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.

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.

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.

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.

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.

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.

Human endogenous retroviruses (HERVs) constitute ∼8 % of the human genome, far exceeding the 2 % occupied by protein-coding genes. Although most HERV sequences are inactive, some HERV elements can be reactivated under certain conditions and may contribute to neurodegenerative diseases (NDDs). However, the findings vary across different HERV families, disease models, and detection methods. Here, we systematically review and synthesize the available evidence on the role of HERVs in human NDDs and reconcile inconsistencies in the literature.

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., Fkbp5). The antinociceptive effects of NPD1 were abolished in Gpr37/ mice. Moreover, swimming-induced stress prolonged TBI-evoked pain, and NPD1 prevented this transition from acute to chronic pain in wild-type but not Gpr37/ 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.

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.

Chronic neuropathic pain is frequently accompanied by cognitive impairment, which seriously influence the quality of the patient's life. The stability of synapse is the basis for maintaining neural circuits. And overactive microglia can prune normal synapses through phagocytosis, leading to cognitive impairment. This study aims to investigate the role of microglial synaptic pruning in chronic neuropathic pain-induced cognitive impairment, and explore the mechanisms of microglial activation through Interleukin-17A (IL-17A) activation and copper accumulation. We found that chronic neuropathic pain resulted in cognitive impairment, and microglial activation, abnormal microglial synaptic pruning, synaptic loss in hippocampus. Depleting microglia ameliorated the activations of microglial and complement pathways, and rescued synaptic loss and cognitive impairment. The copper was accumulated in hippocampus, and copper chelator tetrathiomolybdate (TTM) inhibited microglial and complement activations and rescued synaptic loss and cognitive impairment. Further research found that suppressing mitochondrial oxidative stress response inhibited copper accumulation-induced microglial activation. Finally, IL-17A was found to be increased in serum and hippocampus. IL-17A neutralization antibody (anti-IL-17A Abs) alleviated copper accumulation by inhibiting six transmembrane epithelial antigens of prostate 4 (STEAP4) / copper transporter 1 (CTR1), and inhibited microglial and complement activation, interrupting abnormal synaptic elimination and ameliorating cognitive impairment. Our results suggest that IL-17A can induce copper accumulation in microglia through STEAP4/CTR1, the latter promotes complement-mediated microglia synaptic pruning, reducing synapse number, and ultimately resulting in cognitive impairment. These provide a new potential therapeutic target for the treatment of chronic neuropathic pain-induced cognitive impairment.

Metabolic syndrome (MetS) can lead to accelerated brain aging and cognitive decline. Evidence has suggested the involvement of the microbiota-gut-brain axis in the relationship between MetS and cognitive dysfunction, but the underlying mechanisms are unclear. Using magnetic resonance imaging and 16S rRNA gene amplicon sequencing, we collected data of brain structure (gray matter volume and white matter integrity) and gut microbiome from 97 patients with MetS and 103 sex-, age- and education-matched healthy controls. The Trail-making Test A and auditory verbal learning test were used to assess executive function and memory. Group differences in gut microbiome, brain structure, and cognitive function as well as their plausible interactive links in patients with MetS were examined. We found that patients with MetS exhibited impaired executive function and memory ability, both depleted short-chain fatty acids (SCFA)-producing bacteria and enriched inflammation-triggering bacteria, gray matter atrophy of several brain regions and microstructural integrity damage of multiple white matter tracts. Of more importance, correlation and mediation analyses demonstrated that the abnormal brain structure mediated the associations between the depleted anti-inflammatory bacteria (i.e., Clostridium XlVa, Kineothrix and Acetivibrio) and the impaired cognitive function in patients with MetS. Our findings not only point to new hypotheses about potential neurobiological pathways by which gut microbial dysbiosis may lead to cognitive dysfunction in the context of MetS, but also highlight the potential therapeutic value of targeting gut microbiota for cognitive impairments in patients with MetS.

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.

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.

