Chronic pain induced by pathological insults to the sensorimotor system is a typical form of neuropathic pain (NP), and the underlying mechanism is complex. Currently, there are no successful therapeutic interventions for NP. Orexin B is a neuropeptide with a wide range of biological functions. However, the pharmacological function of orexin B in chronic neuropathic pain has been less studied. Here, we aim to examine the neuroprotective effects of orexin B in chronic constriction injury (CCI)- induced NP. Firstly, we found that orexin type 2 receptor (OX2R) but not orexin type 1 receptor (OX1R) was reduced in the spinal cord (SC) of CCI-treated rats. Mechanical withdrawal threshold and thermal withdrawal latency assays display that administration of orexin B clearly ameliorated CCI-evoked neuropathic pain dose-dependently. Notably, orexin B treatment also effectively prevented microglia activation by reducing the levels of IBA1. Additionally, orexin B was also found to suppress the inflammatory response in the SC tissue by reducing the levels of IL-6, TNF-α, iNOS, and COX-2 as well as the production of NO and PGE2 in CCI-treated rats. Furthermore, orexin B administration attenuated oxidative stress (OS) by increasing the activity of SOD and the levels of GSH. Mechanically, orexin B prevented activation of JNK/NF-κB signaling in the SC of CCI-treated rats. Based on these findings, we conclude that orexin B might have a promising role in ameliorating CCI-evoked neuropathic pain through the inhibition of microglial activation and inflammatory response.

UNASSIGNED: Alzheimer\'s disease (AD), a major cause of dementia globally, imposes significant societal and personal costs. This review explores the efficacy of physical exercise as a non-pharmacological intervention to mitigate the impacts of AD.
UNASSIGNED: This review draws on recent studies that investigate the effects of physical exercise on neuroinflammation and neuronal enhancement in individuals with AD.
UNASSIGNED: Consistent physical exercise alters neuroinflammatory pathways, enhances cognitive functions, and bolsters brain health among AD patients. It favorably influences the activation states of microglia and astrocytes, fortifies the integrity of the blood-brain barrier, and attenuates gut inflammation associated with AD. These changes are associated with substantial improvements in cognitive performance and brain health indicators.
UNASSIGNED: The findings underscore the potential of integrating physical exercise into comprehensive AD management strategies. Emphasizing the necessity for further research, this review advocates for the refinement of exercise regimens to maximize their enduring benefits in decelerating the progression of AD.

Ischemic stroke is a common cause of mortality and severe disability in human and currently lacks effective treatment. Neuronal activation and neuroinflammation are the major two causes of neuronal damage. However, little is known about the connection of these two phenomena. This study uses middle cerebral artery occlusion mouse model and chemogenetic techniques to study the underlying mechanisms of neuronal excitotoxicity and severe neuroinflammation after ischemic stroke. Chemogenetic inhibition of neuronal activity in ipsilesional M1 alleviates infarct area and neuroinflammation, and improves motor recovery in ischemia mice. This study identifies that ischemic challenge triggers neuron to produce unique small extracellular vesicles (EVs) to aberrantly activate adjacent neurons which enlarge the neuron damage range. Importantly, these EVs also drive microglia activation to exacerbate neuroinflammation. Mechanistically, EVs from ischemia-evoked neuronal activity induce neuronal apoptosis and innate immune responses by transferring higher miR-100-5p to adjacent neuron and microglia. MiR-100-5p can bind to and activate TLR7 through U18U19G20-motif, thereby activating NF-κB pathway. Furthermore, knock-down of miR-100-5p expression improves poststroke outcomes in mice. Taken together, this study suggests that the combination of inhibiting aberrant neuronal activity and the secretion of specific EVs-miRNAs may serve as novel methods for stroke treatment.

Influenza A virus (IAV) infection can increase the risk of neuroinflammation, and subsequent neurodegenerative diseases. Certain IAV strains, such as avian H7N7 subtype, possess neurotropic properties, enabling them to directly invade the brain parenchyma and infect neurons and glia cells. Host sex significantly influences the severity of IAV infections. Studies indicate that females of the reproductive age exhibit stronger innate and adaptive immune responses to IAVs compared to males. This heightened immune response correlates with increased morbidity and mortality, and potential neuronal damage in females. Understanding the sex-specific neurotropism of IAV and associated mechanisms leading to adverse neurological outcomes is essential. Our study reveals that primary hippocampal cultures from female mice show heightened interferon-β and pro-inflammatory chemokine secretion following neurotropic IAV infection. We observed sex-specific differences in microglia activation: both sexes showed a transition into a hyper-ramified state, but only male-derived microglia exhibited an increase in amoeboid-shaped cells. These disparities extended to alterations in neuronal morphology. Neurons derived from female mice displayed increased spine density within 24 h post-infection, while no significant change was observed in male cultures. This aligns with sex-specific differences in microglial synaptic pruning. Data suggest that amoeboid-shaped microglia preferentially target postsynaptic terminals, potentially reducing neuronal hyperexcitability. Conversely, hyper-ramified microglia may focus on presynaptic terminals, potentially limiting viral spread. In conclusion, our findings underscore the utility of primary hippocampal cultures, incorporating microglia, as an effective model to study sex-specific, virus-induced effects on brain-resident cells.

