Maternal Immune Activation (MIA) during pregnancy is an environmental risk factor implicated in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. While numerous studies have shown that MIA can lead to neuropathological and behavioral abnormalities in offspring, the consequences for immune system development and function are less well characterized.

Sexual minority individuals, including lesbian, gay, bisexual, and other non-heterosexual (LGB + ) adults have significantly greater risk for mental and physical health conditions, disparities linked with minority stress exposure.

Inflammation is increasingly implicated in a wide range of neuropsychiatric and neurodegenerative disorders from depression to dementia. Compelling evidence for an inflammatory role in these disorders includes experimental-medicine studies with IFN-α and endotoxin, alongside therapeutic benefits observed with anti-cytokine agents.

Obesity is associated with depressive symptoms due to biological and psychological factors. Dietary interventions, including the Ketogenic (Keto) and Mediterranean (Med) diets, impact weight loss and mental health differently. While the Keto diet promotes rapid weight loss by increasing ketone body levels, its effects on mental health, particularly in individuals with obesity, remain unclear. This exploratory pilot study explores the impact of both diets on depression and impulsiveness, focusing on the gut-brain axis. Sixty-four participants (Body Mass Index 30-45 kg/m, ages 18-65) were randomly assigned to follow one of the two diets for three months. Due to attrition, 37 participants (Med n = 23; Keto n = 14) completed the study. Depression and impulsivity scores were evaluated before and after the intervention. Stool samples were collected for microbiota analysis, and faecal transplants were performed in healthy mice. Brain and serum metabolites in recipient mice were analysed using High-Resolution Magic Angle Spinning (HR-MAS) and Proton Nuclear Magnetic Resonance (H NMR) spectroscopy. The Med diet showed greater improvement in depression scores compared to the Keto diet, while the latter was associated with reductions in impulsivity (urgency subscale). However, faecal transplants from the Keto group induced anxiety-like behaviours in recipient mice, which correlated with significant microbiota and metabolite changes. The Keto group exhibited increased levels of taurine, alanine, and betaine in the brain, and threonine levels were correlated with behavioural changes. These findings suggest that the Med diet offers more consistent short-term benefits related to depressive symptoms, while the Keto diet modulated impulsivity. The animal model findings highlighted the role of diet-induced microbiota changes and metabolite alterations in the gut-brain axis. Long-term studies in a larger population are needed to tailor dietary interventions, essential for optimizing mental and physical health in obesity.

Neonatal hypoxic-ischemia (HI) represents a major cause of brain injury in the perinatal period. Post-ischemic neuroinflammation plays a key role in HI pathophysiology and is characterized by the infiltration of peripheral immune cells in support of resident microglia. To investigate the effects of peripheral macrophages as a possible treatment for HI, 10-day old CX3CXR1/CCR2 mice were subjected to electrocoagulation of the right carotid artery and 1 hour hypoxia with 10 % oxygen. CCR2 cell migration to the brain was assessed by flow cytometry 1, 3, 5, 7, 10 and 14 days after HI, and a biphasic infiltration pattern was identified. Five days post-surgery injured and sham pups received an intraperitoneal administration of bone marrow-derived macrophages (BMDMs) previously polarized into M0 or M2 states in vitro. Open field, beam walk and rotarod behavioral tests were performed 3 weeks after HI, and brains were then collected to assess injury extent. Injured mice treated with M2 cells showed significant functional recovery and reduced brain atrophy specifically in males. In contrast, treatment with M0 cells led to a significant worsening of behavioral performances and a greater brain injury specifically in females if compared to HI mice receiving PBS. To further define BMDM plasticity in a post-ischemic environment, M0 and M2 cells were co-cultured in vitro with hippocampal organotypic slices previously subjected to oxygen-glucose deprivation. After 48 h, M2 cells showed significant downregulation of Il1b, Cd68 and Tnfa, while significant upregulation of Il1b, Il6 and Ccl2 was observed in M0 cells, suggesting their switch into a M1 pro-inflammatory polarization state. Overall, these results suggest the therapeutic potential of M2 BMDMs for neonatal HI.

