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RationaleThe chronic mild stress (CMS) paradigm was first described almost 40 years ago and has become a widely used model in the search for antidepressant drugs for major depression disorder (MDD). It has resulted in the publication of almost 1700 studies in rats alone. Under the original CMS procedure, the expression of an anhedonic response, a key symptom of depression, was seen as an essential feature of both the model and a depressive state. The prolonged exposure of rodents to unpredictable/uncontrollable mild stressors leads to a reduction in the intake of palatable liquids, behavioral despair, locomotor inhibition, anxiety-like changes, and vegetative (somatic) abnormalities. Many of the CMS studies do not report these patterns of behaviors, and they often fail to include consistent molecular, neuroanatomical, and physiological phenotypes of CMS-exposed animals.ObjectivesTo critically review the CMS studies in rats so that conceptual and methodological flaws can be avoided in future studies.ResultsAnalysis of the literature supports the validity of the CMS model and its impact on the field. However, further improvements could be achieved by (i) the stratification of animals into ‘resilient’ and ‘susceptible’ cohorts within the CMS animals, (ii) the use of more refined protocols in the sucrose test to mitigate physiological and physical artifacts, and (iii) the systematic evaluation of the non-specific effects of CMS and implementation of appropriate adjustments within the behavioral tests.ConclusionsWe propose methodological revisions and the use of more advanced behavioral tests to refine the rat CMS paradigm, which offers a valuable tool for developing new antidepressant medications.

The prevailing motor neuron-centric view of amyotrophic lateral sclerosis (ALS) pathogenesis could be an important factor in the failure to identify disease-modifying therapy for this neurodegenerative disorder. Non-neuronal cells have crucial homeostatic functions within the CNS and evidence of involvement of these cells in the pathophysiology of several neurodegenerative disorders, including ALS, is accumulating. Microglia and astrocytes, in crosstalk with peripheral immune cells, can exert both neuroprotective and adverse effects, resulting in a highly nuanced range of neuronal and non-neuronal cell interactions. This Review provides an overview of the diverse roles of non-neuronal cells in relation to the pathogenesis of ALS and the emerging potential of non-neuronal cell biomarkers to advance therapeutic development.The failure to identify disease-modifying therapies for amyotrophic lateral sclerosis (ALS) could relate to the prevailing motor neuron-centric view of this neurodegenerative disorder. This Review considers the evidence for involvement of non-neuronal cells — in particular, microglia, astrocytes and oligodendrocytes — in ALS pathogenesis.

The process of macrophage polarization is involved in many pathologies such as anti-cancer immunity and autoimmune diseases. Polarized macrophages exhibit various levels of plasticity when M2/M(IL-4) macrophages are reprogrammed into an M1-like phenotype following treatment with IFNγ and/or LPS. At the same time, M1 macrophages are resistant to reprogramming in the presence of M2-like stimuli. The molecular mechanisms responsible for the macrophages polarization, plasticity of M2 macrophages, and lack of plasticity in M1 macrophages remain unknown. Here, we explored the role of Egr2 in the induction and maintenance of macrophage M1 and M2 polarization in the mouse and models of inflammation. Egr2 knockdown with siRNA treatment fail to upregulate either M1 or M2 markers upon stimulation, and the overexpression of Egr2 potentiated M1 or M2 marker expression following polarization. Polarisation with M2-like stimuli (IL-4 or IL-13) results in increased Egr2 expression, but macrophages stimulated with M1-like stimuli (IFNγ, LPS, IL-6, or TNF) exhibit a decrease in Egr2 expression. Egr2 was critical for the expression of transcription factors CEBPβ and PPARγ in M2 macrophages, and CEBPβ was highly expressed in M1-polarized macrophages. In siRNA knockdown studies the transcription factor CEBPβ was found to negatively regulate Egr2 expression and is likely to be responsible for the maintenance of the M1-like phenotype and lack plasticity. During thioglycolate-induced peritonitis, adoptively transferred macrophages with Egr2 knockdown failed to become activated as determined by upregulation of MHC class II and CD86. Thus, our study indicates that Egr2 expression is associated with the ability of unstimulated or M2 macrophages to respond to stimulation with inflammatory stimuli, while low levels of Egr2 expression is associated with non-responsiveness of macrophages to their activation.

