DESCRIPTION (provided by applicant): The long-term goals of these preclinical studies are to enhance our understanding of individual differences in the neurobiological underpinnings of post-traumatic stress disorder (PTSD), and the potential synergy between several easily accessible biomarkers that might predict individuals that are at-risk for developing PTSD after combat-related trauma. Neuropeptide Y (NPY) has been suggested as a potential marker of resiliency, and NPY administration is anxiolytic. Stress-induced increases in peripheral NPY levels are thought to reflect sympathetic activation, since they correlated with measures of hypothalamic-pituitary- adrenal (HPA) activity and other indices of sympathetic activation including norepinephrine (NE) and epinephrine (EPI) levels. Although studies suggest that individual differences in NPY responses are associated with behavioral outcomes, the complexity of PTSD suggests that determining at risk populations may involve identifying individual differences in a combination of biomarkers. Therefore, we will examine multiple markers that can be easily assayed in both rodent and human populations, including circulating levels of NPY, corticosterone (CORT) as a measure of HPA activity, cytokines as markers of immune function, and indices of sympathetic activation including NE, EPI, heart rate (HR) and blood pressure (BP). This proposal expands our previous work showing individual differences in anxiety-related responses, to examine markers that predict individual differences in a predator odor/fear-conditioning model of rat trauma. Our studies also examine how peripheral changes are reflected in brain (amygdalar) changes and if NPY administration can enhance resiliency in anxiety-prone individuals. The Aims test our overarching hypothesis that a combination of NPY, HPA, cytokine, and sympathetic responses associated with traumatic stress can serve as biomarkers for risk or resilience for developing a PTSD-like phenotype. In Aim 1 we use our predator odor traumatic stress model and compare groups of high-anxiety, PTSD-like subjects that are resistant to fear extinction with low anxiety, resilient rats to determine if they exhibit enhanced stress-induced levels of circulating NPY, CORT, sympathetic markers, and cytokines, plus more persistent levels of fear conditioning and enhanced startle responses and risk-assessment behaviors. Using vascular ports and our rat PTSD model we will examine individual differences in circulating NPY, CORT, NE, EPI, cytokines, autonomic responses, neuronal activation during extinction, and brain NPY levels. Aim 2 uses microdialysis to assess individual differences in amygdalar responses in NPY, CORT and NE during extinction of fear-conditioned responses, while Aim 3 will examine if high anxiety animals can be made more "resilient" by amygdalar administration of NPY. The results of our studies will improve our understanding of the individual differences in response to a traumatic event, and will be critical in assessing possible at-risk Veterans for the development of PTSD, developing new pharmacologic treatment targets, and in appropriately treating Veterans using evidence-based approaches. OIF/OEF DEPLOYMENT: These studies examine the role of hormonal and physiological stress responses in predisposing Veterans to phenotypic expression of PTSD after exposure to combat trauma. PTSD outcomes may reflect reactivity to environmental stressors that are part of a common pathway of genetic/epigenetic modification for vulnerability to neuroendocrine dysregulation. This basic research provides a translational framework for examining neurobiological factors contributing to PTSD outcomes after combat trauma exposure, and a potential intervention to improve resiliency against developing PTSD in soldiers.

Relevance to VA Research Goals: The proposed studies use innovative technologies and translational animal models to help establish evidence-based medical practices for treatment of PTSD, and restore the capability of men and women Veterans with disabilities. The VA's ORD supports a strong program of research for understanding, treating, and preventing the neurobiological responses to experiencing a traumatic event during combat duty. The proposed studies use an animal model of traumatic stress to determine if we can we identify a combination of easily measured endocrine or physiological biomarkers indicative of what individuals are at risk, or resilient, to effects of combat trauma. We also assess the neurobiological underpinnings of responses to a traumatic event and test a therapeutic target for treating PTSD. These preclinical studies will provide evidenced-based biomarkers for vulnerability that will be critical in developing new treatments and individualizing therapies for combat Veterans with PTSD.