In vivo serotonin 1A receptor hippocampal binding potential in depression and reported childhood adversity.

BACKGROUND: Reported childhood adversity (CA) is associated with development of depression in adulthood and predicts a more severe course of illness. Although elevated serotonin 1A receptor (5-HT1AR) binding potential, especially in the raphe nuclei, has been shown to be a trait associated with major depression, we did not replicate this finding in an independent sample using the partial agonist positron emission tomography tracer [11C]CUMI-101. Evidence suggests that CA can induce long-lasting changes in expression of 5-HT1AR, and thus, a history of CA may explain the disparate findings. METHODS: Following up on our initial report, 28 unmedicated participants in a current depressive episode (bipolar n = 16, unipolar n = 12) and 19 non-depressed healthy volunteers (HVs) underwent [11C]CUMI-101 imaging to quantify 5-HT1AR binding potential. Participants in a depressive episode were stratified into mild/moderate and severe CA groups via the Childhood Trauma Questionnaire. We hypothesized higher hippocampal and raphe nuclei 5-HT1AR with severe CA compared with mild/moderate CA and HVs. RESULTS: There was a group-by-region effect (p = 0.011) when considering HV, depressive episode mild/moderate CA, and depressive episode severe CA groups, driven by significantly higher hippocampal 5-HT1AR binding potential in participants in a depressive episode with severe CA relative to HVs (p = 0.019). Contrary to our hypothesis, no significant binding potential differences were detected in the raphe nuclei (p-values > 0.05). CONCLUSIONS: With replication in larger samples, elevated hippocampal 5-HT1AR binding potential may serve as a promising biomarker through which to investigate the neurobiological link between CA and depression.

Mu Opioid Receptor Dynamics in Healthy Volunteers with a History of Childhood Maltreatment.

Evidence suggests that adults with a history of childhood maltreatment, the experience of emotional or physical neglect and/or abuse within the family during childhood, have blunted reward and stress processing, and higher risk of depression. The mu opioid receptor rich nucleus accumbens and amygdala are critical to reward and stress processing respectively. We hypothesized that nucleus accumbens and amygdala mu opioid receptor densities and activity (change in receptor binding due to endogenous opioid release or receptor conformation change) were negatively associated with childhood maltreatment in healthy young adults. Maltreatment was assessed with the Childhood Trauma Questionnaire (CTQ). Healthy participants, n = 75 (52% female) completed [11C]carfentanil positron emission tomography imaging labeling mu opioid receptors. The relationship between CTQ score and binding potential (BPND, proportional to density of unoccupied receptors) was evaluated with a linear mixed effects model. No significant relationship was found between CTQ score and BPND (f = 3.28; df = 1, 73; p = 0.074) or change in BPND (activity) (t = 1.48; df = 198.3; p = 0.14). This is the first investigation of mu opioid receptors in those with childhood maltreatment. We did not identify a significant relationship between mu opioid receptor dynamics and severity of maltreatment in those without psychopathology. Because this cohort has a low CTQ score average, this may indicate that those with low severity of maltreatment may not have associated changes in mu opioid receptor dynamics. Future directions include evaluating a cohort with increased severity of childhood maltreatment.

Does the change in glutamate to GABA ratio correlate with change in depression severity? A randomized, double-blind clinical trial.

Previous proton magnetic resonance spectroscopy (1H-MRS) studies suggest a perturbation in glutamate and/or GABA in Major Depressive Disorder (MDD). However, no studies examine the ratio of glutamate and glutamine (Glx) to GABA (Glx/GABA) as it relates to depressive symptoms, which may be more sensitive than either single metabolite. Using a within-subject design, we hypothesized that reduction in depressive symptoms correlates with reduction in Glx/GABA in the anterior cingulate cortex (ACC). The present trial is a randomized clinical trial that utilized 1H-MRS to examine Glx/GABA before and after 8 weeks of escitalopram or placebo. Participants completed the 17-item Hamilton Depression Rating Scale (HDRS17) and underwent magnetic resonance spectroscopy before and after treatment. Two GABA-edited MEGA-PRESS acquisitions were interleaved with a water unsuppressed reference scan. GABA and Glx were quantified from the average difference spectrum, with preprocessing using Gannet and spectral fitting using TARQUIN. Linear mixed models were utilized to evaluate relationships between change in HDRS17 and change in Glx/GABA using a univariate linear regression model, multiple linear regression incorporating treatment type as a covariate, and Bayes Factor (BF) hypothesis testing to examine strength of evidence. No significant relationship was detected between percent change in Glx, GABA, or Glx/GABA and percent change in HDRS17, regardless of treatment type. Further, MDD severity before/after treatment did not correlate with ACC Glx/GABA. In light of variable findings in the literature and lack of association in our investigation, future directions should include evaluating glutamate and glutamine individually to shed light on the underpinnings of MDD severity. Advancing Personalized Antidepressant Treatment Using PET/MRI, ClinicalTrials.gov, NCT02623205.

