Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner

Abstract

Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can enhance the acquisition and consolidation of fear extinction in male rats, but the effects of exercise on relapse of fear after extinction are not well understood. Here, we characterized the effects of 2 h of voluntary exercise during the consolidation phase of contextual or auditory fear extinction learning on long-term fear extinction memory and renewal in adult, male and female, LongEvans rats. Results indicate that exercise enhances consolidation of fear extinction memory and reduces fear relapse after extinction in a sex-dependent manner. These data suggest that brief bouts of exercise could be used as an augmentation strategy for exposure therapy, even in previously sedentary subjects. Fear memories of discrete cues, rather than of contextual ones, may be most susceptible to exercise-augmented extinction, especially in males. Additionally, exercise seems to have the biggest impact on fear relapse phenomena, even if fear extinction memories themselves are only minimally enhanced.

Acute exercise-induced enhancement of fear inhibition is moderated by BDNF Val66Met polymorphism

“…Additionally, an interaction between BDNF genotype and exercise condition significantly predicted fear recovery such that Met allele carriers, but not Val homozygotes, displayed impaired retention of extinction training. This is the first study to extend recent animal research demonstrating that a single bout of wheel running enhances extinction memory consolidation 19,22 , and provides initial evidence that this influence may be moderated by BDNF genotype.…”

“…Given divergent gender differences in the manner in which BDNF polymorphism impacts reactivity to stress 49,51 , and exercise can be considered a physical stressor, it would be important for future studies to disentangle the extent to which this gender × stress interaction impacts upon subsequent exercise-induced BDNF expression and related extinction retention. This may be especially relevant with recent rodent research evidencing exercise-induced enhancement of extinction retention that is limited to male rodents 19 .…”

“…Recent animal work has demonstrated that a single bout of immediate exercise following extinction training of conditioned fear subsequently reduced expression of fear on a delayed retention test 19,22 . Importantly, a dose-response effect of exercise on extinction memory retention has been evidenced whereby distance covered in the wheel running correlated with reduced fear 22 .…”

Activation of Nigrostriatal Dopamine Neurons during Fear Extinction Prevents the Renewal of Fear

“…Auditory fear conditioning (4 CS-US presentations: 10 s, 80 dB, 2 kH auditory CS co-terminating with a 1 s, 0.8 mA foot shock, 1 min ITI), auditory fear extinction (20 CS; 1 min ITI), and fear renewal testing (4 CS; 1 min ITI) took place in contexts A, B, and C, respectively, following protocols used previously (Bouchet et al, 2017;Wang et al, 2016; see Supplementary Methods for details). ABC, as opposed to ABA, renewal was used to limit the contribution of contextual fear memory to fear expression during renewal.…”

Running from fear: Exercise modulation of fear extinction

“…Bouchet et al (2017) investigated the impact of single voluntary exercise bouts occurring after fear extinction on proximal and distal fear extinction memory. Unlike the Siette et al (2014) study, Bouchet et al (2017) did not observe a significant improvement in retention of contextual fear extinction during a proximal memory test occurring 24 h following the first extinction session. However, Bouchet et al (2017) allowed the rats to run again for 2 h after this proximal extinction memory test, which also served as an extinction session.…”