Chronic adolescent stress alters GR-FKBP5 interactions in the hippocampus of adult female rats.

Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones-such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures.

A randomized proof-of-mechanism trial of TNF antagonism for motivational anhedonia and related corticostriatal circuitry in depressed patients with high inflammation.

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein > 3mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dmPFC, ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka "neural signature") sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.

Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen.

Psychosocial stress has been shown to prime peripheral innate immune cells, which take on hyper-inflammatory phenotypes and are implicated in depressive-like behavior in mouse models. However, the impact of stress on cellular metabolic states that are thought to fuel inflammatory phenotypes in immune cells are unknown. Using single cell RNA-sequencing, we investigated mRNA enrichment of immunometabolic pathways in innate immune cells of the spleen in mice subjected to repeated social defeat stress (RSDS) or no stress (NS). RSDS mice displayed a significant increase in the number of splenic macrophages and granulocytes (p < 0.05) compared to NS littermates. RSDS-upregulated genes in macrophages, monocytes, and granulocytes significantly enriched immunometabolic pathways thought to play a role in myeloid-driven inflammation (glycolysis, HIF-1 signaling, MTORC1 signaling) as well as pathways related to oxidative phosphorylation (OXPHOS) and oxidative stress (p < 0.05 and FDR<0.1). These results suggest that the metabolic enhancement reflected by upregulation of glycolytic and OXPHOS pathways may be important for cellular proliferation of splenic macrophages and granulocytes following repeated stress exposure. A better understanding of these intracellular metabolic mechanisms may ultimately help develop novel strategies to reverse the impact of stress and associated peripheral immune changes on the brain and behavior.

Manufactured tissue-to-tissue barrier chip for modeling the human blood-brain barrier and regulation of cellular trafficking.

Microphysiological system or organ-on-a-chip technologies can replicate the key structure and function of 3D human tissues with higher reproducibility than less controllable 3D cell aggregate models, providing great potential to become advanced drug toxicity and efficacy test platforms alternative to animal models. However, these organ chip models remain to be manufactured and standardized in a highly reproducible manner for reliable drug screening and mechanism of action research. Herein, we present a manufactured form of 'micro-engineered physiological system-tissue barrier chip' called MEPS-TBC for the highly replicable modeling of the human blood-brain barrier (BBB) with a 3D perivascular space. The perivascular region was controlled by tunable aspiration, where human astrocytes reside in 3D, create a network, and communicate with human pericytes facing human vascular endothelial cells, thereby replicating the 3D BBB. The lower channel structure of MEPS-TBC was designed and optimized using a computational simulation to facilitate aspiration while maintaining multicellular construction. Our human BBB model of the 3D perivascular unit and the endothelium perfused by physiological shear stress secured significantly enhanced barrier function exhibiting greater TEER and lower permeability, compared to the only endothelial model, indicating that the cellular interactions between BBB cells significantly contribute to the BBB formation. Importantly, our BBB model showed the cellular barrier function for homeostatic trafficking regulation against inflammatory peripheral immune cells, as well as for molecular transport control across the BBB. We believe our manufactured chip technology will construct reliable and standardized organ-chip models for disease mechanism research and predictive drug screening.

Inflammation-Related Functional and Structural Dysconnectivity as a Pathway to Psychopathology.

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.

Connecting the dots from east to west.

Clinical depression and anxiety are not just national health issues. They are significant global health problems, with a worldwide prevalence of clinical depression amounting to nearly 4%. Moreover, its prevalence is certainly underreported, particularly since the beginning of the COVID19 pandemic. This suggests that at least 26 million people are sad, fatigued, do not enjoy life, struggle with weight changes and experience suicidal thoughts. This Special Issue provides cutting-edge, new information from laboratories around the world about inflammation and depression. It consists of four review articles and five original research articles.

Glucocorticoid Receptor Function and Cognitive Performance in Women With HIV.

