This study investigated how prolonged aggression in male CD1 mice alters responses to chronic LPS (lipopolysaccharide)-induced inflammation. Experience of aggression induced pathological aggression in 36% of mice. Following LPS, aggressors resolved systemic inflammation within five days—evidenced by normalized locomotor activity, WBC (white blood cells), and lymphocyte counts—while controls remained inflamed. LPS did not alter established aggression or anxiety. Furthermore, aggressors demonstrated accelerated inflammation resolution in the brain, showing a higher proportion of resting microglia and a lower percentage of activated microglia following LPS-induced inflammation compared to control animals. Gene expression analysis revealed a more pronounced inflammatory response in the hypothalamus than in the nucleus accumbens. Aggressive mice exhibited a profile associated with inflammation resolution, indicated by increased expression of the Trem2 gene. These differential immune responses may be modulated by the dopaminergic system. Elevated Drd1 gene expression in the hypothalamus could possibly contribute to the anti-inflammatory signaling, while changes in nucleus accumbens dopaminergic activity, involving D2 receptor activation, appear linked to the development of pathological aggression. Thus, this study demonstrates that prolonged aggression induces persistent changes in behavioral, neuroimmune, and neuroendocrine systems in male CD1 mice. Aggressive animals develop a distinct neuroimmune phenotype characterized by accelerated resolution of both systemic and brain inflammation following LPS challenge.

ABSTRACTChronic fatigue, mood disturbances, and cognitive deficits characterize the neurological post‐COVID syndrome (PCS). This study aimed to find out if PCS shows a diagnostic brain metabolic pattern that might also support clarification of the PCS pathology. Whole brain proton magnetic resonance spectroscopy imaging (wbMRSI) was applied to assess brain metabolites in PCS patients. Patients' data were compared to those of matched healthy controls examined before the COVID pandemic. Patients underwent clinical and neuropsychological assessment and filled in self‐report questionnaires related to fatigue, mood, and health‐related quality of life. Thirty PCS patients were enrolled into the study. WbMRSI showed significantly reduced levels of brain myo‐inositol, which is considered as representative of astrocyte and microglia activity, in the frontal, temporal and parietal lobes, bilaterally, and in the cerebellum of the patients compared to controls. Patients' creatine was higher in the left frontal lobe and the combined glutamate/glutamine peak was lower in the right parietal lobe. N‐acetyl‐aspartate, an indicator of neuronal integrity, as well as choline that reflects cell membrane turnover, showed no group differences. The findings suggest an alteration of the neuroimmune system in PCS patients, without indication of disturbed neuronal integrity or alteration of the cerebral energy metabolism.

Adolescent opioid use in the United States commands attention: millions of twelve- to nineteen-year-olds are exposed to opioids each year by prescription and misuse. Recent findings show that opioids bind not only to canonical opioid receptors but also interact with receptors on immune cells within both the central and peripheral nervous systems. The potential for early life opioid exposure to give rise to long-term changes in the neuroimmune system is not fully understood, particularly given the adolescent brain’s high susceptibility to neuroplastic changes. The goal of this study was to investigate the hypothesis that adolescent opioid use potentiates physiological and behavioral responses to lipopolysaccharide (LPS)-induced sickness later in life. To achieve this, we treated adolescent (postnatal day 35–42) male and female C57/BL6 mice with saline or bi-daily escalating doses of morphine for 5 days to model opioid dependence and, in adulthood (postnatal day 60–67), administered saline or a low dose of LPS (0.1 mg/kg) to promote an immune response. Body weight, body surface temperature, and locomotor activity were recorded up to 48 hours after LPS administration. Mice were also tested in the forced swim test 52 hours after LPS administration to assess depressive-like behavior. In contrast to our hypotheses, we found that adolescent morphine exposure had no additive effect on low-dose LPS-induced sickness measures when assessed in adulthood. These data suggest that adolescent opioid exposure may have minimal effects on future immune challenges, although further research is needed to confirm this.

Imaging Neuroimmune Dysfunction: From TSPO to Emerging PET Targets.

Bovine milk casein-derived sleep-enhancing peptides (CSEPs), as natural bioactive substances, demonstrate significant potential in sleep promotion. This review focuses on the digestion, absorption, and metabolic characteristics of CSEPs, conducts a comprehensive review of its sleep-enhancing mechanism, and discusses new development strategies. On the one hand, CSEPs can directly act on the central nervous system, cause changes in neuronal potential through the structure-activity compatibility mechanisms, and thereby promote sleep. On the other hand, CSEPs can regulate gut microbiota composition and metabolites, activate the neuroimmune and endocrine systems, and affect the formation of neurons through the gut-brain axis, thereby indirectly mediating sleep. New development strategies for CSEPs are proposed. Computer-aided technology can be utilized to model and predict their structure-activity relationship. Then, through the bacterium-enzyme synergy technology, CSEPs can be prepared in a targeted manner. Finally, electrophysiological technology and animal models can be used to explore the mechanism of CSEPs.