Broad-spectrum β-lactam antibiotics, such as ampicillin, disrupt the commensal gut microbiota and reduce its diversity. However, their potential short-term impact on the translocation of bacterial peptidoglycan (PGN) fragments to the brain and subsequent effects on brain function remain unexplored. In this study, we investigate the effects of a clinically relevant dose of ampicillin on PGN translocation into the brain, gene expression, brain functional connectivity, and social behavior in young adult mice. PGN translocation and gene expression were analyzed at 24-, 48-, and 72-h time points, while behavior, functional connectivity, and gut microbiota were analyzed at 72 h post-exposure. We find that ampicillin increases region-specific PGN translocation into the brain, which correlates with variations in the gene expression levels of PGN transporters and receptors in naïve animals. Antibiotic-treated mice exhibit impaired sociability and social recognition at 72 h post-exposure, which correlate with changes in the expression of synaptic (Syp, Ppp1r9b, Dlg4) and immune (Trem-2) genes in both the prefrontal cortex and striatum, along with disrupted brain functional connectivity. Furthermore, antibiotic-treated mice show an increase in the relative abundance of Gram-negative bacteria at 72 h post-exposure. Mice treated with iE-DAP, a unique PGN fragment from Gram-negative bacteria, exhibit key antibiotic-induced behavioral and molecular traits. Similar to antibiotic-treated mice, iE-DAP-exposed mice show impaired social recognition while maintaining normal motor activity, and reduced expression of synaptic-related genes in the prefrontal cortex and striatum. These findings provide novel insights into the neurobiological mechanisms underlying antibiotic-induced behavioral and functional disruptions and highlight the potential risks to brain health associated with repeated antibiotic use.

Both clinical and preclinical evidence demonstrates a robust association between mood disorders and cerebrovascular diseases, but the underlying mechanism remains elusive. In this study, to model the comorbidity of depression and cerebral hypoperfusion, we combined two different types of chronic stress paradigms, chronic unpredictable mild stress (CUMS) and social defeat (SD), with bilateral carotid artery stenosis (BCAS). Mice in the comorbidity group exhibited additive impairments in cognitive behaviors, surpassing the effects observed in the sham, stress-only, or BCAS-only groups. Notably, the most prominent change was massive microglial activation in the comorbidity group extending into critical gray matter areas, accompanied by severe brain lesion including blood-brain barrier (BBB) damage, demyelination, localized neuronal disruption, and abnormal vessel formation. Importantly, microglia emerged as central players in all observed cellular events, displayed stage-specific roles mediated by distinct subpopulations, driving neuroinflammation in response to BCAS and promoting angiogenesis under comorbid condition. Our findings suggest chronic stress impairs microglial function, increasing vulnerability to cerebral hypoperfusion. This study highlights chronic stress as a key risk factor for cerebrovascular events and underscores the importance of stress management in patients with this comorbidity.

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 ex vivo 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.

Autophagy is essential for maintaining cellular homeostasis, particularly under stress conditions such as neurotrauma. In experimental models of spinal cord injury (SCI), dysregulated autophagy has been closely associated with secondary injury cascades. Our previous work demonstrated that post-injury inflammation is exacerbated by genetic inhibition of autophagy and alleviated by pharmacological enhancement. Emerging evidence also indicates that SCI can induce neuropathological changes in the brain, leading to cognitive impairments; however, the underlying molecular mechanisms remain largely unclear. In this study, we utilized Becn1 knock-in (BMut) mice to investigate how genetically enhanced autophagy influences transcriptomic profiles, neural cell responses, tissue pathology, and functional recovery following contusion SCI. Transcriptomic analysis of BMut mouse spinal cord (SPC) tissues at 3 days post-injury revealed enhanced autophagy flux, reduced inflammatory responses, and altered microglial function and immune activity. Ten weeks after injury, BMut mice exhibited distinct transcriptomic profiles in the SPC, somatosensory cortex, and hippocampus. Further analyses revealed that the Becn1 mutation enhanced autophagy and altered inflammatory responses to SCI across all three regions. Behavioral assessments demonstrated improved functional recovery in BMut mice, accompanied by better-preserved spared white matter and reduced lesion volume. Immunofluorescence staining analysis showed that the Becn1 mutation reduced microglial activation and enhanced neurogenesis in the hippocampal dentate gyrus. Our study showed that genetic enhancement of autophagy altered transcriptomic responses, particularly inflammation, after SCI, reducing neuropathology in the spinal cord and brain and improving function. This is the first evidence linking autophagy enhancement to modulation of neuroinflammation after SCI, highlighting its therapeutic potential.