OBJECTIVE: Alterations in glucocorticoid receptor (GCR) function may be a risk factor for cognitive complications among older people with human immunodeficiency virus (HIV). We evaluated whether HIV serostatus and age modify the GCR function-cognition association among women. METHODS: Eighty women with HIV ( n = 40, <40 years of age [younger]; n = 40, >50 years of age [older]) and 80 HIV-uninfected women ( n = 40 older, n = 40 younger) enrolled in the Women's Interagency HIV Study completed a comprehensive neuropsychological test battery. Peripheral blood mononuclear cells collected concurrent with neuropsychological testing were assessed for GCR function. Multivariable linear regression analyses were conducted to examine whether a) HIV serostatus and age were associated with GCR function, and b) GCR function-cognition associations are moderated by HIV serostatus and age adjusting for relevant covariates. RESULTS: Among older women, higher baseline FKBP5 expression level was associated with lower attention/working memory performance among women with HIV ( B = 6.4, standard error = 1.7, p = .0003) but not in women without HIV infection ( B = -1.7, standard error = 1.9, p = .37). There were no significant HIV serostatus by age interactions on dexamethasone (DEX)-stimulated expression of the genes regulated by the GCR or lipopolysaccharide-stimulated tumor necrosis factor α levels (with or without DEX stimulation; p values > .13). HIV serostatus was associated with GC target genes PER1 ( p = .006) and DUSP1 ( p = .02), but not TSC22D3 ( p = .32), after DEX stimulation. CONCLUSIONS: Collectively, these data suggest that HIV serostatus and age may modify the influence of the GCR, such that the receptor is likely engaged to a similar extent, but the downstream influence of the receptor is altered, potentially through epigenetic modification of target genes.

Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study.

Increased inflammation in major depressive disorder (MDD) has been associated with low functional connectivity (FC) in corticostriatal reward circuits and symptoms of anhedonia, relationships which may involve the impact of inflammation on synthesis and release of dopamine. To test this hypothesis while establishing a platform to examine target engagement of potential therapies in patients with increased inflammation, medically stable unmedicated adult MDD outpatients enrolled to have a range of inflammation (as indexed by plasma C-reactive protein [CRP] levels) were studied at two visits involving acute challenge with the dopamine precursor levodopa (L-DOPA; 250 mg) and placebo (double-blind, randomized order ~1-week apart). The primary outcome of resting-state (rs)FC in a classic ventral striatum to ventromedial prefrontal cortex reward circuit was calculated using a targeted, a priori approach. Data available both pre- and post-challenge (n = 31/40) established stability of rsFC across visits and determined CRP > 2 mg/L as a cut-point for patients exhibiting positive FC responses (post minus pre) to L-DOPA versus placebo (p < 0.01). Higher post-L-DOPA FC in patients with CRP > 2 mg/L was confirmed in all patients (n = 40) where rsFC data were available post-challenge (B = 0.15, p = 0.006), and in those with task-based (tb)FC during reward anticipation (B = 0.15, p = 0.013). While effort-based motivation outside the scanner positively correlated with rsFC independent of treatment or CRP, change in anhedonia scores negatively correlated with rsFC after L-DOPA only in patients with CRP > 2 mg/L (r = -0.56, p = 0.012). FC in reward circuitry should be further validated in larger samples as a biomarker of target engagement for potential treatments including dopaminergic agents in MDD patients with increased inflammation.

Cellular and immunometabolic mechanisms of inflammation in depression: Preliminary findings from single cell RNA sequencing and a tribute to Bruce McEwen.

