Interaction of Brain-derived Neurotrophic Factor, Exercise, and Fear Extinction: Implications for Post-traumatic Stress Disorder.

Brain-Derived Neurotrophic Factor (BDNF) plays an important role in brain development, neural plasticity, and learning and memory. The Val66Met single-nucleotide polymorphism is a common genetic variant that results in deficient activity-dependent release of BDNF. This polymorphism and its impact on fear conditioning and extinction, as well as on symptoms of post-traumatic stress disorder (PTSD), have been of increasing research interest over the last two decades. More recently, it has been demonstrated that regular physical activity may ameliorate impairments in fear extinction and alleviate symptoms in individuals with PTSD via an action on BDNF levels and that there are differential responses to exercise between the Val66Met genotypes. This narrative literature review first describes the theoretical underpinnings of the development and persistence of intrusive and hypervigilance symptoms commonly seen in PTSD and their treatment. It then discusses recent literature on the involvement of BDNF and the Val66Met polymorphism in fear conditioning and extinction and its involvement in PTSD diagnosis and severity. Finally, it investigates research on the impact of physical activity on BDNF secretion, the differences between the Val66Met genotypes, and the effect on fear extinction learning and memory and symptoms of PTSD.

Impaired fear memory in a rat model of the brain-derived neurotrophic factor Val66Met polymorphism is reversed by chronic exercise.

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release in the brain and has been implicated in fear and anxiety disorders, including post-traumatic stress disorder. Exercise has been shown to have benefits in affective disorders but the role of BDNF Val66Met remains unclear. Male and female BDNF Val66Met rats were housed in automated running-wheel cages from weaning while controls were housed in standard cages. During adulthood, all rats underwent standard three-day fear conditioning testing, with three tone/shock pairings on day 1 (acquisition), and extinction learning and memory (40 tones/session) on day 2 and day 3. Expression of BDNF and stress-related genes were measured in the frontal cortex. Extinction testing on day 2 revealed significantly lower freezing in response to initial cue exposure in control Met/Met rats, reflecting impaired fear memory. This deficit was reversed in both male and female Met/Met rats exposed to exercise. There were no genotype effects on acquisition or extinction of fear, however chronic exercise increased freezing in all groups at every stage of testing. Exercise furthermore led to increased expression of Bdnf in the prefrontal cortex of females and its isoforms in both sexes, as well as increased expression of FK506 binding protein 51 (Fkpb5) in females and decreased expression of Serum/glucocorticoid-regulated kinase (Sgk1) in males independent of genotype. These results show that the Met/Met genotype of the Val66Met polymorphism affects fear memory, and that chronic exercise selectively reverses this genotype effect. Chronic exercise also led to an overall increase in freezing in all genotypes which may contribute to results.

Behavioral phenotyping of a rat model of the BDNF Val66Met polymorphism reveals selective impairment of fear memory.

The common brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release and increased risk for anxiety disorders and PTSD. Here we behaviorally phenotyped a novel Val66Met rat model with an equivalent valine to methionine substitution in the rat Bdnf gene (Val68Met). In a three-day fear conditioning protocol of fear learning and extinction, adult rats with the Met/Met genotype demonstrated impaired fear memory compared to Val/Met rats and Val/Val controls, with no genotype differences in fear learning or extinction. This deficit in fear memory occurred irrespective of the sex of the animals and was not seen in adolescence (4 weeks of age). There were no changes in open-field locomotor activity or anxiety measured in the elevated plus maze (EPM) nor in other types of memory measured using the novel-object recognition test or Y-maze. BDNF exon VI expression in the dorsal hippocampus was higher and BDNF protein level in the ventral hippocampus was lower in female Val/Met rats than female Val/Val rats, with no other genotype differences, including in total BDNF, BDNF long, or BDNF IV mRNA. These data suggest a specific role for the BDNF Met/Met genotype in fear memory in rats. Further studies are required to investigate gene-environment interactions in this novel animal model.