Rejection sensitivity and mu opioid receptor dynamics associated with mood alterations in response to social feedback.

Rejection sensitivity (RS) is the heightened expectation or perception of social rejection and is a feature of many psychiatric disorders. As endogenous opioid pathways have been implicated in response to social rejection and reward, we hypothesize that RS will be negatively associated with mu opioid receptor (MOR) baseline binding and activity during rejection and acceptance stimuli. In exploratory analyses, we assessed the relationships between MOR activity and changes in mood and self-esteem before and after stimuli. Healthy participants, N = 75 (52% female), completed rejection and acceptance tasks during [11C]carfentanil positron emission tomography (PET) scans. MOR activity in the amygdala, midline thalamus, anterior insula, and nucleus accumbens (NAc) was evaluated. RS was not related to MOR baseline binding potential or activity during acceptance or rejection tasks in any region. Increased MOR activity in the NAc was associated with increase in ratings of self-esteem and positive mood during the period between acceptance task administration and approximately 5 min after the task completion. Our results suggest that endogenous opioid response to social rejection is independent of RS in healthy individuals. MOR activity in the NAc was associated with increase self-esteem and positive mood after experiencing social feedback, warranting further investigation.

Measuring brain glucose metabolism in order to predict response to antidepressant or placebo: A randomized clinical trial.

There is critical need for a clinically useful tool to predict antidepressant treatment outcome in major depressive disorder (MDD) to reduce suffering and mortality. This analysis sought to build upon previously reported antidepressant treatment efficacy prediction from 2-[18F]-fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) using metabolic rate of glucose uptake (MRGlu) from dynamic FDG-PET imaging with the goal of translation to clinical utility. This investigation is a randomized, double-blind placebo-controlled trial. All participants were diagnosed with MDD and received an FDG-PET scan before randomization and after treatment. Hamilton Depression Rating Scale (HDRS-17) was completed in participants diagnosed with MDD before and after 8 weeks of escitalopram, or placebo. MRGlu (mg/(min*100 ml)) was estimated within the raphe nuclei, right insula, and left ventral Prefrontal Cortex in 63 individuals. Linear regression was used to examine the association between pretreatment MRGlu and percent decrease in HDRS-17. Additionally, the association between percent decrease in HDRS-17 and percent change in MRGlu between pretreatment scan and post-treatment scan was examined. Covariates were treatment type (SSRI/placebo), handedness, sex, and age. Depression severity decrease (n = 63) was not significantly associated with pretreatment MRGlu in the raphe nuclei (ß = -2.61e-03 [-0.26, 0.25], p = 0.98), right insula (ß = 0.05 [-0.23, 0.32], p = 0.72), or ventral prefrontal cortex (ß = 0.06 [-0.23, 0.34], p = 0.68) where ß is the standardized estimated coefficient, with a 95% confidence interval, or in whole brain voxelwise analysis (family-wise error correction, alpha = 0.05). MRGlu percent change was not significantly associated with depression severity decrease (n = 58) before multiple comparison correction in the RN (ß = 0.20 [-0.07, 0.47], p = 0.15), right insula (ß = 0.24 [-0.03, 0.51], p = 0.08), or vPFC (ß = 0.22 [-0.06, 0.50], p = 0.12). We propose that FDG-PET imaging does not indicate a clinically relevant biomarker of escitalopram or placebo treatment response in heterogeneous major depressive disorder cohorts. Future directions include focusing on potential biologically-based subtypes of major depressive disorder by implementing biomarker stratified designs.