Antimicrobial resistance (AMR) poses a profound threat to modern healthcare, with vancomycin-resistant Enterococcus faecium (VREfm) emerging as a particularly resilient and clinically significant pathogen. This mini-review examines the biological mechanisms underpinning VREfm resistance, including biofilm formation, stress tolerance, and the acquisition of resistance genes such as vanA and vanB. It also explores the behavioural, social, and healthcare system factors that facilitate VREfm transmission, highlighting disparities in burden across vulnerable populations and low-resource settings. Prevention strategies are mapped across the disease pathway, spanning primary, secondary, and tertiary levels, with a particular focus on the role and evolving challenges of antimicrobial stewardship programmes (ASP). We highlight emerging threats, such as rifaximin-induced cross-resistance to daptomycin, which challenge conventional stewardship paradigms. Finally, we propose future directions to enhance global surveillance, promote equitable stewardship interventions, and accelerate the development of innovative therapies. Addressing VREfm requires a coordinated, multidisciplinary effort to safeguard the efficacy of existing antimicrobials and protect at-risk patient populations.

Non-alcoholic fatty liver disease (NAFLD) and depression are common disorders and have bidirectional contributing relationships to metabolic syndrome. We aimed to determine whether a fasting serum signature of recent, self-reported depressive symptoms could be identified in a heterogeneous NAFLD cohort using nuclear magnetic resonance (NMR)-based metabolomics integrated with clinical chemistry. Serum nuclear magnetic resonance (NMR) metabolite profiles and corresponding clinical chemistry were compared between patients with depressive symptoms in the last 12-months (n = 81) and patients without recent depressive symptoms (n = 137 controls) using multivariate statistics. Orthogonal partial least squares discriminant analysis (OPLS-DA) of the biochemical and metabolomic data identified NAFLD patients with recent depression with a cross-validated accuracy of 61.5%, independent of age, sex, medication, and other comorbidities. This led to the development of a diagnostic algorithm with AUC 0.83 for future testing in larger clinical cohorts. Serum triglycerides, VLDL cholesterol, and the inflammatory biomarker GlycA were key metabolites increased in patients with recent depressive symptoms, while serum glutamine level was reduced. Here, serum NMR metabolite analysis provides a link between disturbed lipid metabolism, inflammation, and active mental health issues in NAFLD, irrespective of disease severity.

Endotoxemia and sepsis induce neuroinflammation and increase the risk of neurodegenerative disorders although the mechanism by which peripheral infection leads to brain inflammation is not well understood. While circulating serum lipoproteins are known immunometabolites with the potential to modulate the acute phase response and cross the blood brain barrier, their contribution to neuroinflammation during systemic infection is unknown. The objective of this study was to elucidate the mechanisms by which lipoprotein subclasses modulate lipopolysaccharide (LPS)-induced neuroinflammation. Adult C57BL/6 mice were divided into 6 treatment groups, including a sterile saline vehicle control group (n = 9), an LPS group (n = 11), a premixed LPS + HDL group (n = 6), a premixed LPS + LDL group (n = 5), a HDL only group (n = 6) and an LDL only group (n = 3). In all cases injections were administered intraperitoneally. LPS was administered at 0.5 mg/kg, and lipoproteins were administered at 20 mg/kg. Behavioural testing and tissue collection was performed 6 h post-injection. The magnitude of peripheral and central inflammation was determined by qPCR of pro-inflammatory genes in fresh liver and brain. Metabolite profiles of liver, plasma and brain were determined by 1 H NMR. Endotoxin concentration in the brain was measured by the Limulus Amoebocyte Lysate (LAL) assay. Co-administration of LPS + HDL exacerbated both peripheral and central inflammation, whilst LPS + LDL attenuated this inflammation. Metabolomic analysis identified several metabolites significantly associated with LPS-induced inflammation, which were partially rescued by LDL, but not HDL. Endotoxin was detected at significantly greater concentrations in the brains of animals that received LPS + HDL compared to LPS + saline, but not those that received LPS + LDL. These results suggest that HDL may promote neuroinflammation through direct shuttling of endotoxin to the brain. In contrast, LDL was shown to have anti-neuroinflammatory properties in this study. Our results indicate that lipoproteins may be useful targets in neuroinflammation and neurodegeneration associated with endotoxemia and sepsis.

Inflammation following traumatic injury to the central nervous system (CNS) persists long after the primary insult and is known to exacerbate cell death and worsen functional outcomes. Therapeutic interventions targeting this inflammation have been unsuccessful, which has been attributed to poor bioavailability owing to the presence of blood-CNS barrier. Recent studies have shown that the magnitude of the CNS inflammatory response is dependent on systemic inflammatory events. The acute phase response (APR) to CNS injury presents an alternative strategy to modulating the secondary phase of injury. However, the communication pathways between the CNS and the periphery remain poorly understood. Extracellular vesicles (EVs) are membrane bound nanoparticles that are regulators of intercellular communication. They are shed from cells of the CNS including microglia, astrocytes, neurons and endothelial cells, and are able to cross the blood-CNS barrier, thus providing an attractive candidate for initiating the APR after acute CNS injury. The purpose of this review is to summarize the current evidence that EVs play a critical role in the APR following CNS injuries.

