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Research Focus

There are 3 main research directions in the lab

Posttraumatic Stress Disorder (PTSD) and Panic Disorder: Novel targets and mechanisms

1) PTSD develops in a subpopulation of individuals who are exposed to a severe emotional trauma or traumas. Therefore, identifying neurobiological factors and mechanisms contributing to PTSD susceptibility/resilience is important. Using bench as well as bedside approaches facilitated by studies in the veteran population, we were the first to identify reduction in CSF Neuropeptide Y (NPY), a stress resiliency peptide in combat veterans with PTSD.  Studies in rodent stress models revealed potential NPY dysregulation in areas related to threat and fear processing such as the amygdala and the medial prefrontal cortex.

Panel 1Sah Figures 1A-C

Panel 1: A. Significantly lower concentration of stress resiliency peptide NPY in CSF collected from combat veterans with PTSD. B. Dense NPY fibers (green) in the medial prefrontal cortex, an area dysregulated in PTSD. C. Schematic showing how impaired NPY function may promote susceptibility to PTSD. (Adapted from Sah et al Biol Psychiatry 2009, Sah et al Psychoneuroendocrinology 2014, Vollmer et al J. Neurosci. 2016, Schmeltzer et al Exp. Neurology 2016)


2) Panic Disorder is a prevent psychiatric condition, yet the neurobiology of panic remains poorly understood. Research in the lab has focused on investigating mechanisms contributing to panic attacks and associated fear. A primary hypothesis being pursued is the role of acid/base imbalance and acid chemosensory mechanisms in panic genesis. We reported acid sensing G protein coupled receptor (GPCR), T cell death associated gene-8 receptor (TDAG8) as a novel target in Panic Disorder.

Panel 2

Sah Figures 2A-B

Panel 2 A. Potential pathogenesis of uncued and cued panic attacks in panic disorder: Initial unexpected attacks may result from an acid/base imbalance or from altered chemosensory mechanisms that represent a ‘threat to homeostasis’. B. Expression of acid sensing GPCR TDAG8 in patients with Panic Disorder. Relative TDAG8 expression is increased in patients with PD compared to healthy comparison subjects and is associated with the severity of PD symptoms (Adapted from Vollmer et al Transl. Psychiatry 2015, Strawn et al Brain Behavior Immunity 2018)


Homeostatic regulation of fear: from molecules to circuits

Most research on fear regulation focuses on responses to aversive external threats or triggers. However, the importance of "within-the body" homeostatic perturbations in emotional regulation is being recognized. Recent work from our group reveals an important role of immune cells and cytokine mediators in fear regulation. We are also exploring specialized brain areas, the sensory circumventricular organs (CVOs) that have a “leaky” blood brain barrier (BBB) enabling access to circulating factors. Interestingly, circumventricular areas have neurons that project to stress and fear regulatory brain areas. The CVOs thus provide a unique opportunity for investigating body-to-brain signaling and homeostatic regulation of fear. We reported that immune cells, microglia, within the CVO, subfornical organ (SFO) can sense acidosis evoked by carbon dioxide inhalation, a panic inducer generating fear behavior. Currently we are investigating how microglia engage endothelial interleukin 1 receptor in regulating SFO neurons. We are also exploring circuits connecting homeostatic sites such as the SFO to emotional regulatory areas.

Panel 3

Sah Figures 3A-C

Panel 3 A. Localization of sensory CVOs within the brain. The subfornical organ (SFO) houses acid sensing receptor TDAG8 on microglia but not neurons. C. Schematic outlining how microglial acid sensing regulates fear evoked by carbon dioxide inhalation, a commonly used inducer of panic attacks in humans (Adapted from Vollmer et al Biol Psychiatry 2016)

Comorbidities are more than “hanging out” together: unraveling panic-PTSD and asthma-PTSD associations

Disease and disorders never occur in isolation. Comorbidity results in symptom aggravation, treatment resistance and chronicity. While researching comorbidity is important for improving treatments, we believe that it can also provide valuable inform on predisposition, vulnerabilities and overlapping mechanisms. Currently, we are investigating associations between panic-PTSD and asthma-PTSD. To facilitate these studies, we have developed suitable rodent paradigms, that attempt to simulate behavior and physiology relevant to each condition. For example, the CO2-fear conditioning (for panic-PTSD) and house dust mite (HDM)-fear conditioning (for asthma-PTSD). We are using these models to investigate underlying mechanisms. A primary focus is the role of severe asthma associated T helper cells, Th17 and IL17a in regulation of fear.

Panel 4

Sah Figures4A-B

Panel 4 A. High behavioral sensitivity to CO2 inhalation associates with impaired extinction of fear. B. Potential pathways by which airway inflammation can impact and regulate brain function and behavior (Adapted from McMurray et al Neuroscience 2020, Lewkowich et al Brain Behavior Immunity 2020 and Johnson et al (Brain Behavior Immunity in press)
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Pharmacology and Systems Physiology

College of Medicine
231 Albert Sabin Way
Cincinnati, OH 45267-0575

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