Recent studies suggest that autoreactive immunoglobulin G (IgG) antibodies binding to satellite glia cells (anti-SGC IgG) in the dorsal root ganglia influence pain intensity in a subgroup of fibromyalgia subjects (FMS), thus indicating altered immune activation. The main aim of this study was to identify proteins distinguishing female FMS from female healthy controls (HC) and within the FM group, proteins distinguishing FMS with high vs low levels of anti-SGC IgG. The secondary aim was to assess the associations between serum proteins and anti-SGC IgG, respectively, and FM symptoms.

The proinflammatory cytokine Interleukin-1 beta (IL-1β) regulates nearly all aspects of immune function. In the brain, IL-1β is implicated in neural and immune functions under both basal and inflammatory conditions. Under basal conditions, IL-1β is known to alter sleep, memory, and affect. Under inflammatory conditions, IL-1β can induce sickness behaviors, HPA activation, and exacerbate neurological and psychological disorders. Sensitive detection and specific manipulation of IL-1β-expressing cells in the brain is currently not achievable; therefore, we generated the first mouse line to allow both robust visualization and genetic manipulation of the IL-1β-expressing cells.

Insomnia, a widespread sleep disorder, significantly impacts mental and physical health. Emerging research highlights the crucial role of gut microbiota (GM) in modulating circadian rhythms (CR), which regulate sleep-wake cycles. This review explores the interplay between GM dysbiosis, CR disruptions, and insomnia, synthesizing findings from human and animal studies. GM dysbiosis is linked to reduced microbial diversity and altered abundance of key taxa, such as short-chain fatty acid-producing bacteria, which influence clock gene expression and hormonal rhythms. CR disruption exacerbates GM imbalances, forming a feedback loop that impairs sleep regulation through both central and peripheral pathways. We also examine the therapeutic potential of probiotics in restoring GM balance and synchronizing CR. Clinical trials suggest that specific probiotic strains improve sleep quality by modulating microbial metabolites and their downstream effects on the circadian system. However, inconsistencies in outcomes underscore the need for precision interventions. The review concludes by identifying gaps in the current literature, emphasizing the necessity of integrative approaches combining metagenomics and personalized medicine to optimize GM-targeted therapies. These insights pave the way for novel, safer, and more effective strategies to manage insomnia by addressing its biological underpinnings.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaques and tau neurofibrillary tangles, with tau pathology being closely linked to cognitive decline. Growing evidence suggests that metabolic dysfunction including type 1 diabetes (T1D) and type 2 diabetes (T2D), as well as prediabetes (PreDM), exacerbate AD by promoting different degrees of insulinopenia, insulin resistance and hyperglycemia which can drive chronic inflammation and oxidative stress across multiple organs. Precisely how these metabolic disturbances influence tau phosphorylation remains unclear. To address this, we studied mouse models of AD, T1D, PreDM, T2D and the combination of AD with all three metabolic alterations, at 26 weeks of age, when pathologies are well established. The fact that we are including models of insulin resistance and insulin deficiency allows us to further explore the specific role of insulin as observed in the clinic. We assessed metabolic status, tau phosphorylation and cytokine levels in the brain cortex and cognitive function using the Morris water maze (MWM) and novel object discrimination (NOD) tests. Our results revealed that AD mice with metabolic disorders exhibited tau hyperphosphorylation, particularly at Ser199, Ser202/Thr205 and Ser404, correlating with metabolic dysfunction, cognitive impairment and inflammatory markers. Notably, AD-T2D mice showed the most severe deficits in MWM and NOD performance, indicating a synergistic cognitive decline. Machine learning analysis by random forest effectively classified AD-metabolic phenotypes, identifying key molecular and metabolic markers of neurodegeneration, mainly blood glucose and plasma insulin. These findings highlight the critical role of metabolic dysfunction in exacerbating tau pathology and accelerating cognitive decline in AD. Targeting metabolic pathways may provide concomitant therapeutic opportunities for AD patients with diabetes. Future research should explore interventions that restore insulin signaling and glucose metabolism to mitigate AD progression, probably by repurposing antidiabetic drugs.