Monocytes and neutrophils from the myeloid lineage contribute to multiple sclerosis (MS), but the dynamics of myelopoiesis during MS are unclear. Here we uncover a disease stage-specific relationship between lifestyle, myelopoiesis and neuroinflammation. In mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), myelopoiesis in the femur, vertebrae and spleen is elevated prior to disease onset and during remission, preceding the peaks of clinical disability and neuroinflammation. In progressive EAE (P-EAE), vertebral myelopoiesis rises steadily throughout disease, while femur and splenic myelopoiesis is elevated early before waning later during disease height. In parallel, sleep disruption or hyperlipidemia and cardiometabolic syndrome augment M-CSF generation and multi-organ myelopoiesis to worsen P-EAE clinical symptoms, neuroinflammation, and spinal cord demyelination, with M-CSF blockade abrogating these symptoms. Lastly, results from a previous trial show that Mediterranean diet restrains myelopoietic activity and myeloid lineage progenitor skewing and improves clinical symptomology of MS. Together, our data suggest that myelopoiesis in MS is dynamic and dependent on disease stage and location, and that lifestyle factors modulate disease by influencing M-CSF-mediated myelopoiesis. Myeloid cells contribute to the etiology of multiple sclerosis (MS), but the dynamics of myelopoiesis during disease progression is still unclear. Here the authors show, in both mouse models and clinical data, that myelopoiesis is differentially regulated via M-CSF modulation in different organs at distinct stages of MS, with diet and lifestyle being potential modifiers.

Depression and metabolic disease are common disorders that share a bidirectional relationship and continue to increase in prevalence. Maternal diet and maternal behaviour both profoundly influence the developmental trajectory of offspring during the perinatal period. At an epidemiological level, both maternal depression and obesity during pregnancy have been shown to increase the risk of neuropsychiatric disease in the subsequent generation. Considerable progress has been made to understand the mechanisms by which maternal obesity disrupts the developing offspring gut–brain axis, priming offspring for the development of affective disorders. This review outlines such mechanisms in detail, including altered maternal care, the maternal microbiome, inflammation, breast milk composition, and maternal and placental metabolites. Subsequently, offspring may be prone to developing gut–brain interaction disorders with concomitant changes to brain energy metabolism, neurotransmission, and behaviour, alongside gut dysbiosis. The gut microbiome may act as a key modifiable, and therefore treatable, feature of the relationship between maternal obesity and the offspring brain function. Further studies examining the relationship between maternal nutrition, the maternal microbiome and metabolites, and offspring neurodevelopment are warranted to identify novel therapeutic targets.

Post-inflammatory behaviours in rodents are widely used to model human depression and to test the efficacy of novel anti-depressants. Mice injected with lipopolysaccharide (LPS) display a depressive-like phenotype twenty-four hours after endotoxin administration. Despite the widespread use of this model, the mechanisms that underlie the persistent behavioural changes after the transient peripheral inflammatory response remain elusive. The study of the metabolome, the collection of all the small molecule metabolites in a sample, combined with multivariate statistical techniques provides a way of studying biochemical pathways influenced by an LPS challenge. Adult male CD-1 mice received an intraperitoneal injection of either LPS (0.83 mg/kg) or saline, and were assessed for depressive-like behaviour 24 h later. In a separate mouse cohort, pro-inflammatory cytokine gene expression and 1H nuclear magnetic resonance (NMR) metabolomics measurements were made in brain tissue and blood. Statistical analyses included Independent Sample t-tests for gene expression data, and supervised multi-variate analysis using orthogonal partial least squares discriminant analysis for metabolomics. Both plasma and brain metabolites in male mice were altered following a single peripheral LPS challenge that led to depressive-like behaviour in the forced swim test. The plasma metabolites altered by LPS are involved in energy metabolism, including lipoproteins, glucose, creatine, and isoleucine. In the brain, glutamate, serine, and N-acetylaspartate (NAA) were reduced after LPS, whereas glutamine was increased. Serine-modulated glutamatergic signalling and changes in bioenergetics may mediate the behavioural phenotype induced by LPS. In light of other data supporting a central imbalance of glutamate-glutamine cycling in depression, our results suggest that aberrant central glutaminergic signalling may underpin the depressive-like behaviours that result from both inflammation and non-immune pathophysiology. Normalising glutaminergic signalling, rather than seeking to increase serotonergic signalling, might prove to be a more coherent approach to the development of new treatments for mood disorder.