Brain, Behavior, and Immunity最新文献

{"title":"Brief exposure to oral antibiotics has age-dependent effects on morphine reward and gene expression in the medial prefrontal cortex of adolescent and adult mice","authors":"Rebecca S. Hofford ,&nbsp;Jonathon P. Sens ,&nbsp;Ava L. Shipman ,&nbsp;Violet M. Kimble ,&nbsp;Christina Coric ,&nbsp;Katherine R. Meckel ,&nbsp;Drew D. Kiraly","doi":"10.1016/j.bbi.2025.07.005","DOIUrl":"10.1016/j.bbi.2025.07.005","url":null,"abstract":"<div><div>Adolescence is a critical period for the initiation of problematic drug use, which significantly increases the risk of developing substance use disorders later in life. This heightened vulnerability is partly attributed to the immaturity of the prefrontal cortex, a brain region both essential for decision-making and implicated in drug reward. During adolescence, peripheral systems, such as the gut microbiome, also undergo substantial changes. Emerging evidence suggests that disruptions to the gut microbiome can influence gene expression and drug reward behaviors in rodent models. In this study, we investigated the effects of oral antibiotics on morphine reward and prefrontal cortical gene expression in adolescent and adult mice. Using oral antibiotics to transiently disrupt the microbiome, we found that short-term antibiotic exposure reduced morphine place preference specifically in adolescent mice. In a separate cohort, we observed that antibiotic treatment altered the transcriptomic response to morphine in the medial prefrontal cortex across all age groups. Notably, the transcriptomic changes induced by antibiotics and morphine were age-specific, with distinct gene expression patterns observed in adolescents compared to adults. These findings establish a foundation for future research into the role of the gut microbiome in opioid reward and highlight potential gene pathways underlying age-dependent differences in opioid sensitivity.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 724-735"},"PeriodicalIF":8.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616261","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 role of the risk gene CACNA1C in neuroinflammation and peripheral immunity in autism spectrum disorder","authors":"Anna-Lena Boller ,&nbsp;Tillmann Ruland ,&nbsp;Rafael Leite Dantas ,&nbsp;Susanne Michels ,&nbsp;Udo Dannlowski ,&nbsp;Stefanie Scheu ,&nbsp;Bernhard T. Baune ,&nbsp;Carsten Culmsee ,&nbsp;Judith Alferink","doi":"10.1016/j.bbi.2025.07.004","DOIUrl":"10.1016/j.bbi.2025.07.004","url":null,"abstract":"<div><div>Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, restricted and repetitive behaviors and interests, with the severity of symptoms varying greatly among individuals. The pathogenesis of ASD is influenced by the complex interaction of genetic and environmental factors. Increasing evidence suggests that dysregulated immune processes represent a crucial aspect in ASD pathology. The <em>CACNA1C</em> gene, which encodes the pore-forming α1C subunit of the L-type calcium channel (LTCC) Ca_V1.2, is a major genetic risk factor for ASD. Ca_V1.2 channels modulate neuronal excitability, synaptic plasticity, and neurotransmitter release in the central nervous system (CNS), all of which are essential for brain development and function. Ca_V1.2 channels are also expressed in generally non-excitable immune cells, including CNS microglia and peripheral immune cells, where they influence activation, differentiation, and cytokine release. These immune functions may contribute to ASD pathogenesis; however, the specific role of Ca_V1.2 in immune regulation and neuroinflammation in ASD is yet to be elucidated. Here, we will review recent research on the role of <em>CACNA1C</em> in immune mechanisms relevant to ASD. We will summarize current knowledge on the function of Ca_V1.2 in brain microglia and peripheral immune cells such as T cells, B cells, and dendritic cells that contribute to immune dysfunction in ASD. In addition, we will discuss the therapeutic prospects of targeting Ca_V1.2 channels in immune cells to manage both behavioral and inflammatory conditions associated with ASD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 709-723"},"PeriodicalIF":8.8,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590462","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":"Association