Extinction of Blood Pressure and Heart Rate Responses to Conditioned Fear

Abstract

BackgroundPost‐traumatic stress disorder (PTSD) is characterized by an impaired ability to extinguish fear associations that trigger exaggerated neurophysiological responses, which may contribute to increased cardiovascular (CV) risk in these individuals. The objective of this study was to evaluate the effects of learned inhibition or extinction on the conditioned cardio‐autonomic response during fear memory recall. We hypothesized that extinction training would lead to a temporary reduction of conditioned heart rate (HR) and systolic blood pressure (SBP) responses.MethodsIn male C57BL/6 mice, Pavlovian fear conditioning combined with simultaneous in‐vivo telemetry was used to assess CV and behavioral measures in both home‐cage and testing contexts. Mice were fear conditioned with five tone/shock pairings followed by two days of extinction training, each consisting of 30 conditioned stimulus (CS) presentations. The conditioned CV response was evaluated during short‐term (STR) (1‐hour post‐extinction) and long‐term recall (LTR) (2 weeks post‐extinction) of the CS in the home‐cage.ResultsFreezing behavior, systolic blood pressure (SBP) and heart rate (HR) were simultaneously measured over two days of extinction training. Freezing in response to the CS from Day 1 to Day 2 was reduced in fear conditioned mice (80% ± 7 vs. 57% ± 11; p<0.05), whereas non‐conditioned animals did not respond to the CS on either day. SBP and HR were elevated to near‐physiological maximums throughout each session, regardless of whether or not the animals had been previously fear conditioned. However two‐weeks after extinction training, fear‐conditioned animals in the home‐cage context exhibited a strong conditioned CV response to the CS, which remained elevated over the course of four CS presentations (change in SBP 18 mmHg ± 2 and HR 166 bpm ± 42; n= 8; p<0.05) (Fig. 1). We then assessed short‐term CV responses before and after extinction training. 24 hours after fear conditioning, we observed increased CV activity in response to the CS (change in SBP 17 mmHg ± 4.3 and HR 101 bpm ± 34.3; n= 9–12; p<0.05) over 4CS trials. Interestingly, this STR was similar to that of animals 2 weeks after extinction training. Conditioned mice were then split into two groups: (1) extinction (2) no extinction. The extinction group was repeatedly re‐exposed to the CS over two days of extinction training. At the end of this two‐day period, both groups went through a final conditioned CV response test in the home cage. In non‐extinguished controls, there was a significant increase in SBP during CS exposure (114 mmHG ± 2.7 vs. 124 mmHG ± 4.3; p<0.05), while in the extinction group, the SBP response was completely abolished. Heart rate did not change in response to CS exposure in either group at this time point.ConclusionsThese data demonstrate for the first time that both short and long‐term recall of fear memory elicit a conditioned blood pressure response that can be temporarily attenuated by extinction training. Furthermore, these data suggest that conditioned blood pressure and heart rate responses may vary in their sensitivity to inhibitory learning. Understanding the effects of extinction training on autonomic regulation of blood pressure and heart rate may help identify or improve interventions that lead to better PTSD‐CVD comorbidity outcomes.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.