Zebrafish are a powerful model for imaging studies of development and neurobiology. However, most studies have focused on developing zebrafish due to technical and biological challenges of imaging adult stages. These include increased tissue opacity and illumination depth limitations, and difficulty maintaining life support and anesthesia in a 2–4cm long fish. There are currently limited tools for intravital imaging of the adult zebrafish brain. The ability to image the brain in the same individual repeatedly without physical damage would allow zebrafish to be better utilized to study aging and neurodegenerative disease. We designed and applied a 3D-printable device for non-invasive, repeatable multiphoton neural imaging of genetically non-pigmented adult zebrafish from 2 months to 19 months old. Animals successfully recovered after multi-hour imaging sessions and can be imaged repeatedly over periods of weeks to years. We show the utility of this approach through imaging the neuroimmune system, revealing that microglia in aged zebrafish have enhanced cellular dynamics. This technique could be widely used and beneficial for other cell-scale neuroimaging studies in the adult fish.

Autism is a complex neurodevelopmental disorder characterized by a wide range of cognitive, behavioural and communication impairments. Children with autism have a distinctive and underdeveloped range and volume of gut bacteria (microbiome) which is often not related to their diet. Evidence gathered throughout years of research suggests that the pathway between gut bacteria and the central nervous system, referred to as the gut-brain axis (GBA), has a profound effect on the social behaviours of autistic children. The gut microbiome has been shown to play a vital role in the manifestation of autism spectrum disorder (ASD) symptoms as gut dysbiosis - an imbalance in the gut microbiome - affects brain development through processes regulated by the neuroendocrine, neuroimmune and autonomic nervous systems. Although dysregulation of the gut microbiome and subsequent disruption of GBA are thought to contribute to the pathogenesis of autism, the underlying mechanisms and the extent to which the microbiome contributes to neurodevelopmental disorders remain unclear. In this review, we focus on understanding the complex and multidirectional interplay between gut microbiota and ASD based on evidence mounted over the years. Furthermore, we examine how genomics, metabolomics and microbiome components can be integrated to unravel this multifactorial disorder. The ability to understand the underlying mechanisms involved in ASD will pave the way for future advancements in therapy and treatment.

Neuroimmune integration in chronic stress: mechanisms of TRPV1-CB2 crosstalk, inflammation, and neural resilience.

Microbial regulation of serotonin and neuroimmune interactions.

The primary clinical manifestation of osteoarthritis (OA) is pain, yet considerable variability exists in the pain experience among OA patients. This narrative review aims to explore the mechanisms driving OA pain heterogeneity to inform the development of targeted interventions that improve treatment efficacy and patient outcomes. A comprehensive literature search was conducted across multiple databases (PubMed, Scopus, and Google Scholar) for papers published between January 1, 2020, and December 31, 2024. Inclusion criteria focused on studies addressing pain mechanisms and therapeutic interventions in OA. This review identifies key mechanisms of OA pain, including joint alterations, angiogenesis, nervous system involvement, peripheral and central sensitization, and psychosocial factors. It highlights the underlying distinct mechanisms in OA pain, which contribute to the variability in individuals' responses to treatment. It was suggested that interactions between neuroimmune and neurovascular systems are key contributors to chronic pain in OA. This narrative review emphasizes the complexity of OA pain, highlighting the importance of thoroughly understanding the underlying mechanisms for developing personalized and effective pain management strategies. Additional research is required to refine treatment approaches and explore long-term effects.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), a refractory urinary system disorder, is closely associated with dysregulation of the brain-gut-prostate axis. Emerging evidence highlights the pivotal role of gut microbiota dysbiosis and its bidirectional interactions with the neuroimmune system in CP/CPPS pathogenesis. This systematic review integrates perspectives from microbiomics, neuroimmunology, and metabolomics to propose a theoretical framework of the brain-gut-prostate axis and multi-dimensional therapeutic strategies targeting this axis. By transcending conventional localized anti-inflammatory approaches, these strategies aim to address clinical resistance and phenotypic heterogeneity. Mechanistic insights into microbiota-derived metabolites (e.g., short-chain fatty acids, SCFAs), neuroendocrine signaling (e.g., thyrotropin-releasing hormone, TRH), and immune crosstalk (e.g., Th17/Treg imbalance) are explored, alongside innovative therapies such as microbiome modulation, neural interventions, and immune regulation. This holistic paradigm not only provides new mechanistic insights but also offers promising avenues for personalized management and translational research in CP/CPPS, potentially overcoming current therapeutic bottlenecks.