Early life experiences, such as repetitive neonatal procedural pain (RNP), may result in alterations in the function of the nervous and immune systems. In this study, we investigated the effect of RNP (postnatal day 0-7, 4 times/day) in male juvenile mice. Specifically, we evaluated (1) the spatial learning and memory, (2) the hippocampal microglia change, and (3) the regulatory role of microglial SIRP in hippocampal neuroinflammatory response. Our results show that RNP led to cognitive-behavioral changes. In addition, RNP activated hippocampal microglia in mice, promoting a proinflammatory phenotype and increasing the expression of relevant markers. Both in vivo and in vitro experiments revealed abnormal hippocampal microglia-mediated synaptic pruning in the pain model. Hippocampus-specific knockout model of microglial SIRPα, as well as microglial SIRPα overexpression/knockdown in vitro, was performed to demonstrate the regulatory role of SIRPα in microglia-mediated synaptic pruning and its contribution to RNP-induced brain function abnormalities and behavioral development abnormalities. Taken together, our results suggest that RNP causes spatial learning and memory impairment in juveniles. SIRPα as a "don't eat me" signaling molecule regulates engulfment of spines by activated microglia, potentially contributing to pain-related cognitive-behavioral development deficits, as well as impairment of microglia-mediated synaptic pruning.

Alcohol use disorder (AUD) continues to negatively impact millions of men and women in the United States each year, and current available treatments for AUD lack widespread efficacy. Major depressive disorder (MDD) is the most common comorbid condition with AUD and is also often treatment resistant. Many studies have found a relationship of immune modulators with both alcohol use and depression. There are many sex differences within the immune system that may contribute to both AUD and MDD, as well as to sex differences in their prevalence and presentation. Examining these mechanisms may offer more effective treatment options. The following review focuses on immune signaling mechanisms, including pattern recognition receptors and proinflammatory cytokines, which have been strongly associated with alcohol use and MDD. Within the context of these signaling systems, we will further discuss known sex differences in their function that may contribute to behavioral outcomes.

Childhood maltreatment increases subsequent risk for major depressive disorder (MDD), potentially through inflammatory pathways. The timely diagnosis and treatment of MDD may thus interrupt the association between inflammation and depressive symptoms, but diagnosis is frequently delayed. Additionally, sex-differences may affect timely diagnosis and treatment, contributing to differences in inflammation and depressive symptoms as individuals age.

Long COVID has emerged as a global health concern, with depression being one of its most debilitating and poorly understood manifestations. Despite evidence pointing to the role of neuroinflammation and astrocyte-mediated disruptions in brain function, the mechanistic details remain elusive.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in communication and social interaction and may stem from an imbalance between excitatory and inhibitory (E/I) signaling in neural circuits. Parvalbumin-expressing (PV+) interneurons are crucial for maintaining E/I balance and regulating network oscillations. Alterations in the number of PV+ interneurons or reductions in PV expression have been observed in both the postmortem brains of individuals with ASD and in animal models, including those induced by in utero exposure to maternal brain-reactive antibodies. In this study, we investigate the impact of in utero exposure to maternal anti-Caspr2 IgG on PV+ interneuron development and function in the hippocampus. Our results demonstrate a selective reduction in PV+ interneurons and perisomatic inhibitory synapses in the hippocampal CA1 region of juvenile and adult male offspring exposed in utero to anti-Caspr2 antibodies compared to controls. Additionally, local field potential (LFP) recordings from these mice show increased gamma power and altered neuronal firing patterns during social interactions, indicating functional impairments in inhibitory circuitry. These findings highlight the consequences of exposure to maternal anti-Caspr2 antibodies on PV+ interneuron development and function, providing insights into the neurobiological mechanisms underlying ASD associated behavioral phenotypes.

