There is considerable interest in pre-trauma individual differences that may contribute to increased risk for developing post-traumatic stress disorder (PTSD). Identification of underlying vulnerability factors that predict differential responses to traumatic experiences is important. Recently, the relevance of homeostatic perturbations in shaping long-term behavior has been recognized. Sensitivity to CO2 inhalation, a homeostatic threat to survival, was shown to associate with the later development of PTSD symptoms in veterans. Here, we investigated whether behavioral sensitivity to CO2 associates with PTSD-relevant behaviors and alters forebrain fear circuitry in mice. Mice were exposed to 5% CO2 or air inhalation and tested one week later on acoustic startle and footshock contextual fear conditioning, extinction and reinstatement. CO2 inhalation evoked heterogenous freezing behaviors (high freezing CO2-H and low freezing CO2-L) that significantly associated with fear conditioning and extinction behaviors. CO2-H mice elicited potentiated conditioned fear and delayed extinction while behavioral responses in CO2-L mice were similar to the air group. Persistent neuronal activation marker ΔFosB immunostaining revealed altered regional neuronal activation within the hippocampus, amygdala and medial pre-frontal cortex that correlated with conditioned fear and extinction. Inter-regional co-activation mapping revealed disruptions in the coordinated activity of hippocampal dentate-amygdala-infralimbic regions and infralimbic-prelimbic associations in CO2-H mice that may explain their enhanced fear phenotype. In conclusion, our data support an association of behavioral sensitivity to interoceptive threats such as CO2 with altered fear responding to exteroceptive threats and suggest that "CO2-sensitive" individuals may be susceptible to developing PTSD.
Keywords: CO(2) sensitivity; PTSD; extinction; fear; startle.
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