Angiotensin Type 1 Receptor (AT1R) Inhibition Disrupts Reconsolidation of Conditioned Auditory Fear

Abstract

BackgroundFear and anxiety disorders are associated with increased cardiovascular disease (CVD) risk, and recent clinical studies suggest that autonomic dysregulation may link these conditions. After retrieval, fear memories become temporarily vulnerable during a state of reconsolidation, and interventions that disrupt this process may improve post‐traumatic stress disorder (PTSD) and potential CVD risk. The renin angiotensin system has been shown to contribute to memory processes in rodent models of Pavlovian conditioning, however its role in reconsolidation of auditory fear conditioning is unknown. In the present study, we examined the effects of AT1R inhibition on fear memory reconsolidation and conditioned cardiovascular responses.MethodsPavlovian auditory fear conditioning was conducted in C57Bl/6 mice. 24hrs later, animals were subjected to a single cue retrieval, followed by an acute intraperitoneal (10mg/kg) or intracerebroventricular (4ug/ul) injection of the AT1R antagonist losartan or saline control. As an index of fear memory, behavioral responses were calculated as the percentage of time spent freezing during cue presentation 24hr hours and one week later (Actimetrics Freeze Frame; Wilmette, IL). In a separate group of animals, cue‐dependent blood pressure and heart rate responses during memory recall and following drug injections were assessed using radio telemetry (DSI HDX‐11 transmitters; St. Paul, MN).ResultsAnimals injected with peripheral losartan after memory retrieval showed a significant reduction in freezing behavior relative to saline controls during 24hr memory tests (F (1, 22) = 5.756, p = 0.025, n=12), and a trend for reduction during 1wk memory tests (F (1, 21) = 2.883, p = 0.104 n=12). When injections were given before and after fear conditioning, or in the absence of a retrieval stimulus, no differences in percent freezing were observed. Cue presentation in the home cage elicited similar blood pressure and heart rate increases in saline and losartan groups 24hr after retrieval (Saline: ΔMAP= 24mmHg ± 7, ΔHR= 140bpm ± 54 n=4; losartan: ΔMAP= 20mmHg ± 8, ΔHR= 131bpm ± 3 n=3). Central losartan injections had at no effect on freezing behavior at either time point.ConclusionsThese findings suggest that peripheral AT1R inhibition disrupts the reconsolidation of conditioned fear memory in a retrieval‐dependent manner. Interestingly, these effects were observed in freezing behavior, but not in blood pressure or heart rate responses to conditioned fear stimuli. Additionally, we show that systemic losartan does not affect freezing behavior when given immediately before and after conditioning, suggesting that it does not impair the initial consolidation of auditory fear memories. Taken together, these findings suggest that AT1R antagonism during the window of reconsolidation may modify behavioral responses to previously consolidated intrusive memories, while leaving the cardiovascular responses to these memories unaltered.Support or Funding InformationThis research was supported by NIH1R01HL137103‐01A1 and American Heart Association 15CSA24340001.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.