Binge alcohol and the neuroendocrinology of the aging female.

Immune cells in dorsal root ganglia are associated with pruritus in a mouse model of allergic contact dermatitis and co-culture study.

Disturbances in neuroimmune system have significant implication in eliciting cognitive and neurobehavioral deficit, and biochemical changes associated with CuSO4-induced neurotoxicity. Plant-based food rich in phytochemical property is suggested to inhibit the mechanism implicated in CuSO4-induced neurotoxicity. Thus, this study investigated the mechanisms through which Zingiber officinale Roscoe methanol extract (MEZO) exerts its therapeutic effects after CuSO4 exposure in mice. Male mice were randomly divided into five experimental groups (n = 8) including a control group administered distilled water (10 mL/kg, p.o), CuSO4-exposed group (20 mg/kg, i.p), and MEZO (50 and 100 mL/kg, p.o) and Vit. C (100 mL/kg, p.o) treated groups. MEZO and Vit. C treatment was done after 1 hr of daily exposure to CuSO4 for 28 days. Cognitive functions and phenotypes of neurobehavioral impairment, markers of oxidative stress, inflammatory mediators, neurochemical transmission and hippocampal CA3 subfield were evaluated. The result showed that following CuSO4 assault, MEZO treatment prevent the reduction in locomotor activity and improved the spatial memory deficit and anxiety- and depressive-like behavior in mice. MEZO treatment modulated the hippocampal neuroimmune system by inhibiting oxidants, pro-inflammatory mediators and inflammatory enzyme activities, and improving the release of endogenous antioxidant enzymes associated with Nrf2 upregulation. Further, MEZO enhances cholinergic transmission by suppressing the AChE activity as well as abated the loss of hippocampal CA3 subfield. The endpoint of the study suggests that MEZO exact a neuroprotective effect by targeting the redo-inflammatory pathway associated with upregulation of Nrf2 protein.

Heightened sympathetic reflexes (sympathetic hyperreflexia, SH) post-high-level spinal cord injury (SCI) detrimentally impact effector organs, resulting in peripheral immune dysfunction and cardiovascular disease, two leading causes of morbidity and mortality in SCI. We previously found that an activated neuroimmune system after SCI contributes to intraspinal plasticity in the spinal sympathetic reflex (SSR) circuit, underlying SH. We hypothesize that activation of NF-κB, a key regulator of inflammation, in spinal cord below-SCI contributes to driving SSR circuit plasticity, resulting in SH-associated autonomic dysreflexia (AD) and peripheral immune dysfunction. Here, we demonstrate inhibition of central NF-κB signaling via intrathecal delivery of dimethylamino parthenolide (DMAPT) significantly decreases SH post-complete transection of thoracic spinal segment 3 in adult rats. This included reduced AD severity that was associated with decreased interneuron recruitment into the SSR circuit after SCI. We also observed intrathecal DMAPT-treatment improved survival post-SCI that corresponded with normalized numbers of splenic regulatory T-cells. These findings underscore central NF-κB signaling as a key component driving SH after SCI.

Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the innate neuroimmune system. We have studied the neuroprotective action of masitinib on the manifestations of experimental autoimmune encephalitis (EAE) induced axonal and neuronal damage. EAE is a model of neuroimmune-driven chronic neuroinflammation and therefore highly relevant to masitinib's mechanism of action in neurodegenerative diseases. Importantly, neuronal damage, or prevention thereof, can be rapidly assessed by measuring serum neurofilament light chain (NfL) concentration in EAE-induced mice. EAE induction was performed in healthy female C57BL/6 mice via active MOG 35-55 peptide immunization. Treatments were initiated 14 days post EAE induction. On day-0, 39 mice with established EAE symptoms were randomly assigned to 3 treatment groups (n = 13): EAE control, masitinib 50 mg/kg/day (M50), and masitinib 100 mg/kg/day (M100). The treatment started on day-1 and ended on day-15. Blood samples were collected on day-1 and day-8, via tail vein sampling, and on day-15, via intracardiac puncture. Assessments included quantification of serum NfL levels along the disease duration, cytokine quantification at day-15, and clinical assessments. Masitinib treatment significantly (p < 0.0001) limited NfL production with respect to control; specifically, relative change in serum NfL concentration at day-8 was 43% and 60% lower for the M50 and M100 groups, respectively. Likewise, for the assessment of absolute serum NfL at day-8 and day-15, there was a significantly lower NfL concentration for masitinib treatment as compared with control. Furthermore, EAE mice treated with masitinib showed significantly lower concentrations of several well-established pro-inflammatory cytokines relative to control at day-15. A beneficial effect of masitinib on functional performance was also observed, with both M50 and M100 groups showing significantly less relative deterioration in grip strength at day-15 as compared with control (p < 0.001). This study is the first demonstration that masitinib, a drug that targets the innate as opposed to the adaptive neuroimmune system, can lower serum NfL levels, and by extension therefore, neuronal damage, in a neuroimmune-driven neurodegenerative disease model. Overall, findings indicate that masitinib has a neuroprotective effect under conditions of chronic neuroinflammation and therefore plausible disease-modifying activity across a broad range of neurodegenerative diseases.

