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Inflammatory stimuli administered to humans and laboratory animals affect mesolimbic and nigrostriatal dopaminergic pathways in association with impaired motivation and motor activity. Alterations in dopaminergic corticostriatal reward and motor circuits have also been observed in depressed patients with increased peripheral inflammatory markers. The effects of peripheral inflammation on dopaminergic pathways and associated neurobiologic mechanisms and consequences have been difficult to measure in patients. Postmortem tissue (n = 11) from an established, translationally-relevant non-human primate model of cytokine-induced depressive behavior involving chronic interferon-alpha (IFN-a) administration was utilized herein to explore the molecular mechanisms of peripheral cytokine effects on striatal dopamine. Dopamine (but not serotonin or norepinephrine) was decreased in the nucleus accumbens (NAcc) and putamen of IFN-a-treated animals (p < 0.05). IFN-a had no effect on number of striatal neurons or dopamine terminal density, suggesting no overt neurodegenerative changes. RNA sequencing examined in the caudate, putamen, substantia nigra, and prefrontal cortical subregions revealed that while IFN-a nominally up-regulated limited numbers of genes enriching inflammatory signaling pathways in all regions, robust, whole genome-significant effects of IFN-a were observed specifically in putamen. Genes upregulated in the putamen primarily enriched synaptic signaling, glutamate receptor signaling, and inflammatory/metabolic pathways downstream of IFN-a, including MAPK and PI3K/AKT cascades. Conversely, gene transcripts reduced by IFN-a enriched oxidative phosphorylation (OXPHOS), protein translation, and pathways regulated by dopamine receptors. Unsupervised clustering identified a gene co-expression module in the putamen that was associated with both IFN-a treatment and low dopamine levels, which enriched similar inflammatory, metabolic, and synaptic signaling pathways. IFN-a-induced reductions in dopamine further correlated with genes related to excitotoxic glutamate, kynurenine, and altered dopamine receptor signaling (r = 0.78-97, p < 0.05). These findings provide insight into the immunologic mechanisms and neurobiological consequences of peripheral inflammation effects on dopamine, which may inform novel treatment strategies targeting inflammatory, metabolic or neurotransmitter systems in depressed patients with high inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Inflammatory biomarkers like C-reactive protein (CRP) are elevated in a subset of patients with depression and have been associated with lower functional connectivity (FC) in a ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) reward circuit and symptoms of anhedonia. Evidence linking these relationships to the effects of inflammation on dopamine is consistent with our recent findings that acute levodopa (L-DOPA) increased VS-vmPFC FC in association with deceased anhedonia in depressed patients with higher but not lower CRP (>2 versus ≤ 2 mg/L). To determine whether repeated L-DOPA administration caused sustained effects on FC and behavior in these patients, medically stable depressed outpatients with CRP > 2 mg/L and anhedonia (n = 18) received one week of three doses of L-DOPA (150-450 mg/day/week with carbidopa) or placebo in a randomized order. Resting-state (rs) and task-based (tb; monetary incentive delay) fMRI, effort-based motivation, and exploratory measures of anhedonia and depression severity were assessed at baseline and after one week of placebo and each dose of L-DOPA. Responses to individual doses of L-DOPA varied across outcomes. For example, VS-vmPFC rs-FC was significantly increased by L-DOPA at 150 and 450 mg/day/week (p < 0.01), whereby approximately half of patients responded optimally to 150 mg/day L-DOPA and approximately half required higher doses for maximum effect. While effort-based motivation was only significantly increased by L-DOPA at 150 mg/day (p < 0.05), it correlated with VS-vmPFC rs-FC at this dose (r = 0.64, p = 0.024), and all L-DOPA doses met a clinically significant threshold of ≥ 10 % increase versus placebo. When comparing the maximum response at any L-DOPA dose to placebo, high effect sizes were observed for these primary outcomes and tb-FC during reward anticipation (d z  = 0.82-0.98, p < 0.01), as well as secondary and exploratory measures of anhedonia and depression severity (d z  = 0.48-0.97, p < 0.05). Sustained effects on reward circuitry, effort-based motivation, and anhedonia by repeated L-DOPA administration support the therapeutic potential of agents that increase dopamine in depressed patients with higher inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions., Methods: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism., Results: The IMD clinical dimension and the inflammatory index were positively correlated (r = 0.19, p = 0.