Multiorgan Signaling Mobilizes Tumor-Associated Erythroid Cells Expressing Immune Checkpoint Molecules.

Hematopoietic-derived cells are integral components of the tumor microenvironment and serve as critical mediators of tumor-host interactions. Host cells derived from myeloid and lymphoid lineages perform well-established functions linked to cancer development, progression, and response to therapy. It is unclear whether host erythroid cells also contribute to shaping the path that cancer can take, but emerging evidence points to this possibility. Here, we show that tumor-promoting environmental stress and tumor-induced hemodynamic changes trigger renal erythropoietin production and erythropoietin-dependent expansion of splenic erythroid cell populations in mice. These erythroid cells display molecular features indicative of an immature erythroid phenotype, such as the expression of both CD71 and TER119 and the retention of intact nuclei, and express genes encoding immune checkpoint molecules. Nucleated erythroid cells with similar properties are present in mouse and human tumor tissues. Antibody-mediated erythropoietin blockade reduces tumor-responsive erythroid cell induction and tumor growth. These findings reveal the potential of tumor-induced erythropoietin and erythroid cells as targets for cancer treatment. IMPLICATIONS: : Our study identifies erythropoietin and erythroid cells as novel players in tumor-host interactions and highlights the involvement of multiorgan signaling events in their induction in response to environmental stress and tumor growth.

Skin tape stripping identifies gene transcript signature associated with allergic contact dermatitis.

BACKGROUND: Allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD) are common skin conditions with an overlapping clinical and histological appearance, but distinct underlying mechanisms. Patch testing is the gold standard for ACD diagnosis, yet the interpretation of its results may be confounded by weak and varying macroscopic reactions. OBJECTIVE: To examine whether gene transcript profiling of RNA sampled from patch tested patient skin by tape stripping (TS) could differentiate ACD from ICD and the baseline skin state (control) METHODS: Nine patients (seven females, two males; mean age 38.6 years, range 24-72 years) with confirmed ACD through patch testing were recruited. Total RNA was isolated from TS samples and relative transcript abundance was determined by quantitative real-time polymeraise chain reaction using 39 gene-specific primers. RESULTS: TS captured gene transcripts derived from diverse skin cell types, including not only keratinocytes, but also epidermal and dermal antigen-presenting cells. Among the genes analysed in transcript profiling, genes encoding epidermal barrier components and inflammatory mediators exhibited changes in transcript abundance in ACD skin compared to ICD or control skin. CONCLUSIONS: Our findings reveal the potential of skin TS for non-invasive biopsy during patch testing and molecular marker-based ACD diagnosis.

Intracellular signaling modules linking DNA damage to secretome changes in senescent melanoma cells.

Cellular senescence is a major barricade on the path of cancer development, yet proteins secreted from senescent cells exert complex and often discordant effects on subsequent cancer evolution. Somatic genome alternations driving the formation of nevi and melanoma are efficient inducers of cellular senescence. Melanocyte and melanoma cell senescence is likely to come into play as a key factor affecting the course of tumorigenesis and responsiveness to therapy; little mechanistic information has been generated, however, that substantiates this idea and facilitates its clinical translation. Here, we established and characterized a model of melanoma cell senescence in which pharmacologically induced DNA damage triggered divergent ATM kinase- and STING-dependent intracellular signaling cascades and resulted in cell cycle arrest, cytomorphologic remodeling, and drastic secretome changes. Targeted proteome profiling revealed that senescent melanoma cells in this model secreted a panoply of proteins shaping the tumor immune microenvironment. CRISPR-mediated genetic ablation of the p38α and IKKß signaling modules downstream of the ATM kinase severed the link between DNA damage and this secretory phenotype without restoring proliferative capacity. A similar genetic dissection showed that loss of STING signaling prevented type I interferon induction in DNA-damaged melanoma cells but otherwise left the senescence-associated processes in our model intact. Actionable proteins secreted from senescent melanoma cells or involved in senescence-associated intracellular signaling hold potential as markers for melanoma characterization and targets for melanoma treatment.