanie M. Muscat ,&nbsp;Maria Elisa Caetano-Silva ,&nbsp;Akriti Shrestha ,&nbsp;Casey Kin Yun Lim ,&nbsp;Sabrina E. Mackey-Alfonso ,&nbsp;Bryan D. Alvarez ,&nbsp;Robert H. McCusker ,&nbsp;Jacob M. Allen ,&nbsp;Kedryn K. Baskin ,&nbsp;Ruth M. Barrientos","doi":"10.1016/j.bbi.2025.106220","DOIUrl":"10.1016/j.bbi.2025.106220","url":null,"abstract":"<div><div>Western-style diets, high in saturated fats and refined carbohydrates and low in dietary fiber, are strongly linked to cognitive decline, particularly in aging. However, the specific macronutrient contributions and mechanisms underlying these effects remain unclear. Here, we investigated how short-term exposure to refined-ingredient diets (RDs) varying in fat and sugar content impacts memory, mitochondrial function, and metabolic signaling in young adult and aged male rats. A key finding was that amygdala-dependent memory was broadly impaired in aged rats across all RDs, regardless of fat or sugar content, suggesting a unique vulnerability of the aging amygdala to refined dietary ingredients. In contrast, hippocampal-dependent memory impairments were observed only in aged rats fed a high-fat, low-sugar RD. Functional mitochondrial assays revealed significant RD-induced reductions in oxygen consumption in amygdalar and hippocampal mitochondria isolated from aged rats. Cell-type–specific analyses identified aged microglia as particularly susceptible, showing widespread suppression of mitochondrial respiration with limited metabolic flexibility. Astrocytes and synaptic mitochondria exhibited more region- and age-specific effects. All RDs lacked dietary fiber, and consistent with prior findings, butyrate, a microbial-derived short-chain fatty acid, was rapidly and robustly depleted in both gut and circulation, especially in aged animals. Proteomic and phosphoproteomic analyses identified diet-induced disruptions in mitochondrial proteins and synaptic signaling pathways, including complex I subunits and glutamate receptor signaling. Together, these findings reveal that the aged amygdala is especially sensitive to refined diet exposure and highlight microbial, metabolic, and inflammatory pathways that may underlie diet-induced cognitive decline.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106220"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741122","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":"NPD1/GPR37 signaling protects against painful traumatic brain injury and comorbidities by regulating demyelination, glial responses, and neuroinflammation in the mouse brain","authors":"Junli Zhao ,&nbsp;Runda Li ,&nbsp;Yuqing Wang ,&nbsp;Sharat Chandra ,&nbsp;Vivian Zhang ,&nbsp;Haichen Wang ,&nbsp;Ru-Rong Ji","doi":"10.1016/j.bbi.2025.106219","DOIUrl":"10.1016/j.bbi.2025.106219","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) often leads to neuropathic pain and a range of comorbidities, including post-traumatic stress disorder (PTSD), cognitive decline and depression. Neuroprotectin D1 (NPD1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA), exhibits neuroprotective properties; however, the distinct roles of NPD1 and DHA in mitigating TBI-induced deficits remain unclear. In a mouse model of closed-head TBI, transient neuropathic pain lasting less than two weeks was observed, characterized by periorbital and cutaneous mechanical allodynia/hyperalgesia, motor deficits, and cognitive impairment. Peri-surgical administration of NPD1 (500 ng/mouse), but not DHA (500 µg/mouse), effectively prevented mechanical hypersensitivity, motor deficits, and cognitive impairment. NPD1 treatment also attenuated TBI-induced microgliosis, astrogliosis, and demyelination in the sensory cortex and hippocampus. RNA sequencing revealed that NPD1 suppressed neuroinflammatory responses and normalized the alteration of PTSD-related genes (e.g., <em>Fkbp5</em>). The antinociceptive effects of NPD1 were abolished in <em>Gpr37⁻/⁻</em> mice. Moreover, swimming-induced stress prolonged TBI-evoked pain, and NPD1 prevented this transition from acute to chronic pain in wild-type but not <em>Gpr37⁻</em>/<em>⁻</em> mice. Chronic pain was accompanied by depression- and anxiety-like behaviors, both of which were mitigated by NPD1 via GPR37. In addition, NPD1 post-treatment attenuated stress/TBI-induced chronic pain and comorbidities. Together, these findings identify the NPD1/GPR37 signaling axis as a key protective mechanism that modulates glial responses, demyelination, and neuroinflammation, offering a promising therapeutic target for TBI-associated pain and neuropsychiatric comorbidities.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106219"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741102","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":"Biomarkers of neuroaxonal and astrocytic pathology in autoimmune encephalitis","authors":"Robb Wesselingh ,&nbsp;Sarah Griffith ,&nbsp;Katherine Ko ,&nbsp;Nabil Seery ,&nbsp;Christina Kazzi ,&nbsp;William T O’Brien ,&nbsp;Tiffany Rushen ,&nbsp;Amy Halliday ,&nbsp;Liora ter Horst ,&nbsp;Mirasol Forcadela ,&nbsp;Tracie Tan ,&nbsp;Genevieve Skinner ,&nbsp;Hannah Ford ,&nbsp;Cassie Nesbitt ,&nbsp;Katherine Buzzard ,&nbsp;Andrew Duncan ,&nbsp;Wendyl D’Souza ,&nbsp;Stuart McDonald ,&nbsp;Anneke Van Der Walt ,&nbsp;Amy Brodtmann ,&nbsp;Mastura Monif","doi":"10.1016/j.bbi.2025.106206","DOIUrl":"10.1016/j.bbi.2025.106206","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Autoimmune encephalitis (AE) is an immune mediated central nervous system disorder that results in significant symptoms and disability including cognitive dysfunction. Biomarkers of neuro-axonal (neurofilament light, NfL) and astrocytic (glial fibrillary acidic protein, GFAP) pathology in autoimmune encephalitis (AE) are altered in the cerebrospinal fluid and serum in AE. However, their relationship to disease phase and outcomes, particularly cognition, is not well established. Understanding their association with the AE disease course may enhance monitoring and prognostication.