Traumatic brain injury (TBI) affects over 69 million people every year, and mild traumatic brain injury (mTBI) accounts for 70-90 % of cases. TBI has two components: i) primary injury - direct damage to the tissue from the mechanical impact and ii) secondary injury - additional or extended damage to the tissue from the ensuing biochemical and physiological processes such as neuroinflammation. Neuroinflammation triggered in part by activated microglia, determines whether the post-injury outcome is recovery or long-term neurodegeneration. Microglia, key components of the neuroinflammatory process, release cytokines such as TNF-α, which affect neuronal activity. Our study investigated the effects of acute microglia depletion on hippocampal neurophysiology in male mice (7-10 days after mTBI), a time window that allows us to target sub-acute microglial responses post-injury. An additional objective of the study was to determine if the pro-inflammatory cytokine TNF-α contributed to the injury-induced network excitability shifts in the hippocampal circuitry. We demonstrate that depleting microglia with PLX-3397 treatment for 7-10 days after mTBI restores network excitability in hippocampal area CA1 and the dentate gyrus (DG). Furthermore, treatments with thalidomide and etanercept show that TNF-α plays a role in altering the network excitability after mTBI. These findings provide new insights into the physiological changes after injury and highlight potential targets for future interventions to specifically address the detrimental effects of chronic inflammation.

Elucidating the biochemical pathways affected by pediatric traumatic brain injury (TBI) is essential for identifying informative blood-based biomarkers that may support future precision medicine and clinical trials. The kynurenine pathway (KP)-the primary route for tryptophan (Trp) degradation-represents a promising candidate due to its established link to (neuro)inflammation and TBI. The current study used liquid chromatography with tandem mass spectrometry to investigate KP metabolites in serum from 54 human patients with pediatric mild TBI (pmTBI; age 8-18 years) at ∼ 7 days and ∼ 4 months post-injury and 38 age- and sex-matched healthy controls (HC). The early temporal trajectories of KP metabolites were examined in more detail in serum samples collected from 33 juvenile swine with mild-to-moderate traumatic brain injury (mmTBI) at pre-injury baseline, and at 5 min, 35 min, 2.5 h, 24 h, and 7 days post-injury. Data from 10 sham animals were collected at equivalent time points. Interleukin 1 receptor antagonist (IL-1RA), IL-1β, IL-6, IL-10 and tumor necrosis factor (TNF) α were examined as measures of inflammation. In human pmTBI, significantly lower concentrations of Trp, 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HA), xanthurenic acid (XA) and picolinic acid (PA) were observed relative to HC, with stronger effects at 4 months relative to 7 days post-injury. Lower concentrations of Trp, 3HA, and XA at 4 months were associated with persistent post-concussive symptoms (PCS). As predicted, findings for inflammatory markers were null at these time points. In the large-animal model, an increased response of the anti-inflammatory IL-1RA was found at 2.5 h post-injury in mmTBI relative to sham animals, without any group differences in KP metabolites or other inflammatory markers. Both animal groups showed prominent temporal metabolite changes, including increased Trp at 2.5 h and decreased PA up to 24 h post-injury, likely reflecting cumulative effects of isoflurane anesthesia and associated dampening of pro-inflammatory responses. Altogether, our findings indicate long-lasting effects of pmTBI on the KP in humans. Disparate profiles were observed for human and large-animal injuries, which highlights the importance of incorporating clinically relevant biomarkers in preclinical studies to improve the translation of preclinical findings into successful future clinical trials.