Neuroimmune regulation of the prefrontal cortex tetrapartite synapse.

Regulation of the brain's neuroimmune system is central to development, normal function, and disease. Neuronal communication to microglia, the primary immune cells of the brain, is well known to involve purinergic signaling mediated via ATP secretion and the cytokine fractalkine. Recent evidence shows that neurons release multiple cytokines beyond fractalkine, yet these are less studied and poorly understood. In contrast to ATP, cytokines are a class of signaling molecule that are much larger, with longer signaling and farther diffusion. We posit that neuron-expressed cytokines are an essential mechanism of neuron-microglia communication that arises as part of both normal learning and memory and in response to tissue pathology. Thus, neurons are underappreciated immunomodulatory cells that express diverse immunomodulatory signals. While neuronally sourced cytokines have been understudied, new technical advances make this a timely topic. The goal of this review is to define what is known about the cytokines expressed from neurons, how they are regulated, and the effects of these cytokines on microglia. We delineate key knowledge gaps and needs for new tools to define and analyze neuronal roles in immunomodulation. Given that cytokines are central regulators of microglial function, a broad new body of work is required to illuminate functional links between these neuronally expressed cytokines and sustained and transient microglial function.

Greater Neuroimmune System Deficit in Women Than Men With Alcohol Use Disorder.

The neuroimmune system represents a promising target for novel medications for alcohol use disorder (AUD). Ibudilast is a neuroimmune modulator which selectively inhibits phosphodiesterases (PDE) 3, PDE4, PDE10, and PDE11, and macrophage migration inhibitory factor (MIF). To test the efficacy of ibudilast for AUD compared with placebo. This randomized clinical trial was a double-masked, phase 2 trial conducted at an academic research center between October 2018 and April 2023. Eligible participants were adults seeking treatment for moderate or severe AUD. After completing the 12-week treatment period, participants were followed up for an additional 4 weeks. Ibudilast taken twice daily in 50 mg doses for 12 weeks vs placebo. Percentage of heavy drinking days; secondary efficacy outcomes included drinks per day, drinks per drinking day, and percentage of days abstinent. Registered exploratory analyses tested whether the effects of ibudilast of drinking outcomes were moderated by baseline depressive symptomatology. Registered exploratory analyses also tested whether ibudilast reduced inflammation compared with placebo, as indicated by circulating levels of proinflammatory markers over the 12-week trial. Additionally, a post hoc exploratory analysis investigated whether sex moderated the effect of ibudilast on drinking outcomes. Data were analyzed between October 2018 and April 2023. A total of 102 participants were enrolled in the study (mean [SD] age, 44.3 [10.8] years; 61 male [59.8%]; 24 Black [23.5%], 32 Hispanic [31.4%], 52 White [51.0%]). Baseline demographic characteristics and alcohol use patterns did not significantly differ between the 2 medication conditions. There was no significant difference between ibudilast vs placebo on percentage of heavy drinking days (β = 0.06, SE = 0.08 [95% CI, -0.09 to 0.21]; P = .46). There were no significant differences between ibudilast vs placebo on registered secondary outcomes. There were no significant effects of ibudilast compared with placebo on peripheral markers of inflammation. Moderation analyses found that baseline depressive symptomology (time 2 for drinks per drinking day: β = 0.25, SE = 0.11 [95% CI, 0.03 to 0.48]; P = .03) and sex (β = -2.48, SE = 1.07 [95% CI, -4.59 to -0.37]; P = .02) may moderate the effects of ibudilast. In this randomized clinical trial of ibudilast for the treatment of AUD, there was no support for the efficacy of ibudilast over placebo; additionally, no effect of ibudilast on markers of peripheral inflammation was observed. As novel treatments for AUD are developed for novel molecular targets, their effects may depend on mechanisms and moderators of efficacy. ClinicalTrials.gov Identifier: NCT03594435.