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Findings from numerous laboratories and across neuroimaging modalities have consistently shown that exogenous administration of cytokines or inflammatory stimuli that induce cytokines disrupts circuits and networks involved in motivation and motor activity, threat detection, anxiety, and interoceptive and emotional processing. While inflammatory effects on neural circuits and relevant behaviors may represent adaptive responses promoting conservation of energy and heightened vigilance during immune activation, chronically elevated inflammation may contribute to symptoms of psychiatric illnesses. Indeed, biomarkers of inflammation such as cytokines and acute phase reactants are reliably elevated in a subset of patients with unipolar or bipolar depression, anxiety-related disorders, and schizophrenia and have been associated with differential treatment responses and poor clinical outcomes. A growing body of literature also describes higher levels of endogenous inflammatory markers and altered, typically lower functional or structural connectivity within these circuits in association with transdiagnostic symptoms such as anhedonia and anxiety in psychiatric and at-risk populations. This review presents recent evidence that inflammation and its effects on the brain may serve as one molecular and cellular mechanism of dysconnectivity within anatomically and/or functionally connected cortical and subcortical regions in association with transdiagnostic symptoms. We also discuss the need to establish reproducible methods to assess inflammation-associated dysconnectivity in relation to behavior for use in translational studies or biomarker-driven clinical trials for novel pharmacological or behavioral interventions targeting inflammation or its effects on the brain. [ABSTRACT FROM AUTHOR]

Highlights • High plasma CRP previously predicted antidepressant response to infliximab. • Gene transcripts related to glucose and lipid metabolism also predicted this response. • We assessed plasma markers of glucose and lipid metabolism pre and post infliximab. • Cholesterols, triglycerides and NEFA were elevated in responders to infliximab. • Infliximab lowered total, LDL, HDL and non-HDL cholesterol in high CRP patients. Abstract The tumor necrosis factor (TNF) antagonist infliximab was previously found to reduce depressive symptoms in patients with treatment-resistant major depression (TRD) who exhibited high baseline inflammation, as reflected by plasma C-reactive protein (CRP) >5 mg/L. Further predictors of antidepressant response to infliximab included differential expression of peripheral blood gene transcripts that were related not only to inflammation but also to glucose and lipid metabolism. To determine whether plasma biomarkers of glucose and lipid metabolism were similarly associated with antidepressant response to infliximab and with relevant gene transcripts, we measured concentrations of glucose, insulin, and protein hormones that regulate glucose homeostasis and metabolism (leptin, resistin, and adiponectin), as well as cholesterols, triglycerides, and non-esterified fatty acids (NEFA), in medically-stable TRD outpatients at baseline and 2 weeks after the first infusion of infliximab (n = 26) or placebo (n = 26). Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. We found that baseline cholesterol (total, low-density lipoprotein [LDL], and non-high-density lipoprotein [non-HDL]), triglycerides and NEFA were elevated in patients who exhibited an antidepressant response to infliximab (all p < 0.05) but not placebo (all p > 0.299). HDL and non-HDL cholesterol concentrations also correlated with two lipid-related gene transcripts that were predictive of antidepressant response (r = 0.33 to 0.39, p < 0.05). Although not associated with response to infliximab, resistin correlated with numerous glucose-related transcripts (r = −0.32 to 0.37, p < 0.05) and was higher at 2 weeks post-infusion in patients treated with infliximab compared to placebo (p = 0.028). Concentrations of cholesterol (total, LDL, HDL, non-HDL) were also lower at 2 weeks in patients treated with infliximab compared to placebo, but only in those patients with CRP >5 mg/L at baseline (all p < 0.05). These results are consistent with previous work showing that high inflammation in patients with depression is associated with metabolic alterations, which together predict response to both traditional and experimental antidepressant therapies. Additionally, our findings suggest a causal relationship between increased inflammation and high cholesterol in depression, as a single infusion of infliximab reduced cholesterol in TRD patients with high CRP compared to placebo. [ABSTRACT FROM AUTHOR]