Inflammation is associated with symptoms of anhedonia, a core feature of major depression (MD). We have shown that MD patients with high inflammation as measured by plasma C-reactive protein (CRP) and anhedonia display gene signatures of metabolic reprograming (e.g., shift to glycolysis) necessary to sustain cellular immune activation. To gain preliminary insight into the immune cell subsets and transcriptomic signatures that underlie increased inflammation and its relationship with behavior in MD at the single-cell (sc) level, herein we conducted scRNA-Seq on peripheral blood mononuclear cells from a subset of medically-stable, unmedicated MD outpatients. Three MD patients with high CRP (>3 mg/L) before and two weeks after anti-inflammatory challenge with the tumor necrosis factor antagonist infliximab and three patients with low CRP (≤3 mg/L) were studied. Cell clusters were identified using a Single Cell Wizard pipeline, followed by pathway analysis. CD14+ and CD16+ monocytes were more abundant in MD patients with high CRP and were reduced by 29% and 55% respectively after infliximab treatment. Within CD14+ and CD16+ monocytes, genes upregulated in high CRP patients were enriched for inflammatory (phagocytosis, complement, leukocyte migration) and immunometabolic (hypoxia-inducible factor [HIF]-1, aerobic glycolysis) pathways. Shifts in CD4+ T cell subsets included ∼30% and ∼10% lower abundance of CD4+ central memory (TCM) and naïve cells and ∼50% increase in effector memory-like (TEM-like) cells in high versus low CRP patients. TCM cells of high CRP patients displayed downregulation of the oxidative phosphorylation (OXPHOS) pathway, a main energy source in this cell type. Following infliximab, changes in the number of CD14+ monocytes and CD4+ TEM-like cells predicted improvements in anhedonia scores (r = 1.0, p < 0.001). In sum, monocytes and CD4+ T cells from MD patients with increased inflammation exhibited immunometabolic reprograming in association with symptoms of anhedonia. These findings are the first step toward determining the cellular and molecular immune pathways associated with inflammatory phenotypes in MD, which may lead to novel immunomodulatory treatments of psychiatric illnesses with increased inflammation.

Metabolomic and inflammatory signatures of symptom dimensions in major depression.

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.

Inflammation as a Pathophysiologic Pathway to Anhedonia: Mechanisms and Therapeutic Implications.

Anhedonia, characterized by a lack of motivation, interest, or ability to experience pleasure, is a prominent symptom of depression and other psychiatric disorders and has been associated with poor response to standard therapies. One pathophysiologic pathway receiving increased attention for its potential role in anhedonia is inflammation and its effects on the brain. Exogenous administration of inflammatory stimuli to humans and laboratory animals has reliably been found to affect neurotransmitters and neurocircuits involved in reward processing, including the ventral striatum and ventromedial prefrontal cortex, in association with reduced motivation. Moreover, a rich literature including meta-analyses describes increased inflammation in a significant proportion of patients with depression and other psychiatric illnesses involving anhedonia, as evident by elevated inflammatory cytokines, acute phase proteins, chemokines, and adhesion molecules in both the periphery and central nervous system. This endogenous inflammation may arise from numerous sources including stress, obesity or metabolic dysfunction, genetics, and lifestyle factors, many of which are also risk factors for psychiatric illness. Consistent with laboratory studies involving exogenous administration of peripheral inflammatory stimuli, neuroimaging studies have further confirmed that increased endogenous inflammation in depression is associated with decreased activation of and reduced functional connectivity within reward circuits involving ventral striatum and ventromedial prefrontal cortex in association with anhedonia. Here, we review recent evidence of relationships between inflammation and anhedonia, while highlighting translational and mechanistic work describing the impact of inflammation on synthesis, release, and reuptake of neurotransmitters like dopamine and glutamate that affects circuits to drive motivational deficits. We will then present insight into novel pharmacological strategies that target either inflammation or its downstream effects on the brain and behavior. The meaningful translation of these concepts through appropriately designed trials targeting therapies for psychiatric patients with high inflammation and transdiagnostic symptoms of anhedonia is also discussed.

Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming.

Inflammation impacts basal ganglia motor circuitry in association with psychomotor retardation, a key symptom of major depression (MD). We previously reported associations between circulating protein inflammatory biomarkers and psychomotor slowing as measured by neuropsychological tests probing psychomotor speed in patients with MD. To discover novel transcriptional signatures in peripheral blood immune cells related to psychomotor slowing, microarray data were analyzed in a primary cohort of 88 medically-stable, unmedicated, ambulatory MD patients. Results were confirmed and extended in a second cohort of 57 patients with treatment resistant depression (TRD) before and after anti-inflammatory challenge with the tumor necrosis factor antagonist infliximab versus placebo. Composite scores reflecting pure motor and cognitive-motor processing speed were linearly associated with 403 and 266 gene transcripts in each cohort, respectively (|R| > 0.30, p < 0.01), that were enriched for cytokine signaling and glycolysis-related pathways (p < 0.05). Unsupervised clustering in the primary cohort revealed two psychomotor slowing-associated gene co-expression modules that were enriched for interferon, interleukin-6, aerobic glycolysis, and oxidative phosphorylation pathways (p < 0.05, q < 0.1). Transcripts were predominantly derived from monocytes, plasmacytoid dendritic cells, and natural killer cells (p's < 0.05). In infliximab-treated TRD patients with high plasma C-reactive protein concentrations (>5 mg/L), two differential co-expression modules enriched for oxidative stress and mitochondrial degradation were associated with improvements in psychomotor reaction time (p < 0.05). These results indicate that inflammatory signaling and associated metabolic reprogramming in peripheral blood immune cells are associated with systemic inflammation in depression and may affect relevant brain circuits to promote psychomotor slowing.

