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Background The brain mechanisms that underlie threat sensitivity and enduring sense of danger in PTSD are not yet understood, and may perpetuate or sustain this disorder. We had proposed that deficits in the processing of contextual information are at the core of PTSD pathophysiology, and they involve complex interplay between fear associated learning, memory, sleep, hyperarousal and stress responses in PTSD. We performed genetic and functional neuroimaging studies in PTSD subjects as well as translational studies in animal model of PTSD, to identify brain regions, as well as physiological (sleep) and molecular mechanisms involved in contextual processing deficits.

Methods The evolution of functional neuroimaging studies from early studies of responses to emotional probes to recent multi-day studies of fear conditioning, extinction, renewal, and of intrinsic connectivity networks, will be discussed and novel finding in OIF/OEF veterans (PTSD subjects and combat controls) presented, highlighting their contribution to the evolving concepts of PTSD pathophysiology. Targeted gene association studies examined genetic risk factors in prospective cohort of Ohio National Guard soldiers. Parallel, fear conditioning, extinction and renewal data, multi-day sleep recording, and recording from the LC neurons in Single Prolong Stress exposed animals (rodent model of PTSD) will be presented. Prefrontal, hippocampal and amygdala tissue findings of glucocorticoids receptor levels as well as glutamate and glutamine concentrations, will be reported.

Results PTSD subjects exhibit unimpaired fear conditioning and extinction, but altered psychophysiology and prefrontal and hippocampal BOLD responses during fear renewal and reinstatement, pointing toward abnormalities in contextual processing. Genetic risk studies identified novel genetic variant in adrenergic receptors that conveys risk/resilience to PTSD development. In parallel studies, exaggerated fear renewal is present in SPS animals, especially these with increased REM and decreased hippocampal theta power. Subsequent studies linked upregulation in glucocorticoid receptors (GR) in hippocampus and prefrontal cortex to exaggerated fear renewal. SPS animals were also found to have changes in LC firing (norepinephrine) and decreased glutamate and glutamine concentrations in prefrontal regions.

Conclusions The findings from human neuroimaging studies and animal models both implicate contextual processing abnormalities in PTSD. Animal model further implicated upregulation of GR receptors in mPFC and hippocampus, changes in noradrenergic tone in LC, and in norepinephrine dependent sleep parameters, in these context-processing deficits. In concert, human genetic studies link altered noradrenergic signaling with PTSD pathophysiology. Together these studies had transformed our understanding of PTSD pathophysiology from a single site (amygdala) single function (fear), to a more complex, nuanced and accurate model of multilevel pathophysiologic processes that lead to PTSD development.