Biology subjects

Mellon, S. H.

Publications and source records attributed to Mellon, S. H..

3 recordsLinked to original sources

bioRxiv2019

Role of enhanced glucocorticoid receptor sensitivity in inflammation in PTSD: Insights from a computational model for circadian-neuroendocrine-immune interactions

Although glucocorticoid resistance contributes to increased inflammation, individuals with post-traumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation co-exists with a hyper-responsive hypothalamic pituitary adrenal axis (HPA axis). To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone suppression test and IC50-dexamethasone for cytokine suppression, by varying model parameters. The model analysis suggests that increasing the steepness of the dose response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels thereby increasing pro-inflammatory response. The adaptive response of pro-inflammatory cytokine mediated stimulatory effects on the HPA-axis is reduced due to dominance of the GR-mediated negative feedback on the HPA-axis. To verify these hypotheses we analyzed the clinical data on neuro-endocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, pro-inflammatory cytokines TNF and IL6, hs-CRP, promoter methylation of GR gene and IC50-Dex for lysozyme suppression. Causal inference modelling revealed significant associations between cortisol suppression and post-dex cortisol decline, promoter methylation of NR3C1-1F, IC50-Dex and pro-inflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation, therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.

systems biology↗

bioRxiv2018

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

PTSD is associated with metabolic comorbidities; however it is not clear how the neuroendocrine disturbances affect metabolism. To analyze this we employed a systems biological approach using an integrated mathematical model of metabolism, HPA axis and inflammation. We combined the metabolomics, neuroendocrine, clinical lab and cytokine data from combat-exposed veterans with and without PTSD, to characterize the differences in regulatory effects. We used the pattern of fold change in metabolites representing pathway level differences as reference for metabolic control analysis (MCA) using the model. MCA revealed parameters constituting the HPA axis, inflammation and GPCR pathway that yielded metabolic dysfunction consistent with PTSD. To support this, we performed causal analysis between regulatory components and the significantly different metabolites in our sample. Causal inference revealed that the changes in glucocorticoid receptor sensitivity were mechanistically associated with metabolic dysfunction and the effects were jointly mediated by insulin resistance, inflammation, oxidative stress and energy deficit.

systems biology↗

bioRxiv2018

Cortisol Predicts Antidepressant Treatment Outcome, Memory Improvement, and Brain Response to Negative Emotions: The Importance of Aging

BackgroundStudies testing the relationship between cortisol levels, depression, and antidepressant treatment response have yielded divergent results suggesting the possibility of moderators of a cortisol effect. Several studies indicate that age may moderate the relationship between cortisol and psychopathology. In patients with Major Depressive Disorder (MDD), we studied the interactive effects of age and cortisol on predicting diagnostic status, improvement in mood and memory function with antidepressant treatment, and brain response to negative emotional stimuli.\n\nMethods66 unmedicated patients with MDD and 75 matched healthy controls had serum assayed at pre-treatment baseline for cortisol. Logistic regression was used to determine an association of age, cortisol and their interaction with MDD diagnosis. Thirty-four of the MDD participants (age range: 19-65 years; median: 36) underwent treatment with a selective serotonin reuptake inhibitor (SSRl) for 8 weeks. Clinician and self-ratings of depression symptoms, as well as tests of verbal and visual delayed recall were obtained at baseline and post treatment. Moderation analyses determined the effect of age on the relationship between baseline cortisol and treatment outcome. A separate sample of 8 MDD participants prospectively underwent fMRI neuroimaging and cortisol collection while viewing negative emotional faces.\n\nResultsAge moderated the effects of cortisol on predicting MDD diagnosis (p<.05), treatment-associated reduction of depression symptoms (p<.001), improvement of delayed recall (p<.001), and baseline brain response to negative emotions (p<.05, whole brain corrected). Modeling the Age X Cortisol interaction suggested that for the participants below the median age of our sample, lower cortisol levels predicted a lower rate of MDD diagnosis, higher antidepressant effects and decreased brain reactivity in emotion regulation regions such as the anterior cingulate gyrus. On the contrary, in those above the median sample age, lower cortisol predicted a higher rate of MDD, less improvement in depression symptoms and memory performance, and more brain reactivity in the anterior cingulate.\n\nConclusionsOur results indicate that age moderates the relationship between peripheral cortisol levels and (1) MDD diagnosis, (2) brain reactivity to emotional stimuli, and (3) antidepressant-associated improvement in depression and memory symptoms. These results indicate that previous disparities in the literature linking peripheral cortisol levels with depression characteristics and treatment response may critically relate, at least in part, to the age of the patients studied.

physiology↗