Highlights • Depressive symptoms associated with elevated baseline expression of Fkbp5 and Nr3c1. • HIV serostatus associated with elevated baseline expression of Fkbp5 and Nr3c1. • Depressive symptoms associated with reduced LPS-induced release of IL-6 and TNF-α. Abstract Chronic inflammation caused by HIV infection may lead to deficient glucocorticoid (GC) signaling predisposing people living with HIV to depression and other psychiatric disorders linked to GC resistance. We hypothesized that comorbid HIV and depressive symptoms in women would synergistically associate with deficits in GC signaling. This cross-sectional study used samples obtained from the Women’s Interagency HIV Study (WIHS). The Centers for Epidemiological Studies (CES-D) was used to define depression in four groups of women from the Women’s Interagency HIV Study (WIHS): 1) HIV-negative, non-depressed (n = 37); 2) HIV-negative, depressed (n = 34); 3) HIV-positive, non-depressed (n = 38); and 4) HIV-positive, depressed (n = 38). To assess changes in GC signaling from peripheral blood mononuclear cells (PBMCs), we examined baseline and dexamethasone (Dex)-stimulated changes in the expression of the GC receptor (GR, gene: Nr3c1) and its negative regulator Fkbp5 via quantitative RT-PCR. GR sensitivity was evaluated in vitro by assessing the Dex inhibition of lipopolysaccharide (LPS)-stimulated IL-6 and TNF-α levels. Depressive symptoms and HIV serostatus were independently associated with elevated baseline expression of Fkbp5 and Nr3c1. Depressive symptoms, but not HIV status, was independently associated with reduced LPS-induced release of IL-6. Counter to predictions, there was no interactive association of depressive symptoms and HIV on any outcome. Comorbid depressive symptoms with HIV infection were associated with a gene expression and cytokine profile similar to that of healthy control women, a finding that may indicate further disruptions in disease adaptation. [ABSTRACT FROM AUTHOR]

Accurate assessment of plasma corticosterone, the primary stress hormone in rodents, is an essential part of characterizing the stress response in experimental animals. To this end, both enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) remain widely used. However, considerable assay-specific variability exists among commercially available corticosterone assays due to differing assay principles, detection methods, range, and sensitivity. While technical comparisons of commercially available corticosterone assays have previously been conducted, the ability to detect acute stress-induced endocrine changes has not been compared among these methods to date. Using the forced swim test, a commonly utilized behavioral paradigm in rodents as a physiologically-relevant acute stress challenge, we compared four commercial corticosterone assays – three ELISA kits and one RIA kit – in their ability to detect corticosterone across a dynamic range of both baseline and acute swim stress-driven concentrations. While all methods yielded results that were consistent at measuring relative differences between samples, only two of the four assays evaluated detected a statistically significant increase in corticosterone in rats exposed to acute swim stress compared to rats at baseline. The ELISA kit from Enzo Life Sciences demonstrated the greatest percent increase in plasma corticosterone from baseline to acute stress conditions. The RIA kit from MP Biomedicals also detected a significant corticosterone increase and yielded higher concentrations of corticosterone both at baseline and in the acute stress condition relative to the other three assays. We conclude that choice of assay can impact interpretation of data due to differences in efficacy across a dynamic range of physiological concentrations of corticosterone. [ABSTRACT FROM AUTHOR]

Euthanasia by anesthetic agents is commonly performed prior to tissue collection in order to minimize pain and distress to the animal. However, depending on their mechanism of action as well as administration regimen, different methods of anesthesia may trigger an acute stress response through engaging the hypothalamic-pituitary-adrenal (HPA) axis, which can impact numerous other physiological processes that the researcher may wish to examine as endpoints. We investigated the effects of the commonly used anesthetic agent isoflurane on two different endpoints related to the stress response: plasma corticosterone levels and gene expression of the glucocorticoid receptor (GR) as well as several of its regulators including FK506-binding protein 51 ( Fkbp5 ) in the hippocampus of male and female rats. Our results indicate that brief exposure to anesthesia by isoflurane prior to decapitation can alter plasma corticosterone levels differentially in male and female rats within minutes without impacting gene expression in the hippocampus. We conclude that collection methods can influence stress-related physiological endpoints in female rats and the potential influence of even brief anesthesia as well as sex differences in response to anesthesia should be evaluated during the experimental design process and data interpretation. This finding is particularly important in light of new NIH standards regarding sex and reproducibility, and care should be taken to be certain that sex differences in endpoints of interest are not an artifact of sex differences in response to collection paradigms. [ABSTRACT FROM AUTHOR]