Dopamine function, inflammation and connectivity in PTSD

PROJECT SUMMARY
The objective of this research proposal is to assess changes in stress-induced dopamine function and
inflammatory response with connectivity and behavioral symptoms in posttraumatic stress disorder
(PTSD). Imaging studies of PTSD from our group and others have described altered activation and functional
connectivity between a variety of brain regions including the medial prefrontal cortex (mPFC), amygdala, and
hippocampus. Despite increasing knowledge of circuit dysfunction in PTSD, functional neuroimaging studies
performed to date have not provided adequate information about neurotransmitter systems and neurobiological
pathways that affect such circuits to maintain PTSD symptoms. PTSD is an important public health problem that
affects 7 to 8 % of the general population with higher rates of occurrence in victims of sexual abuse (10%).
Psychosocial stress and trauma activate neuroendocrine and immune systems and elevate circulating
concentrations of inflammatory markers. Activation of the immune system and release of inflammatory cytokines
disrupts the mesocortical/limbic dopamine system and are associated with symptoms of anxiety, re-experiencing,
arousal and avoidance that are prominent in PTSD. Findings from our group demonstrate blunted release of
dopamine, as measured by microdialysis, in a cytokine-induced inflammatory animal models. Elevated
inflammatory markers (e.g. plasma CRP and cytokines) were also associated with disrupted mesolimbic and
mesocortical circuits, including decreased ventral striatum and amygdala to mPFC functional connectivity, in
association with symptoms of anxiety in major depressive disorder, and particularly in patients with comorbid
PTSD. Functional brain imaging studies to date have outlined a neural circuitry of PTSD but these imaging
measures provide only general measures of brain function (e.g. blood flow) and do not address specific
neurochemical pathways. The proposed research will address this knowledge gap by examining the following
questions 1) Is stress-induced prefrontal and limbic DA neurotransmission reduced in patients with PTSD?, 2)
Are stress-induced inflammatory biomarkers higher in PTSD and associated with symptom severity? and 3) Are
disruptions in resting measures of functional behavior and connectivity associated with PTSD and symptom
severity? Our proposed work builds on our laboratory’s experience in imaging PTSD including demonstration of
blood flow and blood oxygen level-dependent reductions in mPFC function. Our long-term goal is to improve our
mechanistic framework of stress-induced dopaminergic function and the inflammatory response in PTSD, and
to identify mechanisms that can predict PTSD symptoms and their severity that may improve future treatment
approaches.

Grant Number: 5R01MH120262-04
NIH Institute/Center: NIH
Principal Investigator: James Bremner