This review offers a comprehensive examination of the role of microglia in the pathogenesis of autoimmune uveitis, an inflammatory eye disease with significant potential for vision impairment. Central to our discussion is the dual nature of microglial cells, which act as both protectors and potential perpetrators in the immune surveillance of the retina. We explore the mechanisms of microglial activation, highlighting the key signaling pathways involved, such as NF-κB, JAK/STAT, MAPK, and PI3K/Akt. The review also delves into the genetic and environmental factors influencing microglial behavior, underscoring their complex interaction in disease manifestation. Advanced imaging techniques and emerging biomarkers for microglial activation, pivotal in diagnosing and monitoring the disease, are critically assessed. Additionally, we discuss current and novel therapeutic strategies targeting microglial activity, emphasizing the shift towards more precise and personalized interventions. This article aims to provide a nuanced understanding of microglial dynamics in autoimmune uveitis, offering insights into potential avenues for effective treatment and management.

Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.

BACKGROUND: Alzheimer disease (AD) is a heterogenous and multifactorial disease, and its pathology is partly driven by microglia and their activated phenotype. Brain organoids (BOs) are gaining prominence as a relevant model of the human brain for the study of AD; however, BOs are commonly devoid of microglia. To overcome this limitation, current protocols incorporate microglia through either (1) co-culture (BO co-culture), or (2) molecular manipulation at critical windows of BO development to have microglia arise innately (BO innate cultures). It is currently unclear whether the microglia incorporated into BOs by either of these two protocols differ in function.
METHODS: At in vitro day 90, BO innate cultures and BO-co-cultures were challenged with the AD-related β-amyloid peptide (Aβ) for up to 72 h. After Aβ challenge, BOs were collected for immunoblotting. Immunoblots compared immunodensity and protein banding of Aβ and ionized calcium-binding adapter molecule 1 (IBA1, a marker of microglial activation) in BOs. The translational potential of these observations was supported using 56 human cortical samples from neurocognitively normal donors and patients with early-onset AD and late-onset AD. Statistical analyses were conducted using the Kruskal-Wallis test, a two-way ANOVA, or a simple linear regression, and where applicable, followed by Dunn\'s or Sidak\'s test.
RESULTS: We show that BO co-cultures promote Aβ oligomerization as early as 24 h and this coincides with a significant increase in IBA1 levels. In contrast, the Aβs do not oligomerize in BO innate cultures and the IBA1 response was modest and only emerged after 48 h. In human cortical samples, we found IBA1 levels correlated with age at onset, age at death, and the putative diagnostic Aβ(1-42)/Aβ(1-40) ratio (particularly in their oligomeric forms) in a sex-dependent manner.
CONCLUSIONS: Our unique observations suggest that BOs with innate microglia model the response of a healthy brain to Aβ, and by extension the initial stages of Aβ challenge. It would be impossible to model these early stages of pathogenesis in BOs where microglia are already compromised, such as those with microglia incorporated by co-culture.

In Alzheimer\'s disease, chronic neuroinflammation is accompanied by amyloid and tau pathologies. Especially, aberrant microglial activation is known to precede the regional tau pathology development, but the mechanisms how microglia affect tau spread remain largely unknown. Here, we found that toll-like receptor 2 (TLR2) in microglia recognizes oligomeric tau as a pathogenic ligand and induces inflammatory responses. Knockout of TLR2 reduced tau pathology and microglial activation in rTg4510 tau transgenic mice. Treatment of oligomeric tau induced TLR2 activation and increased inflammatory responses in microglial cells. TLR2 further mediated the tau-induced microglial activation and promoted tau uptake into neurons in neuron-microglia co-culture system and in mouse hippocampus after intracranial tau injection. Importantly, treatment with anti-TLR2 monoclonal antibody Tomaralimab blocked TLR2 activation and inflammatory responses in a dose-dependent manner, and significantly reduced tau spread and memory loss in rTg4510 mice. These results suggest that TLR2 plays a crucial role in tau spread by causing aberrant microglial activation in response to pathological tau, and blocking TLR2 with immunotherapy may ameliorate tau pathogenesis in Alzheimer\'s disease.

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BACKGROUND: Sleep deprivation (SD) is a common disorder in modern society. Hippocampus is an important region of the brain for learning, memory, and emotions. Dysfunction of hippocampus can lead to severe learning and memory disorder, significantly affecting quality of life. SD is accompanied by hippocampal microglia activation and a surge in inflammatory factors, but the precise mechanism remains unclear. Moreover, the ongoing unknown persists regarding how activated microglia in SD lead to neuronal damage. Topoisomerase 1 (TOP1) plays an essential role in the inflammatory process, including the tumor system and viral infection. In this study, we observed a significant elevation in TOP1 levels in the hippocampus of mice subjected to SD. Therefore, we hypothesize that TOP1 may be implicated in SD-induced microglia activation and neuronal damage.
OBJECTIVE: To investigate the role of TOP1 in SD-induced microglial activation, neuronal damage, and neurobehavioral impairments, and the molecular basis of SD-induced elevated TOP1 levels.
METHODS: TOP1-specific knockout mice in microglia were used to study the effects of TOP1 on microglial activation and neuronal damage. Transcription factor prediction, RNA interference, ChIP-qPCR, ChIP-seq database analysis, and luciferase reporter assays were performed to explore the molecular mechanisms of YY1 transcriptional activation. Untargeted metabolic profiling was employed to investigate the material basis of YY1 transcriptional activation.
RESULTS: Knockdown of TOP1 in hippocampal microglia ameliorates SD-induced microglial activation, inflammatory response, and neuronal damage. Mechanistically, TOP1 mediates the release of IL-6 from microglia, which consequently leads to neuronal dysfunction. Moreover, elevated TOP1 due to SD were associated with neopterin, which was attributed to its promotion of elevated levels of H3K27ac in the TOP1 promoter region by disrupting the binding of YY1 and HDAC1.
CONCLUSIONS: The present study reveals that TOP1-mediated microglial activation is critical for SD induced hippocampal neuronal damage and behavioral impairments.