of immune-metabolic parameters and brain structural changes in depression – Is there a common regulator?","authors":"Harald Murck","doi":"10.1016/j.bbi.2025.07.001","DOIUrl":"10.1016/j.bbi.2025.07.001","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 662-663"},"PeriodicalIF":8.8,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587676","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":"Prenatal alcohol exposure promotes nerve injury-induced pathological pain following morphine treatment via NLRP3-mediated peripheral and central proinflammatory immune actions","authors":"Andrea A. Pasmay,&nbsp;Ariana N. Pritha,&nbsp;Justin R. Carter,&nbsp;Alissa Jones,&nbsp;Annette K. Fernandez-Oropeza,&nbsp;Melody S. Sun,&nbsp;Diane C. Jimenez,&nbsp;Minerva Murphy,&nbsp;C.Fernando Valenzuela,&nbsp;Shahani Noor","doi":"10.1016/j.bbi.2025.06.041","DOIUrl":"10.1016/j.bbi.2025.06.041","url":null,"abstract":"<div><div>Adverse in-utero conditions may exert a lifelong impact on neuroimmune function. Our prior work showed that prenatal alcohol exposure (PAE) increases pathological pain sensitivity (allodynia) following peripheral sciatic nerve injury. While the immune mechanism(s) of PAE-induced immune dysfunction are poorly understood, prior studies implicated the involvement of Toll-like receptor 4 (TLR4) and the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasomes. Interestingly, emerging data suggest a surprising overlap of spinal glial proinflammatory activation via the TLR4-NLRP3-interleukin (IL)-1β axis due to opioid treatment in nerve-injured non-PAE rodents. Considering this preclinical evidence, we explored whether PAE poses a risk factor in creating proinflammatory immune bias consequent to opioid (morphine) exposure. We hypothesized that under nerve injury conditions, PAE may interact with morphine, promoting peripheral and CNS proinflammatory factors in a NLRP3-dependent manner. Using a minor nerve injury model in adult mice, we demonstrate that PAE prolongs the chronicity of ongoing allodynia in both sexes, with a more pronounced effect observed in male mice. Our study shows that PAE amplifies proinflammatory responses at the injury site and the spinal cord, driving morphine-prolonged allodynia through NLRP3 inflammasome activation. Furthermore, high mobility group box 1 (HMGB1), a well-established pain-promoting TLR4 agonist, is elevated in allodynic PAE mice. NLRP3 inhibitor, MCC950, effectively reverses morphine-induced allodynia and reduces Caspase-1 activity, IL-1β, and related proinflammatory factors. Although few sex-specific effects were observed, our data convincingly support that PAE and morphine interactions ultimately converge on NLRP3-driven mechanisms in both sexes. Together, this study suggests that PAE modulates later-life neuroimmune function and provides critical insights into immune regulators underlying PAE-induced biological vulnerability to pathological pain processing and adverse effects of opioids.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 736-756"},"PeriodicalIF":8.8,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590461","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":"Gabaergic signalling in Autism Spectrum disorders (ASD): Role of glial cells and therapeutic perspectives","authors":"Rashid Giniatullin ,&nbsp;Enrico Cherubini","doi":"10.1016/j.bbi.2025.07.003","DOIUrl":"10.1016/j.bbi.2025.07.003","url":null,"abstract":"<div><div>During postnatal development, GABA, the major inhibitory neurotransmitter in the adult brain, depolarizes immature neurons via an outward flux of chloride. This effect results from the high intracellular chloride concentration due to activity of the cation- chloride importer NKCC1. GABA induced depolarization gives rise to Giant Depolarizing Potentials (GDPs), a primordial form of coherent network oscillations involved in neuronal networks refinement. After a critical postnatal period, the increased expression of the chloride exporter KCC2, shifts GABA’s action from depolarizing to hyperpolarizing, a process altered in many neurodevelopmental disorders including ASD. The development of sharp waves ripples, a form of network oscillations implicated in memory consolidation, is controlled by GABAergic signalling