</div></div><div><h3>Methods</h3><div>In this cross-sectional observational study patients with acute and chronic (&gt;3 months post treatment) AE recruited through the Australian Autoimmune Encephalitis Consortium underwent serum NfL and GFAP analysis and were compared to a control cohort using linear mixed modelling. Participants with chronic AE underwent a comprehensive cognitive assessment and were stratified by level of cognitive dysfunction. Correlations between NfL or GFAP and cognitive dysfunction, modified Rankin Scale [mRS] or Clinical Assessment Scale in Autoimmune Encephalitis [CASE] scores were analysed with regression modelling.</div></div><div><h3>Results</h3><div>The acute AE cohort (n = 15) had higher NfL (Z score: 2.18 [1.39, 2.98]) and GFAP (212.35 pg/ml [148.09, 304.50) compared with the chronic cohort (n = 51; 0.88 [0.46, 1.29], p &lt; 0.01; 118.97 pg/ml [100.88, 140.30], p = 0.02) and control cohort (n = 28; 0.66 [0.12, 1.21], p &lt; 0.001; 111.35 pg/ml [82.81, 149.75], p = 0.03). Poorer discharge mRS correlated with elevated NfL (OR 3.77 [1.21, 11.70]) and GFAP (OR 47.92 [2.35, 978.68]). Higher GFAP was associated with moderate-severe cognitive dysfunction (150.61 pg/ml [115.94, 195.64] vs 108.43 pg/ml [90.68, 129.65]), p = 0.04) and correlated with poorer follow-up mRS (OR 2.28 [1.27, 4.10]) and CASE (ß = 1.04 [0.34, 1.73]) scores.</div></div><div><h3>Discussion</h3><div>Overall, acute AE is characterized by elevated markers of neuronal and astrocytic pathology. Low levels of sNfL in chronic AE, regardless of current function, suggest that ongoing neuroaxonal injury is unlikely. However, elevated sGFAP in AE patients with ongoing sequalae, most notably cognitive dysfunction, suggest there may be ongoing changes that contribute to the chronic AE disease course.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106206"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699769","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":"Sex differences in microglia morphology and function across the lifespan are mediated by the early hormone environment","authors":"Lourdes K. Davis ,&nbsp;Miranda M. Anders ,&nbsp;Steven P. Guerin ,&nbsp;Sophia E. Khoury ,&nbsp;Lindsay M. Thompson ,&nbsp;Jeffrey S. Darling ,&nbsp;Andrea C. Gore ,&nbsp;Laura K. Fonken","doi":"10.1016/j.bbi.2025.106187","DOIUrl":"10.1016/j.bbi.2025.106187","url":null,"abstract":"<div><div>Microglia, the resident immune cell of the central nervous system (CNS), contribute to a range of physiological processes across the lifespan. Microglia exhibit notable sex differences in morphology, reactivity, and transcriptomic profiles. Steroid hormones in early life are believed to elicit sex differences in many cells, including microglia, in the CNS. However, few studies have examined how neonatal hormone environment impacts microglial morphology and function across the lifespan. Therefore, here we used steroid hormones to manipulate the early hormone environment to assess the appearance and persistence of sex differences in a rat model of healthy aging. Rat pups were dosed with steroid hormones on postnatal day (P)0 and 1: females received testosterone to “masculinize” them and males received flutamide, an androgen antagonist, to “feminize” them. Brain tissue was then collected at three distinct developmental timepoints: adolescence (P30), adulthood (P150), and aging (P700) for immunohistochemistry and <em>ex vivo</em> microglial stimulation. Transcriptomic changes in hippocampal tissue of aged animals were also assessed using 3’UTR biased transcriptome sequencing (Tag-seq). We report that testosterone treatment in females leads to lifelong alterations in body size and vaginal morphology and results in microglia that display a more “masculinized” phenotype compared to controls. Flutamide had more moderate effects on microglia morphology in males, contributing to a more “feminized” phenotype in the hippocampus in adult and aged males. Testosterone treatment also resulted in greater transcriptomic changes in the aged hippocampus compared to flutamide treatment, especially in genes related to mitochondrial function and inflammation. These results indicate that (1) early hormone environment is critical for the induction of sex differences in microglial morphology and (2) sex differences in microglial morphology reverse during aging, and this reversal is also recapitulated with early hormone treatment.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106187"},"PeriodicalIF":7.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573046","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}