Anxiety disorders, including specific phobias, Post Traumatic Stress Disorder (PTSD) and panic disorder (Association, 2014); are some of the most common mental illnesses worldwide, with recent prevalence estimates ranging from 3.8 % to as high as 25 % in some cultures (Remes et al., 2016). The Global Burden of Disease study estimated that anxiety disorders contributed to 26.8 million disability adjusted life years in 2010 (Remes et al., 2016). According to the two-factor learning theory of fear and anxiety, fear in anxiety disorders such as PTSD and phobias is acquired through classical conditioning processes and is maintained through the negative reinforcement of avoidance behaviours (Friedman et al., 2014). Exposure therapy utilizes this theory to treat the symptoms of anxiety disorders by gradually exposing these individuals to stimuli that are associated with the traumatic event, situation or object relevant to their PTSD symptoms, until these stimuli fail to elicit a fear response (Friedman et al., 2014).

Various animal studies have demonstrated that Brain-Derived Neurotrophic Factor (BDNF) has a key role in the consolidation of fear memories and extinction. For example, infusion of BDNF into various regions of the frontal cortex (Kataoka et al., 2018, Peters et al., 2010, Rosas-Vidal et al., 2014) or hippocampus (Kirtley and Thomas, 2010, Radiske et al., 2015) in rodents has been shown to lead to changes in both fear acquisition and fear-conditioned memory and extinction, while induction of fear conditioning leads to changes in BDNF levels throughout the brain (Baker-Andresen et al., 2013, Hill et al., 2016, Kataoka et al., 2018, Psotta et al., 2013, Rosas-Vidal et al., 2014). Male BDNF heterozygous mice, with only about half the level of BDNF compared to wildtype controls, were found to have impaired fear extinction memory (Meis et al., 2018, Psotta et al., 2013). Similarly, BDNF-e4 mice, where BDNF expression from promotor IV is disrupted, demonstrated impaired fear extinction in comparison to wildtypes (Hill et al., 2016). Selective neocortical BDNF knock-out mice demonstrated deficits in the consolidation of cued fear (Choi et al., 2010). Deficits in cued fear consolidation were rescued with TrkB agonists indicating that BDNF-TrkB signalling plays an important role in this process (Choi et al., 2010). These studies demonstrate that deficient BDNF is associated with impaired cued fear consolidation and fear extinction.

Physical exercise has been suggested to provide cognitive benefits and regulate mood through an increase in BDNF concentrations in various brain regions (Arent et al., 2020, Dinoff et al., 2017, Keyan and Bryant, 2019). Animal studies have indicated that exercise increases BDNF concentrations in brain regions responsible for learning, memory, and emotional processing (e.g. hippocampus, prefrontal cortex and amygdala) (Fang et al., 2013, Jaehne et al., 2023, Lu et al., 2014, Marlatt et al., 2012). Meta-analyses have found enhanced peripheral blood BDNF levels after exercise in human participants, an effect which was greater with session duration (Dinoff et al., 2017, Szuhany et al., 2015). An animal study using an inhibitory avoidance task paradigm found that moderate exercise alleviated impaired fear extinction and increased hippocampal BDNF (Shafia et al., 2017). Individuals with a diagnosis of PTSD who received exercise in addition to exposure therapy showed greater improvement in PTSD symptoms in comparison to therapy alone (Powers et al., 2015). This demonstrates efficacy of using physical activity in addition to exposure-like therapies for the treatment of symptoms in anxiety and fear-related disorders. However, it remains unclear which individuals would benefit most from such an effect or how the duration and intensity of exercise correlates with changes in fear memory (Notaras and van den Buuse, 2020, Tanner et al., 2018). Moreover, a number of studies have shown adverse effects of chronic exercise on anxiety-like symptoms (Baruch et al., 2004, Burghardt et al., 2004, Greenwood et al., 2009, Van Hoomissen et al., 2004).

The Val66Met polymorphism is a common variation in the BDNF gene, which leads to deficient activity-dependent release of BDNF (Notaras & van den Buuse, 2020). Several studies have shown that the Met allele is associated with deficits in fear conditioning and extinction compared to the Val/Val genotype (Dincheva et al., 2014, Felmingham et al., 2018, Giza et al., 2018, Mühlberger et al., 2014, Notaras et al., 2016, Raju et al., 2022, Soliman et al., 2010). We recently used a novel Val66Met model, the Val68Met rat, which displays significantly reduced BDNF release from neurons (Mercado et al., 2021), and found that the Met/Met genotype was associated with decreased fear memory compared to both the Val/Val and Val/Met genotypes, although other aspects of fear learning and extinction learning and memory were unchanged (Jaehne et al., 2022). There is limited research investigating the interactive effect of the Val66Met polymorphism and exercise on fear conditioning. Some studies suggest that individuals with the Met allele show most benefit from exercise in fear extinction recovery (Keyan and Bryant, 2019, Pitts et al., 2019), while others suggest that those with the Val/Val genotype are more likely to show benefit in comparison to Met allele carriers (Keyan & Bryant, 2017). We therefore aimed to investigate the impact of the Val66Met polymorphism and its interaction with chronic voluntary exercise on fear acquisition and extinction using the Val68Met rat model (Jaehne et al., 2022, Mercado et al., 2021). To elucidate mechanisms involved, we also measured expression of BDNF and a number of stress-related genes in the frontal cortex, which is involved in consolidation and recall of fear memory as well as consolidation of extinction memory (Howland et al., 2022, Marek et al., 2013, Marek et al., 2019). These included the glucocorticoid receptor (Nr3c1), Serum/glucocorticoid-regulated kinase 1 (Sgk1), which is activated by glucocorticoids, and FK506 binding protein 51 (Fkbp5), which regulates sensitivity of the glucocorticoid receptor.