at the axon initial segment (AIS). The formation and functioning of the AIS are monitored by a special subtype of microglia located at AIS axo-axonic synapses. The persistent depolarizing action of GABA beyond the critical period or its early hyperpolarizing action, as well as aberrant formation/function of AIS, lead to changes in neuronal circuits responsible for cognitive dysfunctions in ASD. In this review, considering various models of ASD, we discuss the multifaceted role of GABA, the regulation of cation-chloride cotransporters by astrocytes and microglia, the functional role of the latter in AIS, and the emerging role of brain-derived neurotrophic factor in ASD. Accordingly, we present novel therapeutic strategies which, could reinstate a proper chloride homeostasis and GABAergic signalling in selective neuronal circuits involved in behavioural and cognitive deficits observed in ASD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 681-689"},"PeriodicalIF":8.8,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583128","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":"Ontogeny and plasticity of resilience and susceptibility in a mouse model of maternal immune activation","authors":"Ron Schaer ,&nbsp;Nicole Wenger ,&nbsp;Felisa Herrero ,&nbsp;Tina Notter ,&nbsp;Urs Meyer","doi":"10.1016/j.bbi.2025.06.040","DOIUrl":"10.1016/j.bbi.2025.06.040","url":null,"abstract":"<div><div>Maternal immune activation (MIA) during pregnancy results in variable neurodevelopmental and behavioral outcomes in both humans and animal models. In a mouse model of MIA using prenatal poly(I:C) administration, we recently identified subgroups of MIA-exposed offspring with distinct behavioral and transcriptional profiles even under genetic homogeneity. Here, we used the same model to explore whether the expression of resilient and susceptible phenotypes after MIA represents stable traits or whether they exhibit plasticity throughout adolescent maturation. Conducting longitudinal testing in a first cohort, we revealed that MIA offspring can be stratified into subgroups with distinct behavioral profiles at juvenile age. This early divergence was sex-dependent and predictive of different behavioral outcomes at adult age. In a second cohort, we examined the effects of repeated social intervention during peri-adolescence on brain and behavioral trajectories. In male MIA offspring displaying juvenile deficits in sociability and hyperactivity, the intervention did not alleviate adult deficits in sociability or temporal order memory but prevented the adult emergence of prepulse inhibition impairments. Conversely, in female MIA offspring with juvenile social deficits, the intervention improved adult deficits in sociability and temporal order memory, but it failed to normalize adult impairments in prepulse inhibition. These sex-specific behavioral outcomes were paralleled by subgroup-specific changes in oxytocinergic and dopaminergic markers in cortical and subcortical brain regions. Together, our findings indicate that MIA-exposed offspring can be stratified into distinct subgroups early in life, with subsequent risk and resilience trajectories varying by sex. Moreover, our data identify a window of plasticity during which targeted interventions can modulate abnormal maturational trajectories, ultimately mitigating the long-term effects of MIA in a sex-dependent manner.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 666-680"},"PeriodicalIF":8.8,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583137","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":"Immunometabolism perturbations in post-COVID-19 condition: interleukin-6 and monoamine oxidase interactions drive neuropsychiatric syndromes","authors":"Natacha S. Ogando ,&nbsp;Mohamed Elaish ,&nbsp;Hajar Miranzadeh Mahabadi ,&nbsp;Kristopher D. Langdon ,&nbsp;Sumit K. Das ,&nbsp;Jeffrey T. Joseph ,&nbsp;Esther Fujiwara ,&nbsp;Andrew Holt ,&nbsp;Karina Kaur ,&nbsp;William Branton ,&nbsp;Mahmoud Gheblawi ,&nbsp;Paige Lacy ,&nbsp;Gavin Y. Oudit ,&nbsp;Tom C. Hobman ,&nbsp;Grace Y. Lam ,&nbsp;Christopher Power","doi":"10.1016/j.bbi.2025.07.002","DOIUrl":"10.1016/j.bbi.2025.07.002","url":null,"abstract":"<div><div>Neuropsychiatric disorders including depression or anxiety are common in persons with post-COVID-19 condition (PCC). In a clinical cohort, interleukin (IL)-1beta, −2, −6, −8, −10, and TNF-alpha were significantly elevated in serum from PCC compared to control subjects while serum IL-6 levels were selectively increased among PCC subjects with depression. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of primary human neural cells showed viral replication in astrocytes, although IL-6 was released by abortively-infected microglia. In C57BL6/J mice intranasally infected with mouse-adapted SARS-CoV-2, viral RNA was detected in the lungs and multiple brain regions, which persisted in 33 % of infected animals up to 21 days post-infection (dpi), associated with increased brainstem IL-6 expression. As catecholamines are implicated in mood and anxiety, we analyzed monoamine oxidase (MAO) expression, revealing elevated transcript and protein levels for both MAO isoforms in infected human and mouse brain tissues, particularly in glial cells, which was correlated with increased MAO enzymatic activity. Neurobehavioral assessments showed depressive behaviors until 7dpi, transitioning to anxiety behaviors by 21dpi among virus-infected mice, which was attenuated by MAO inhibition. These findings highlight the immunometabolic mechanisms, involving cytokine-enzyme interactions that contribute to PCC-associated neuropsychiatric syndromes while also identifying potential diagnostic and therapeutic options.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 690-708"},"PeriodicalIF":8.8,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574837","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 latent threat of Toxoplasma gondii infection for neurologic disease","authors":"Daniel C. Anthony","doi":"10.1016/j.bbi.2025.06.039","DOIUrl":"10.1016/j.bbi.2025.06.039","url":null,"abstract":"<div><div>Toxoplasma gondii, a ubiquitous neurotropic parasite, infects roughly one-third of the global population. In immunocompetent individuals, infection is typically asymptomatic, yet recent evidence suggests that latent T. gondii infection can subtly impair brain function and increase vulnerability to neurological disorders. This commentary, prompted by recent findings by Baker et al., highlights how chronic infection may exacerbate seizure susceptibility and neuroinflammation, particularly under a ’second hit’ model. The implications of such latent infections in public health and the importance of considering infection history in neurological disease models are discussed.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 664-665"},"PeriodicalIF":8.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567160","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":"Microglial cGAS-STING-TBK1 activation in paraventricular thalamus mediates sleep and emotional disturbances in lupus mice","authors":"Hui Yuan ,&nbsp;Zijie Li ,&nbsp;Xueru Wang ,&nbsp;Siyuan Zeng ,&nbsp;Chenye Jin ,&nbsp;Jingyu Chen ,&nbsp;Xuejiao Wang ,&nbsp;Pingting Yang ,&nbsp;Ling Qin","doi":"10.1016/j.bbi.2025.06.042","DOIUrl":"10.1016/j.bbi.2025.06.042","url":null,"abstract":"<div><div>Sleep and emotional disturbances are prevalent in systemic lupus erythematosus (SLE) patients, yet the neuroinflammatory mechanisms remain unclear. Here, we investigated this issue using pristane-induced lupus (PIL) mice. We firstly confirmed that PIL mice exhibited progressive fragmentation of NREM sleep and decreased cumulative sleep time, correlating with blood–brain barrier (BBB) leakage and IgG deposition in the paraventricular thalamus (PVT). Concurrently, PVT neurons showed aberrant excitatory activity, including a high level of cFos expression, decreased amplitude and increased rate of Ca²⁺ transients during wakefulness. Bulk RNA sequencing and protein analyses demonstrated upregulation of the cyclic GMP-AMP synthase (cGAS) −stimulator of interferon genes (STING) −TANK-binding kinase 1 (TBK1) activation pathway in PVT microglia, with elevated phosphorylation of STING (pSTING) and TBK1 (pTBK1), promoting synthesis of pro-inflammatory cytokines. Selectively knockdown STING in microglia effectively normalized PVT neuronal excitability, restored sleep homeostasis, and ameliorated anxiety/depression-like behaviors. Notably, we identified selective expression of cannabinoid receptor type 2 (CB2R) in PVT microglia. Pharmacological CB2R activation could inhibit TBK1 phosphorylation, attenuate microglial inflammatory responses, and improve sleep and emotional disturbances. Our findings elucidate a novel neuroimmune axis in SLE-related neuropsychiatric symptoms, offering potential therapeutic avenues for mitigating neuroinflammation and associated behavioral comorbidities in lupus.