The neurological complications of HIV or NeuroHIV, representing a spectrum of disorders in people living with HIV, are characterized by memory impairments and cognitive decline. Osteopontin/secreted phosphoprotein 1 (OPN/SPP1), a multifunctional cytokine-like protein secreted by multiple cell types in and outside the central nervous system (CNS), is highly elevated in NeuroHIV and other well-known neurodegenerative disorders. Additionally, previous neuroimaging studies have demonstrated a role for OPN in regulating neuroinflammatory signaling. However, the potential links between CNS-specific functions of OPN and behavior remain unclear. In this study, we used NSG immunodeficient mice (hu-mice) engrafted as neonates with HIV-susceptible human CD34 + hematopoietic stem cells (HSCs) to test the hypotheses that chronic viral infection impairs cognitive function and that systemic disruption of OPN expression can ameliorate the resulting behavioral deficits. We found that HIV-infected hu-mice treated with inhibitory OPN-aptamers to knock down OPN exhibited altered exploratory and anxiety-related behavior compared to uninfected animals. A synergistic relationship between HIV and OPN impaired cognitive performance in an object recognition memory task that was not observed in uninfected mice. The knockdown of OPN expression alleviated this recognition deficit. Interestingly, only the HIV-infected OPN knockdown group showed a marked reduction in motivation/self-care related behavior. Additionally, we found reduced OPN expression in cells located in the midbrain ventral tegmental area of HIV-infected mice, demonstrating for the first time, the systemic delivery of functional aptamers to the brain. Notably, there were no significant differences in OPN levels in similarly treated uninfected mice. Notably, a decrease in tyrosine hydroxylase (TH) expression in midbrain dopaminergic neurons of OPN knockdown compared to OPN wildtype mice, irrespective of HIV infection status was foundsuggests a potential gene expression regulatory link between OPN and TH. These findings highlight the multifaceted role of OPN in HIV-associated neurobehavioral dysfunction, suggesting context-dependent contributions to both cognitive and apathy-based processes.

Olfactory dysfunction (OD) is a common sensory disorder with age-related prevalence and serves as an early clinical manifestation for neurodegenerative and inflammatory diseases. Microglia in the olfactory bulb (OB) rapidly respond to olfactory injury and initiate immune responses, but the cell state dynamics and pathways driving OD remain poorly understood. Here, we performed single-cell RNA sequencing of mouse OBs at 0, 7, and 30 days post olfactory injury, and identified 3 distinct microglial states including inflammatory, negative regulatory, and homeostatic.The inflammatory microglia exacerbated neuroinflammation by secreting cytokines and chemokines that recruited immune cells and amplify local immune responses. Cathepsin B was identified as a key regulator of this inflammatory microglial activity. In vitro studies using BV2 and primary microglia demonstrated that both pharmacological inhibition and genetic deletion of CTSB attenuated lipopolysaccharide (LPS)-induced mitochondrial dysfunction, NLRP3 activation, and pro-inflammatory cytokine release. In mice with OD, pharmacological inhibition of CTSB with CA074me promoted olfactory function recovery and modulated microglial pro-inflammatory responses. Our findings uncover inflammation-associated microglial subpopulations enriched in OD and unveiled a deleterious role for CTSB-mediated neuroinflammatory signaling in OD pathogenesis. Targeting CTSB may therefore serve as a promising therapeutic strategy to mitigate microglia-mediated neuroinflammation and facilitate olfactory recovery in OD.

Depression is closely associated with disruptions in circadian rhythms, and emerging evidence highlights critical roles of gut dysbiosis in its pathogenesis. However, the mechanisms by which FMT chronotherapy influences circadian gene in depression-via gut microbiota-remain poorly understood.

