Assessing Sex Differences in Threat Responding to Posttraumatic Stress Disorder (PTSD): Relevant Challenges in Mice

Abstract

By Allison Wilson, Biological Sciences; Rebecca Ahlbrand, University of Cincinnati; Yuv Sachdeva, Medical Sciences; Patrick Woller, University of Cincinnti; James Wiggins, Medical Sciences; Renu Sah, University of Cincinnati

Advisor: Renu Sah

Presentation ID: 223

Abstract: Post-traumatic stress disorder (PTSD) is a fear-associated disorder that afflicts approximately 6 million individuals annually with higher prevalence in war veterans and females. PTSD is characterized by maladaptive threat responding and persisting trauma-associated fear memories. There is considerable interest in identifying pre-trauma vulnerability factors that may promote PTSD. Pre-deployment studies in veterans showed a role of sensitivity to CO2 inhalation, a homeostatic stressor, in PTSD risk. We developed a mouse model of CO2 associated fear dysregulation where only CO2-sensitive mice develop enhanced fear phenotypes. Our previous study was limited to male animals and studies are currently lacking in females. Here we assessed sex differences in threat responding to CO2 and footshock fear conditioning, a PTSD relevant paradigm. Passive (freezing) and active (rearing) were measured for coping behaviors and neuronal activation (ΔFosB immunostaining) in fear-regulatory amygdala nuclei was quantified. Our data revealed heterogenous freezing and rearing behaviors to CO2 in male and female mice. Females demonstrate significantly higher rearing in both CO2 and fear conditioning phases indicative of active coping behaviors. This was accompanied by alterations in amygdala FosB counts, an effect not observed in male mice. Our data indicate that both male and female mice elicit differential CO2-sensitive distribution similar to humans but significant differences in defensive coping, with females showing active threat responding. Differences in fear circuit recruitment might contribute to these effects. In conclusion, our CO2-fear conditioning paradigm provides a useful model to investigate mechanisms promoting PTSD risk in a sex-dependent manner. Funding Support: VA Merit award (RS)