Vagus nerve stimulation promotes extinction generalization across sensory modalities

Abstract

Traumatic experiences involve complex sensory information, and individuals with trauma-related psychological disorders, such as posttraumatic stress disorder (PTSD), can exhibit abnormal fear to numerous different stimuli that remind them of the trauma. Vagus nerve stimulation (VNS) enhances extinction of auditory fear conditioning in rat models for PTSD. We recently found that VNS-paired extinction can also promote extinction generalization across different auditory cues. Here we tested whether VNS can enhance extinction of olfactory fear and promote extinction generalization across auditory and olfactory sensory modalities. Male Sprague Dawley rats were implanted with a stimulating cuff on the cervical vagus nerve. Rats then received two days of fear conditioning where olfactory (amyl acetate odor) and auditory (9 kHz tones) stimuli were concomitantly paired with footshock. Twenty-four hours later, rats were given three days of sham or VNS-paired extinction (5 stimulations, 30-sec trains at 0.4 mA) overlapping with presentation of either the olfactory or the auditory stimulus. Two days later, rats were given an extinction retention test where avoidance of the olfactory stimulus or freezing to the auditory stimulus were measured. VNS-paired with exposure to the olfactory stimulus during extinction reduced avoidance of the odor in the retention test. VNS-paired with exposure to the auditory stimulus during extinction also decreased avoidance of the olfactory cue, and VNS paired with exposure to the olfactory stimulus during extinction reduced freezing when the auditory stimulus was presented in the retention test. These results indicate that VNS enhances extinction of olfactory fear and promotes extinction generalization across different sensory modalities. Extinction generalization induced by VNS may therefore improve outcomes of exposure-based therapies.

Keywords: Avoidance; Exposure therapy; Fear; Memory; Olfactory conditioning.

Figure 1:

Experimental design and the effects of VNS on enhancing the extinction of olfactory fear conditioning. A) Fear conditioning was carried out in two days. The CS odor was paired with eight US presentations a day (context A). B) Following conditioning, rats underwent three days of Sham or VNS-paired extinction training with the olfactory CS (context B). C) Twenty-four hour later, all rats were habituated to the avoidance chamber (olfactory context C). On the next day, rats were tested in the same apparatus to assess the avoidance of the olfactory CS. VNS group showed reduced avoidance compared to Sham group. Data is represented by the mean ± s.e.m. (* p < 0.05 in comparison to Sham group). The gray horizontal bar represents combined avoidance index from Sham and VNS groups during habituation to the avoidance apparatus in the absence of any CS (95% ± confidence limits).

Figure 2:

Experimental design and the effects of VNS on generalizing the extinction from auditory to olfactory fear. A) Fear conditioning was carried out in two days. The CS odor and sound were paired with eight US presentations a day (context A). B) Following conditioning, rats underwent three days of Sham or VNS-paired extinction training with the auditory CS (context B). C) Twenty-four hours later, all rats were habituated to the avoidance chamber (olfactory context C). On the next day, rats were tested in the same apparatus in the presence of the olfactory CS to assess the avoidance the CS not present during extinction. VNS group showed reduced avoidance compared to Sham group. Data is represented by the mean ± s.e.m. (* p < 0.05 in comparison to Sham group). The gray horizontal bar represents combined avoidance index from Sham and VNS groups during habituation to the avoidance apparatus in the absence of any CS (95% ± confidence limits).

Figure 3:

Experimental design and the effects of VNS on generalizing the extinction from the olfactory to the auditory CS. A) Fear conditioning was carried out in two days. The CS odor and sound were paired with eight US presentations a day (context A). B) Following conditioning, rats underwent three days of Sham or VNS-paired extinction training with the olfactory CS (context B). C) Twenty-four hours later, all rats were habituated to the new auditory chamber (auditory context C). On the next day, rats were tested in the same apparatus where they received 10 trials with the auditory CS not present during extinction. Freezing is represented by the mean % time spent freezing ± s.e.m. (* p < 0.05 in comparison to Sham group). Freezing behavior from both groups during the habituation to the auditory test apparatus in the absence of any CS is represented by the horizontal bar (95% ± confidence limits). Both groups freeze more in the presence of the auditory CS but VNS-treated rats freeze significantly less than Sham-treated rats.

Figure 4:

Experimental design and the effects of VNS on reducing conditioned fear to olfactory and auditory stimuli in the absence of the CS during extinction training. A) Fear conditioning was carried out in two days. The CS odor and sound were paired with eight US presentations a day (context A). B) Following conditioning, rats underwent three days of Sham or VNS-treatment in the absence of any CS (context B). C) Twenty-four hours later, all rats were habituated to the avoidance chamber (olfactory context C). On the next day, rats were tested in the same apparatus in the presence of the olfactory CS to assess the avoidance. D) Twenty-four hours later, all rats were habituated to the new auditory chamber (auditory context C). On the next day, rats were tested in the same apparatus, where they received 10 trials with the auditory CS not present during extinction. VNS treatment alone does not appear to affect the conditioned response to either CS. Data are represented by the mean ± s.e.m. Data from Sham and VNS groups combined during the habituation to the olfactory or auditory tests are represented by horizontal bars (95% ± confidence limits).