Extinction of Fear Memory Attenuates Conditioned Cardiovascular Fear Reactivity

Abstract

Post-traumatic stress disorder (PTSD) is characterized by a heightened emotional and physiological state and an impaired ability to suppress or extinguish traumatic fear memories. Exaggerated physiological responses may contribute to increased cardiovascular disease (CVD) risk in this population, but whether treatment for PTSD can offset CVD risk remains unknown. To further evaluate physiological correlates of fear learning, we used a novel pre-clinical conditioned cardiovascular testing paradigm and examined the effects of Pavlovian fear conditioning and extinction training on mean arterial pressure (MAP) and heart rate (HR) responses. We hypothesized that a fear conditioned cardiovascular response could be detected in a novel context and attenuated by extinction training. In a novel context, fear conditioned mice exhibited marginal increases in MAP (∼3 mmHg) and decreases in HR (∼20 bpm) during CS presentation. In a home cage context, the CS elicited significant increases in both HR (100 bpm) and MAP (20 mmHg). Following extinction training, the MAP response was suppressed while CS-dependent HR responses were variable. These pre-clinical data suggest that extinction learning attenuates the acute MAP responses to conditioned stimuli over time, and that MAP and HR responses may extinguish at different rates. These results suggest that in mouse models of fear learning, conditioned cardiovascular responses are modified by extinction training. Understanding these processes in pre-clinical disease models and in humans with PTSD may be important for identifying interventions that facilitate fear extinction and attenuate hyper-physiological responses, potentially leading to improvements in the efficacy of exposure therapy and PTSD-CVD comorbidity outcomes.

Keywords: PTSD; Pavlovian fear conditioning; cardiovascular disease; extinction; fear memory; physiological hyperarousal.

FIGURE 1

Behavioral and cardiovascular changes during extinction training. Schematic of fear conditioning and 2-day extinction protocol (A). Freezing behavior during fear conditioning (B). Freezing behavior (C,D), mean arterial pressure (F,H), and heart rate (G,I) during 2-day extinction training protocol. Average freezing behavior (E), mean arterial pressure (J), and heart rate (K) during CS 1–4 (Day 1), and CS 27–30 (Day 2) in the extinction context. Error bars indicate standard error of the mean (n = 9–11 per group, ^∗p < 0.05 CS vs. CS-US; ^#p < 0.05 Day 1 vs. Day 2).

FIGURE 2

Schematic of fear conditioning and testing protocol for home cage extinction studies. All animals were fear conditioned on Day 0. Conditioned cardiovascular responses were measured in the home cage 24 h later (Cardiovascular Response Test 1). Animals were then placed into a novel context and exposed to either 35 CS (Ext group) or no CS (No Ext group) for the first extinction session. On Day 2, a home cage test (Cardiovascular Response Test 2) was conducted prior to the second extinction session. The Ext group was then exposed to another 35CS extinction session. One hour later, all animals were tested in the home cage (Cardiovascular Response Test 3).

FIGURE 3

Pre-extinction training CS-dependent cardiovascular response test 1 (home cage). Mean arterial pressure (A), and heart rate (D) collected during 4 CS presentations and averaged every 3 s. (B,E) Depict second-by-second fluctuations in MAP and HR during the first CS presentation. Average MAP (C) and HR (F) during the 5 min pre-CS period, and over 4 CS presentations (n = 6–9 per group, ^∗p < 0.05 pre-CS vs. 4 CS avg).

FIGURE 4

Post-extinction training CS-dependent cardiovascular response tests 2 and 3 (home cage). Mean arterial pressure (A) and heart rate (C) collected during cardiovascular response test 2. Average MAP (B) and HR (D) during 4 CS presentations. Mean arterial pressure (E), and heart rate (G) collected during cardiovascular response test 3. Average MAP (F) and HR (H) during 4 CS presentations (n = 6–9 per group, ^∗p < 0.05 pre-CS vs. 4 CS avg).