Depression is one of the most prevalent mental health diseases, which is characterized by functional or structural changes of neurons. Cancer-induced depression (CID) can bring more serious medical burden. Exosomes have been implicated in cancer progression and depressive disorders; however, their specific role in CID remains unclear. To investigate the role of exosomes in CID, exosomes derived from 4T1 breast cancer cells were extracted using microfluidic chips-based isolation method. Behavioral assessments were performed to explore the effects of intranasal exosomal myeloid differentiation factor 88 (MYD88) on depressive-like behaviors in mice. Additionally, the effects of exosomal MYD88 on neuronal structure and function were researched by Golgi staining, sholl analysis and electrophysiological recordings. Exosomes from 4T1 breast cancer cells induced depressive-like symptoms and altered neuronal structure and function in the medial prefrontal cortex (mPFC) by upregulating MYD88 levels. Conversely, exosomes with reduced MYD88 content did not produce these depressive-like symptoms, suggesting a critical role for MYD88 in the observed effects. Exosomal MYD88 contributes to the development of breast cancer-induced depression. These findings highlight the potential of targeting exosomal pathways, particularly MYD88, as a therapeutic strategy for managing depression in cancer patients.

Stroke is a devastating neurological event with a high risk of mortality that results in long-term sequalae that extend beyond the central nervous system. Notably these include gastrointestinal dysfunction and altered composition of the commensal microbiota in both patients and mouse models, which have been suggested to contribute to secondary infection and poor clinical outcomes following stroke. Strikingly, changes in commensal microbial community composition occur rapidly following stroke and correlate with disease severity. Despite these observations, the underpinning mechanisms that drive perturbation of the microbiota post-stroke remain poorly understood. The gastrointestinal tract is home to a complex network of tissue-resident immune cells that maintain homeostatic interactions with commensal microbes and prevent bacterial-driven inflammation. Here we demonstrate mice subjected to ischaemic stroke exhibit alterations in the intestinal immune system, most notably in class switched germinal centre B cells and the production of Immunoglobulin A (IgA) - a major effector response against commensal microbes. Mice lacking secretory antibodies, including IgA, exhibited a partial reversion of stroke-induced changes in microbiota composition. Together these findings demonstrate stroke is associated with dysregulation of antibody producing immune responses, which may in part explain changes in the intestinal microbiota. A mechanistic understanding of the immunological basis of stroke-associated pathologies in the periphery may open new avenues to manage the secondary complications and long-term prognosis of patients suffering from neurological disease.

Lysosomal dysfunction lies at the nexus of inflammaging, microglial dystrophy and synaptic fragility, making it an attractive target for brain rejuvenation. Here we demonstrate that a five-month oral course of ketotifen, an approved H1-antihistamine and mast-cell stabiliser, re-acidifies lysosomes in aged C57BL/6J male mice, restoring the quinacrine signal of peripheral macrophages and SIM-A9 microglia. This proton rebound is coupled to broad anti-cytokine effects: ketotifen attenuates lipopolysaccharide-evoked release of TNF-α, IL-1β and IL-10 in vitro and ex vivo. In the brain, the drug restores a highly ramified, homeostatic microglial morphology throughout the cortex and hippocampus. Ketotifen robustly elevates cortical synaptophysin and PSD-95 above age-matched levels. Behaviourally, ketotifen enhances spatial learning and object-location memory without altering locomotor activity or anxiety-like behaviour. Collectively, these findings identify lysosomal re-acidification as the initiating trigger of a multifaceted rejuvenation cascade that dampens multi-cytokine signalling, restores microglial morphology and preserves synaptic integrity. Because ketotifen is inexpensive, brain-permeable and already licensed for human use, our work unveils an immediately actionable geroprotective strategy to forestall early cognitive decline.

Neuroinflammation is implicated in epilepsy pathogenesis, and microglia are key immune cells of the brain that participate in neuroinflammatory responses associated with epilepsy. This study investigated the role of early microglial activation following an epileptogenic brain injury on the incidence and severity of epilepsy and associated neurobehavioral impairments in a model of acquired epilepsy.