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 634-648"},"PeriodicalIF":8.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144535226","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":"Dependence of fasting-induced hypothalamic anti-inflammatory microglia mechanisms on adrenal glucocorticoid secretion","authors":"Balázs Juhász,&nbsp;Krisztina Horváth,&nbsp;Dániel Kuti,&nbsp;Szilamér Ferenczi,&nbsp;Zsuzsanna Winkler,&nbsp;Krisztina J. Kovács","doi":"10.1016/j.bbi.2025.06.038","DOIUrl":"10.1016/j.bbi.2025.06.038","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Fasting triggers complex physiological and neuroimmune adaptations, yet its impact on hypothalamic microglia and the underlying regulatory role of glucocorticoids remains incompletely understood. The present study focused on fasting-induced systemic changes and cellular adaptations seen in the hypothalamus where components of metabolic- hormonal- and immune regulations are integrated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Adult male microglia reporter (CX3CR1&lt;sup&gt;+/Gfp&lt;/sup&gt;) mice were subjected short term (18 h) overnight fasting. Metabolic changes were followed using indirect calorimetry. Hypothalamic expression of pro-and anti-inflammatory markers, hypothalamic neuropeptides and select genes involved in metabolic regulation was measured by qPCR. Number of microglia and their morphological characteristics was analysed by Sholl analysis. The dependence of these markers on fasting-induced corticosterone was studied in adrenalectomized (ADX) or metyrapone-treated mice. Plasma levels of corticosterone and ketone body, β-hydroxybutyrate was assayed by radioimmunassay and a colorimetric kit respectively.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Overnight fasting resulted in a decrease in energy expenditure and respiratory exchange ratio (RER) indicating conservation of energy and a metabolic shift towards utilization of fatty acids as alternative energy source. Fasting increased hypothalamic expression of orexigenic neuropeptides and mRNA levels of &lt;em&gt;Pdk4, Glut1&lt;/em&gt;, and &lt;em&gt;Mct2&lt;/em&gt; genes, in line with metabolic compensation. Upregulation of hypothalamic &lt;em&gt;Crh&lt;/em&gt; and increased plasma concentration of corticosterone indicated sustained activation of the HPA axis. Importantly, fasting promoted an anti-inflammatory milieu in the hypothalamus characterized by elevated &lt;em&gt;Il-4&lt;/em&gt;, &lt;em&gt;Il-10&lt;/em&gt; and &lt;em&gt;IkBα&lt;/em&gt; genes without significant activation of pro-inflammatory cytokines (e.g., &lt;em&gt;Il-1β, Il-6, Tnfα&lt;/em&gt;). Morphological analysis revealed region-specific changes in microglia number and branching complexity, particularly in hypothalamic regions directly exposed to blood-borne signals. Functional profiling showed increased microglial expression of IkBα and decreased pIkBα, indicating suppressed NFkB signaling. Adrenalectomy (1 week) and acute pharmacological inhibition of corticosterone synthesis (methyrapone) revealed that fasting-induced anti-inflammatory and metabolic gene expression, as well as microglial plasticity were largely glucocorticoid dependent. Hypothalamic expression of fasting-related neuropeptides (&lt;em&gt;Npy&lt;/em&gt;, &lt;em&gt;Agrp&lt;/em&gt;) and genes, related to the metabolic shift (&lt;em&gt;Pdk4, Glut-1, Mct2, Angptl4&lt;/em&gt;) as well as some immune-related genes (&lt;em&gt;Il10, Iba1&lt;/em&gt;) was dependent on presence of the adrenal gland or fasting-induced elevation of corticosterone.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;These findings highlight short term fasting as a potent modulator of hypothalamic immune-metabolic cr","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 557-572"},"PeriodicalIF":8.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522966","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}