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids., Conclusion: The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Inflammation and altered glucose metabolism are two pathways implicated in the pathophysiology of major depressive disorder (MDD). We have previously shown that high inflammation as measured by C-reactive protein (CRP) in MDD patients is associated with symptoms of anhedonia, a core symptom of MDD, along with deficits in dopaminergic reward circuitry. Increased inflammation can shift metabolic demand and reprogram cellular energy sources, which may collectively impact the brain and reward processing to contribute to symptoms of anhedonia. To determine whether immunometabolic gene signatures were enriched in immune cells of depressed patients with increased inflammation and anhedonia, we examined whole-blood gene expression microarray (Illumina HumanHT-12) data from unmedicated, medically-stable patients with MDD (n = 93). Patients were considered to have increased inflammation based on High (>3mg/L) versus Low (≤3mg/L) plasma CRP, and further classified as having a self-reported phenotype of High (n = 30, 33rd percentile) versus Low (n = 32, 67th percentile) Anhedonia. Functional enrichment of gene pathways was assessed by Gene Set Enrichment Analysis (GSEA) using the KEGG pathway database. Pathways related to glucose metabolism (insulin signaling, insulin resistance, HIF-1, PI3K/AKT signaling), cancer (e.g., genes related to insulin and PI3K/AKT signaling), and inflammation (B cell, T cell and Fc receptor signaling) were specifically enriched in patients with both High CRP and High Anhedonia (all FDR q < 0.25). Within patients with High CRP in GSEA, the insulin signaling pathway was the top enriched pathway in patients with High versus Low Anhedonia (n = 10 and 9 respectively), which was driven by genes expressed predominantly in monocytes (z = 2.95, p < 0.01). Conversely, within patients with High Anhedonia, in addition to enrichment of immunometabolic pathways, the tyrosine metabolism pathway was also reduced in patients with High versus Low CRP (n = 20 and 10 respectively). Of note, enrichment of immunometabolic pathways was confirmed in complementary linear regression analyses examining pathways associated with a CRP-by-Anhedonia interaction term while controlling for clinical covariates in all patients (n = 93). These results indicate that increased glucose and low tyrosine metabolism define a subset of depressed patients with high inflammation and anhedonia. Enrichment of cancer-related pathways driven by metabolic genes also suggests a shift in immune cell metabolism from oxidative phosphorylation to glycolysis. Together these data suggest that anhedonia in MDD with high CRP involves both immunometabolic shifts and reduced dopamine precursor availability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Bidirectional relationships between inflammation and metabolic dysfunction may contribute to the pathophysiology of psychiatric illnesses like depression. Metabolic disturbances drive inflammation, which in turn exacerbate metabolic outcomes including insulin resistance. Both inflammatory (e.g. endotoxin, vaccination) and metabolic challenges (e.g. glucose ingestion) have been shown to affect activity and functional connectivity (FC) in brain regions that subserve reward and motor processing. We previously reported relationships between elevated concentrations of endogenous inflammatory markers including C-reactive protein (CRP) and low corticostriatal FC, which correlated with symptoms of anhedonia and motor slowing in major depression (MD). Herein, we examined whether similar relationships were observed between plasma markers related to glucose metabolism (non-fasting concentrations of glucose, insulin, leptin, adiponectin and resistin) in 42 medically-stable, unmedicated MD outpatients who underwent fMRI. A targeted, hypothesis-driven approach was used to assess FC between seeds in subdivisions of the ventral and dorsal striatum and a region in ventromedial prefrontal cortex (VS-vmPFC), which was previously found to correlate with both inflammation and symptoms of anhedonia and motor slowing. Associations between FC and gene expression signatures were also explored. A composite score of all 5 glucose-related markers (with increasing values reflecting higher concentrations) was negatively correlated with both ventral striatum (VS)-vmPFC (r = -0.33, p < 0.05) and dorsal caudal putamen (dcP)-vmPFC (r = -0.51, p < 0.01) FC, and remained significant after adjusting for covariates including body mass index (p < 0.05). Moreover, an interaction between the glucose-related composite score and CRP was observed for these relationships (F[2,33] = 4.3, p < 0.05) whereby significant correlations between the glucose-related metabolic markers and FC was found only in patients with high plasma CRP (>3 mg/L; r = -0.61 to -0.81, p < 0.05). Insulin and resistin were the individual markers most predictive of VS-vmPFC and dcP-mPFC FC, respectively, and insulin, resistin and CRP clustered together and in association with both LV-vmPFC and dcP-vmPFC in principal component analyses. Exploratory whole blood gene expression analyses also confirmed that gene probes negatively associated with FC were enriched for both inflammatory and metabolic pathways (FDR p < 0.05). These results provide preliminary evidence that inflammation and metabolic dysfunction contribute jointly to deficits in reward and motor circuits in MD. Future studies using fasting samples and longitudinal and interventional approaches are required to further elucidate the respective contributions of inflammation and metabolic dysfunction to circuits and symptoms relevant to motivation and motor activity, which may have treatment implications for patients with psychiatric illnesses like depression., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Adversity during development is a reliable predictor of psychiatric disorders such as depression and anxiety which are increasingly recognized to have an immune component. We have previously demonstrated that chronic adolescent stress (CAS) in rats leads to depressive-like behavior in adulthood along with long-lasting changes to