Recruitment of central angiotensin II type 1 receptor associated neurocircuits in carbon dioxide associated fear.

Individuals with fear-associated conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD) display increased emotional responses to interoceptive triggers, such as CO2 inhalation, that signal a threat to physiological homeostasis. Currently, effector systems and mechanisms underlying homeostatic modulation of fear memory are not well understood. In this regard, the renin angiotensin system (RAS), particularly the angiotensin receptor type 1 (AT1R), a primary homeostatic regulatory target, has gained attention. RAS polymorphisms have been reported in PD and PTSD, and recent studies report AT1R-mediated modulation of fear extinction. However, contribution of AT1Rs in fear evoked by the interoceptive threat of CO2 has not been investigated. Using pharmacological, behavioral, and AT1R/ACE gene transcription analyses, we assessed central AT1R recruitment in CO2-associated fear. CO2 inhalation led to significant AT1R and ACE mRNA upregulation in homeostatic regulatory regions, subfornical organ (SFO) and paraventricular nucleus (PVN), in a temporal manner. Intracerebroventricular infusion of selective AT1R antagonist, losartan, significantly attenuated freezing during CO2 inhalation, and during re-exposure to CO2 context, suggestive of AT1R modulation of contextual fear. Regional Fos mapping in losartan-treated mice post-behavior revealed significantly attenuated labeling in areas regulating defensive behavior, contextual fear, and threat responding; such as, the bed nucleus of stria terminalis, dorsal periaqueductal gray, hypothalamic nuclei, hippocampus, and prefrontal areas such as the prelimbic, infralimbic, and anterior cingulate cortices. Sub-regions of the amygdala did not show CO2-associated AT1R regulation or altered Fos labeling. Collectively, our data suggests central AT1R recruitment in modulation of fear behaviors associated with CO2 inhalation via engagement of neurocircuits regulating homeostasis and defensive behaviors. Our data provides mechanistic insights into the interoceptive regulation of fear, relevant to fear related disorders such as PD and PTSD.