A Novel Prefrontal Neurocircuit Regulating Fear-Associated Defensive Behaviors Relevant to PTSD

Abstract

By Sachi Shukla, Neuroscience

Advisor: Renu Sah

Presentation ID: 5

Abstract: Post-traumatic stress disorder (PTSD) associates with dysregulated fear responding. Recent studies suggest PTSD patients show heightened reactivity to CO2 inhalation, a homeostatic stressor that triggers acidosis and evokes fear- and anxiety-associated responses. Mounting evidence suggests CO2 sensitivity exists prior to pathology and could predict vulnerability to develop PTSD following later trauma. To investigate this, we developed a mouse paradigm to examine the effect of CO2-inhalation on PTSD-relevant behaviors and found prior CO2 exposure compromised fear extinction in a contextual fear conditioning paradigm one week later. This associated with reduced neuronal activation within the infralimbic (IL) cortex, a region strongly associated with fear extinction learning. We previously reported the subfornical organ (SFO) as a key site regulating CO2-evoked fear and recently identified direct SFO projections to the IL cortex. This suggests SFO-IL projections could contribute to the lasting effects of CO2 inhalation. Here, we used an intersectional chemogenetic strategy to test the hypothesis that inhibiting SFO-IL projections during CO2-inhalation would attenuate CO2-evoked defensive behaviors and later extinction deficits. We examined active (rearing) and passive (freezing) coping responses to these threats. Consistent with our hypothesis, DREADD-Gi mediated inhibition of the SFO-IL circuit significantly reduced CO2-evoked defensive behaviors and prevented contextual fear extinction deficits. These data elucidate a novel SFO to IL projection that promotes convergence of homeostatic threat sensing and long-term modulation of fear responding. Our findings highlight the SFO as a novel hub through which interoceptive triggers can regulate vulnerability to external threats and trauma of relevance to PTSD.