the hypothalamic-pituitary-adrenal axis and pro-inflammatory cytokine induction in the hippocampus. However, the mechanisms by which CAS promotes hippocampal inflammation are not yet defined. Here we tested the hypothesis that a history of CAS exaggerates induction of the pro-inflammatory NFκB pathway in the adult rat hippocampus without compromising the peripheral immune response. We also assessed potential sex differences because it is unclear whether females, who are twice as likely to suffer from mood disorders as males, are disproportionally affected by stress-primed inflammation. Male and female adolescent rats underwent a CAS paradigm or received no stress. Six weeks following the last stressor, all rats received a single systemic injection of either lipopolysaccharide or vehicle to unmask possible immune-priming effects of CAS. An NFκB signaling PCR array demonstrated that CAS exaggerated the expression of NFκB-related genes in the hippocampus of both males and females. Interestingly, targeted qPCR demonstrated that CAS potentiated the induction of hippocampal IL1B and REL mRNA in female rats only, suggesting that some immune effects of CAS are indeed sex-specific. In contrast to the hippocampal findings, indices of peripheral inflammation such as NFκB activity in the spleen, plasma IL-1β, IL-6, TNF-α, and corticosterone were not impacted by CAS in female rats. Despite showing no pro-inflammatory changes to hippocampal mRNA, male CAS rats displayed lower plasma corticosterone response to LPS at 2 h after injection followed by an exaggerated plasma IL-1β response at 4 h. This potentially blunted corticosterone response coupled with excessive innate immune signaling in the periphery is consistent with possible glucocorticoid resistance in males. In contrast, the effects of CAS manifested as excessive hippocampal immune reactivity in females. We conclude that while a history of exposure to chronic adolescent stress enhances adult immune reactivity in both males and females, the mechanism and manifestation of such alterations are sex-specific., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Women appear to be more vulnerable to the depressogenic effects of inflammation than men. Chronic stress, one of the most pertinent risk factors of depression and anxiety, is known to induce behavioral and affective-like deficits via neuroimmune alterations including activation of the brain's immune cells, pro-inflammatory cytokine expression, and subsequent changes in neurotransmission and synaptic plasticity within stress-related neural circuitry. Despite well-established sexual dimorphisms in the stress response, immunity, and prevalence of stress-linked psychiatric illnesses, much of current research investigating the neuroimmune impact of stress remains exclusively focused on male subjects. We summarize and evaluate here the available data regarding sex differences in the neuro-immune consequences of stress, and some of the physiological factors contributing to these differences. Furthermore, we discuss the extent to which sex differences in stress-related neuroinflammation can account for the overall female bias in stress-linked psychiatric disorders including major depressive disorder and anxiety disorders. The currently available evidence from rodent studies does not unequivocally support the peripheral inflammatory changes seen in women following stress. Replication of many recent findings in stress-related neuroinflammation in female subjects is necessary in order to build a framework in which we can assess the extent to which sex differences in stress-related inflammation contribute to the overall female bias in stress-related affective disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The mechanisms underlying the association between chronic psychological stress, development of metabolic syndrome (MetS), and behavioral impairment in obesity are poorly understood. The aim of the present study was to assess the effects of mild chronic psychological stress on metabolic, inflammatory, and behavioral profiles in a mouse model of diet-induced obesity. We hypothesized that (1) high-fat high-fructose diet (HFHF) and psychological stress would synergize to mediate the impact of inflammation on the central nervous system in the presence of behavioral dysfunction, and that (2) HFHF and stress interactions would impact insulin and lipid metabolism. C57Bl/6 male mice underwent a combination of HFHF and two weeks of chronic psychological stress. MetS-related conditions were assessed using untargeted plasma metabolomics, and structural and immune changes in the gut and liver were evaluated. Inflammation was measured in plasma, liver, gut, and brain. Our results show a complex interplay of diet and stress on gut alterations, energetic homeostasis, lipid metabolism, and plasma insulin levels. Psychological stress and HFHF diet promoted changes in intestinal tight junctions proteins and increases in insulin resistance and plasma cholesterol, and impacted the RNA expression of inflammatory factors in the hippocampus. Stress promoted an adaptive anti-inflammatory profile in the hippocampus that was abolished by diet treatment. HFHF increased hippocampal and hepatic Lcn2 mRNA expression as well as LCN2 plasma levels. Behavioral changes were associated with HFHF and stress. Collectively, these results suggest that diet and stress as pervasive factors exacerbate MetS-related conditions through an inflammatory mechanism that ultimately can impact behavior. This rodent model may prove useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)