Antenatal depression is linked to adverse neurodevelopmental outcomes in offspring, likely mediated by a multitude of biological mechanisms, including elevated maternal cytokines. However, factors modulating fetal vulnerability or resilience to inflammatory exposure remain unclear. This study examines whether the steroid hormone, oestradiol, can modulate inflammatory responses in an in vitro model of hippocampal neurogenesis, using two fetal hippocampal progenitor cell lines: female-derived HPC0A07/03C and male-derived HIP-009. Cells were pre-treated with oestradiol for 24- and 48-hours during proliferation, followed by interleukin-1beta (IL-1β) exposure prior to the initiation of differentiation. Markers of proliferation and neurogenesis, as well as inflammatory cytokines and kynurenine pathway metabolites, were assessed. In female HPC0A07/03C cells, oestradiol pre-treatment prevented IL-1β-induced proliferation and apoptosis, and reduced cytokine production. Conversely, in male HIP-009 cells, oestradiol pre-treatment did not prevent IL-1β-induced reduction of proliferation and apoptosis and indeed enhanced inflammatory responses after 48 h. In terms of differentiation, IL-1β produced opposite effects on neurogenesis across cell lines, increasing neuronal maturation in female HPC0A07/03C cells, but decreasing neurite complexity in male HIP-009 cells. Notably, oestradiol pre-treatment in both lines reduced neuronal differentiation and increased kynurenine levels, suggesting potentially detrimental long-term effects. These results highlight complex, potentially cell-line-dependent, sex-specific hormone-immune interactions shaping fetal neurodevelopment and underscore the need to investigate these interactions when assessing risks and developing therapeutic interventions for inflammation-related neurodevelopmental disorders.

Preterm birth has been associated with long-term physical, cognitive, behavioural and emotional challenges. Preterm infants are often exposed to significant inflammation in early life, which has been studied in relation to adverse neurodevelopmental outcomes. In later childhood, inflammation has been associated with psychiatric symptoms. However, the developmental processes underlying the association between inflammation and mental health outcomes, particularly in preterm children, are not fully understood. We aimed to investigate the association between inflammation and behavioural outcomes in mid-childhood in preterm- and term-born children.

Chronic morbidities, including cognitive impairment, are a common consequence of traumatic brain injury (TBI), with millions currently living with permanent TBI-related disabilities. Recent work has indicated that altered cellular architecture in the dentate gyrus (DG) may play a significant role in the development of chronic cognitive impairment and excitotoxicity. However, current understanding of the temporal progression of these pathological changes in the context of neuroinflammation and chronic cognitive outcomes is limited. This study characterized temporospatial changes in the hilar region of the DG, showing that the population of reelin- and somatostatin-expressing inhibitory interneurons was significantly reduced as early as 7 days post-injury (dpi), and that aberrant migration of excitatory granule cells occurs gradually in the weeks to months following injury. These findings coincided with upregulation of monocyte/macrophage-associated inflammatory mediators, including MIP-1β, MIG, MCP-1, and TNF-α at 7 days dpi, with differential cytokine regulation persisting 120 dpi. Injury was associated with the development of chronic spatial memory impairment and reduced risk-assessment behavior, with a transient reduction in spontaneous anxiety. TNFR1 and TNFR2 were differentially expressed in inhibitory neurons, further implicating TNF-signaling as a driver of hilar neuron loss. Furthermore, systemic administration of anti-TNF-α monoclonal antibody induced significant neuroprotection, attenuated pro-inflammatory mediators, and hilar interneuron loss. These findings suggest that TNF-TNFR signaling plays a crucial role in driving hilar interneuron loss and aberrant granule cell migration, which, in turn, may contribute to the development of excitotoxicity and chronic cognitive deficits.

Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra and striatum, which accompanied by the activation of NLRP3 inflammasome, autophagic dysfunction and motor disorders. USP9X, as a highly conserved ubiquitin-specific protease, which abnormal expression is closely correlated with various neurodegenerative diseases and neurodevelopmental disorders. However, whether USP9X can regulate the activation of NLRP3 inflammasome in Parkinson's disease (PD) has not been elucidated yet. In this study, LPS was intraperitoneally injected into wild-type mice to simulate neuroinflammation of Parkinson's disease and USP9X-shRNA was stereotactic injected into bilateral lateral ventricles (LV) of the mice brain to inhibit the expression of USP9X. The results showed that inhibition of USP9X expression could siginificantly improve the motor dysfunction, activation of NLRP3 inflammasome, degeneration of dopaminergic neurons and activation of microglia induced by LPS. Additionally, the parkin mice exhibited great activation of the NLRP3 inflammasome, loss of dopaminergic neurons and motor dysfunction at an early age. However, downregulation of USP9X expression in parkin mice also significantly improved the activation of the NLRP3 inflammasome, damage to dopaminergic neurons, autophagic dysfunction and motor dysfunction. Therefore, USP9X can be utilized as an effective potential target for inhibiting NLRP3 inflammasomes activation and activating the autophagic function, which expected to be a potential therapeutic strategy for Parkinson's disease.

