Investigating the role of glucocorticoid function in PTSD Post-traumatic Stress Disorder (PTSD) develops in 8-10% of individuals following experience of a traumatic event. First-line pharmacological interventions for PTSD are only 22% effective at treating the debilitating symptoms, which include threat-related intrusive re-experiencing and hyperarousal, and loss-related emotional numbing and anhedonia. These symptoms occur in the immediate aftermath of a trauma but persist in some individuals as the ?failure to contain the biological stress response? that characterizes PTSD. Dysregulation of the biological stress response in PTSD is evidenced by 1) enhanced negative feedback cortisol onto the hypothalamic-pituitary-adrenal (HPA) axis, and 2) a correlation between low levels of peripheral cortisol with greater loss-related symptoms. Altered corticolimbic connectivity in PTSD, which has been related to increased threat-related symptoms, has also been associated with HPA axis dysregulation. Specifically, low levels of peripheral cortisol were correlated with reduced negative functional connectivity of medial prefrontal cortex (mPFC) with the amygdala. Preclinical experiments have found that increasing local levels of glucocorticoids in the brain recapitulated threat-related behavior and decreasing brain glucocorticoid production decreased this PTSD-like behavior. Thus, I hypothesize that local levels of cortisol in corticolimbic regions of the brain are a mechanism by which corticolimbic connectivity regulates negative feedback onto the HPA axis, resulting in PTSD symptoms and associated HPA axis dysregulation.
In Aim 1, I will measure brain glucocorticoid function in vivo in individuals with PTSD. Equipped with a novel PET radiotracer [18F]MOZAT, I will be able to measure local glucocorticoid levels in the brain. [18F]MOZAT binds to the enzyme 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1), which regenerates cortisol in the brain and thus can be used as a marker of brain glucocorticoid function. Preclinical manipulation of brain glucocorticoid function and clinical neuroimaging studies indicate that 11?-HSD1 levels will be higher in individuals with PTSD compared to trauma-exposed controls.
In Aim 2, I will relate in vivo brain glucocorticoid function to corticolimbic connectivity. Previous work showed associations between altered mPFC-amygdala functional connectivity and low peripheral cortisol. Thus, brain glucocorticoid function may regulate HPA axis activity via modulation of corticolimbic connectivity. Investigating this possibility may provide a brain substrate for the extensive observations of altered corticolimbic connectivity related to PSTD symptoms.
In Aim 3, I will relate in vivo brain glucocorticoid function to threat- and loss-related symptoms of PTSD. This line of investigation will shed light on the potential of 11?-HSD1 as a possible target for pharmacological re-tuning of brain glucocorticoid levels and associated corticolimbic connectivity, to improve PTSD symptoms.

Public Health Relevance

Investigating the role of glucocorticoid function in PTSD Post-traumatic Stress Disorder (PTSD) affects 8-10% of Americans, and the symptoms? including intrusive re- experiencing, hyperarousal, and emotional numbing? are debilitating and often refractory to treatment. In this study, we employ multimodal neuroimaging to examine brain glucocorticoid function as a potential mechanism linking alterations in neuroendocrine stress responses and corticolimbic networks to PTSD symptoms. Measuring brain glucocorticoid function, using a novel PET radiotracer for 11?-hydroxysteroid dehydrogenase type 1, will shed light on a promising neurochemical target for pharmacological therapy in PTSD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Chavez, Mark
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Yale University
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New Haven
United States
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