Panic Disorder (PD) is a chronic and disabling condition that afflicts approximately 6 million people annually. Recent studies report that PD incidence is almost double in veterans. PD has high comorbidity with PTSD and afflicted individuals report higher rates of disability, cost of treatment and treatment resistance. Thus, studies on the search for novel, effective interventions and preclinical models relevant to PD-PTSD comorbidity are of high relevance. Neurobiological models of panic propose a central homeostatically-driven alarm system coupled with a supersensitive fear/anxiety system. Consistently, panic attacks can be triggered in individuals with PD and PTSD following challenges such as carbon dioxide (CO2) inhalation and sodium lactate, suggesting homeostatic imbalance in pH, specifically acidosis. Mechanisms for translation of acidosis to fear/panic are critical to the pathophysiology of panic and may lead to specific therapeutic treatment of panic attacks in veterans. Recently, our group has shown a role of microglial acid-sensing receptor T-cell death associated gene-8 (TDAG8), and ensuing microglial inflammation in CO2-evoked fear and panic responses. Microglial acid-sensing and inflammation may provide a core mechanism to explain the basis of panic, especially following trauma associated with PTSD This Merit Review application proposes to investigate microglial mechanisms in a rodent model of PTSD (single prolonged stress, SPS) expressing panic-like behaviors following CO2 inhalation. The rodent model of SPS simulates intense trauma that leads to PTSD-like behaviors. Importantly, our recent data has shown significant potentiation of CO2-evoked responses, microglial activation and TDAG8 up-regulation in mice exposed to SPS. The objective of this proposal is to delineate the mechanistic link between microglial acid sensing and inflammation with panic and PTSD responses following trauma. Relevance of microglial mechanisms in panic-PTSD model will be investigated under three specific aims.
Aim 1 will test the hypothesis that SPS exposure will exacerbate behavioral, cardiovascular and respiratory responses to CO2 inhalation, a panic inducer.
Aim 2 will test the hypothesis that increased CO2-evoked fear and cardiovascular responses following SPS exposure are dependent on microglial acid sensing TDAG8.
Aim 3 will test the hypothesis that microglial activation and pro-inflammatory cytokine IL-1? is necessary for CO2-evoked panic responses following SPS. Collectively, our data will determine the physiologic relevance of microglial acid sensor TDAG8 and inflammation in panic comorbid with PTSD. Relevance: Microglial inflammatory mechanisms may provide important leads on how exposure to traumatic stress can lead to panic pathophysiology. This association is critical to the pathophysiology of panic comorbid with PTSD in veterans and may lead to more specific and effective therapies.

Public Health Relevance

Studies have reported a high prevalence of panic disorder (PD) among veterans (6-8%), almost double than in the civilian population (3-4%). PD is often comorbid with posttraumatic stress disorder (PTSD) and an association between the two has been reported. Veterans diagnosed with PD report greater disability, treatment resistance and costs. Significant gaps remain in our understanding of PD neurobiology, prevention, and effective therapeutic interventions especially in trauma-exposed veterans with PTSD. This Merit review application focuses on the role of inflammation in immune cells of the brain, microglia, and its relevance to posttraumatic panic responses. Using a preclinical rodent panic-PTSD comorbid model our studies will provide a mechanistic basis for increased PD in veterans with PTSD. Impact on Patient Care: The goal of this research is to identify potential therapeutic targets of intervention in veterans suffering frm PD and PTSD.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology A (NURA)
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Cincinnati VA Medical Center Research
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Schubert, Inga; Ahlbrand, Rebecca; Winter, Andrew et al. (2018) Enhanced fear and altered neuronal activation in forebrain limbic regions of CX3CR1-deficient mice. Brain Behav Immun 68:34-43
Strawn, Jeffrey R; Vollmer, Lauren L; McMurray, Katherine M J et al. (2018) Acid-sensing T cell death associated gene-8 receptor expression in panic disorder. Brain Behav Immun 67:36-41
Winter, Andrew; Ahlbrand, Rebecca; Naik, Devanshi et al. (2017) Differential behavioral sensitivity to carbon dioxide (CO2) inhalation in rats. Neuroscience 346:423-433
Schmeltzer, Sarah N; Vollmer, Lauren L; Rush, Jennifer E et al. (2015) History of chronic stress modifies acute stress-evoked fear memory and acoustic startle in male rats. Stress 18:244-53
Sah, Renu; Ekhator, Nosakhare N; Jefferson-Wilson, Lena et al. (2014) Cerebrospinal fluid neuropeptide Y in combat veterans with and without posttraumatic stress disorder. Psychoneuroendocrinology 40:277-83
E Vollmer, L; Ghosal, S; A Rush, J et al. (2013) Attenuated stress-evoked anxiety, increased sucrose preference and delayed spatial learning in glucocorticoid-induced receptor-deficient mice. Genes Brain Behav 12:241-9
Sah, R; Geracioti, T D (2013) Neuropeptide Y and posttraumatic stress disorder. Mol Psychiatry 18:646-55
Sah, Renu; Ekhator, Nosakhare N; Strawn, Jeffrey R et al. (2009) Low cerebrospinal fluid neuropeptide Y concentrations in posttraumatic stress disorder. Biol Psychiatry 66:705-7