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.

Cancer-related cognitive impairment affects a substantial proportion of cancer patients, significantly reducing quality of life and interfering with daily functioning. Neuroinflammation, oxidative stress, and blood-brain barrier (BBB) dysfunction are mechanistic contributors to cancer-related cognitive impairment. Evidence suggests that dysregulation of the renin-angiotensin system (RAS) is involved, as it modulates these biological processes, and pathway analyses demonstrate that perturbations in gene expression of RAS components in the peripheral blood distinguish cancer patients who experience cognitive symptoms from those who do not. To explore the potential of repurposing angiotensin receptor blockers for cancer-related cognitive impairment, we tested whether candesartan, an angiotensin II type 1 receptor (AT1R) antagonist, could prevent cancer-induced cognitive deficits and alter RAS-related gene expression, cytokine mRNA levels, and BBB integrity. Using the 4T1.2 mammary cancer model, we assessed spatial memory and object recognition and examined molecular changes in the prefrontal cortex and hippocampus. Candesartan blocked cancer-induced spatial memory impairment without affecting primary tumour growth or causing sickness behaviour. Candesartan's efficacy was associated with reduced hippocampal and cortical angiotensin II type 1a receptor (Agtr1a) and cortical angiotensin II type 1b receptor (Agtr1b) expression, alongside increased hippocampal angiotensin II type 2 receptor (Agtr2), consistent with a shift toward a neuroprotective RAS signalling profile. Candesartan lowered tumour necrosis factor (Tnf) expression and improved BBB integrity in the frontal cortex, supporting its anti-inflammatory role. We provide the first evidence that candesartan may offer a low-cost strategy to prevent cancer-related cognitive impairment by modulating the RAS, neuroinflammation and BBB permeability.

Neurodevelopmental disorders (ND) arise from a complex interaction between genetic and maternal environmental factors occurring during pregnancy and involving the immune system. Rodent models, particularly genetic and immune-based approaches, have significantly advanced our understanding of ND etiology and pathogenesis. However, translationally relevant large animal model of maternal immune activation, capable of recapitulating behavioral phenotypes and biomarker associations consistent with ND are missing. In this study, we aimed to model ND in sheep by inducing Maternal Immune Activation (MIA) in pregnant ewes, as prenatal infections are well-replicated environmental factors associated with an increased risk of ND in humans. Pregnant ewes were challenged with bacterial lipopolysaccharide (LPS) to induce MIA at either mid- or late pregnancy, and the lambs' behaviors were monitored after birth. Moreover, we developed and validated a battery of behavioral assays (e.g., Isolation Test, V-Detour Test, and T-Maze) to assess ND-related behavioral domains in lambs, such as social attachment, spatial learning, inhibitory control, and cognitive flexibility. Lambs prenatally exposed to MIA exhibited selective impairments in cognitive domains, including learning, memory consolidation, and cognitive flexibility, while developmental milestones and core social behaviors, such as maternal bonding, remained unchanged. Importantly, individual differences in maternal inflammatory responses, particularly IL-6 levels, correlated with the severity of behavioral alterations in the offspring. The observed behavioral phenotypes and immunological correlations support the validity of the ovine model for studying ND and related behavioral disorders. Our findings lay the groundwork for using sheep in future mechanistic and preclinical research on neurodevelopmental disorders.

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. 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 Faecalibacterium species and short-chain fatty acids and a reduction of opportunistic pathogens. Long-term supplementation also increased blood APOA4 and HSPA5 and reduced symptoms of PD. Our study highlights the potential of dietary interventions to modulate the gut microbiome and improve the quality of life for PD patients.

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.

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.

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.

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.

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.

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.

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.