Adolescent stress sensitizes the adult neuroimmune transcriptome and leads to sex-specific microglial and behavioral phenotypes.

Adolescent exposure to chronic stress, a risk factor for mood disorders in adulthood, sensitizes the neuroinflammatory response to a subsequent immune challenge. We previously showed that chronic adolescent stress (CAS) in rats led to distinct patterns of neuroimmune priming in adult male and female rats. However, sex differences in the neuroimmune consequences of CAS and their underlying mechanisms are not fully understood. Here we hypothesized that biological sex would dictate differential induction of inflammation-related transcriptomic pathways and immune cell involvement (microglia activation and leukocyte presence) in the hippocampus of male and female rats with a history of CAS. Adolescent rats underwent CAS (six restraint and six social defeat episodes during postnatal days 38-49), and behavioral assessments were conducted in adolescence and adulthood. Neuroimmune measures were obtained following vehicle or a systemic lipopolysaccharide (LPS) challenge in adulthood. CAS led to increased time in the corners of the open field in adolescence. In males, CAS also increased social avoidance. As adults, CAS rats displayed an exaggerated enrichment of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway and chemokine induction following LPS challenge, and increased number of perivascular CD45+ cells in the hippocampus. However, CAS females, but not males, showed exaggerated glucocorticoid receptor (GR) pathway enrichment and increased microglial complexity. These results provide further insight to the mechanisms by which peripheral immune events may influence neuroimmune responses differentially among males and females and further demonstrate the importance of adolescent stress in shaping adult responses.

Protein and gene markers of metabolic dysfunction and inflammation together associate with functional connectivity in reward and motor circuits in depression.

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.

Gene signatures in peripheral blood immune cells related to insulin resistance and low tyrosine metabolism define a sub-type of depression with high CRP and anhedonia.

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.

Chronic adolescent stress sex-specifically alters the hippocampal transcriptome in adulthood.

Chronic adolescent stress alters behavior in a sex-specific manner at the end of adolescence and in adulthood. Although prolonged behavioral repercussions of chronic adolescent stress have been documented, the potential underlying mechanisms are incompletely understood. In this study we demonstrate that a history of chronic adolescent stress modified the adult stress response, as measured by corticosterone concentration, such that a history of chronic adolescent stress resulted in a blunted response to a novel acute stressor. In order to begin to address potential mechanistic underpinnings, we assessed the extent to which chronic adolescent stress impacted global DNA methylation. Reduced global hippocampal methylation was evident in females with a history of chronic adolescent stress; thus, it was possible that chronic adolescent stress altered global transcription in the whole hippocampi of adult male and female rats. In addition, because acute stress can stimulate a genomic response, we assessed the transcriptome following exposure to an acute novel stressor to determine the extent to which a history of chronic adolescent stress modifies the adult transcriptional response to an acute stressor in males and females. In addition to the reduction in global methylation, chronic adolescent stress resulted in distinct patterns of gene expression in the adult hippocampus that differentiated by sex. Furthermore, both sex and a history of chronic adolescent stress influenced the transcriptional response to an acute novel stressor in adulthood, suggesting both latent and functional effects of chronic adolescent stress at the level of gene transcription. Pathway analysis indicated that ESR1 and IFN-α may be particularly influential transcription factors mediating these transcriptional differences and suggest candidate mechanisms for future studies. Collectively, these studies demonstrate sex-specific and enduring effects of adolescent stress exposure that are more pronounced in females than in males.

Chronic adolescent stress sex-specifically alters central and peripheral neuro-immune reactivity in rats.

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-1ß, 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-1ß 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.

Glucose and lipid-related biomarkers and the antidepressant response to infliximab in patients with treatment-resistant depression.

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.