Female Carriers of the Met Allele of the BDNF Val66Met Polymorphism Develop Weaker Fear Memories in a Fear-Potentiated Startle Paradigm

The val66met polymorphism of the bdnf gene, which is associated with compromised brain-derived neurotrophic factor (BDNF) signaling, impaired synaptic plasticity, and impaired learning, may increase one’s susceptibility to stress- and anxiety-related disorders. Indeed, previous work has reported greater anxiety-related behaviors and impairments of fear conditioning and extinction in individuals who carry the met allele that results from this polymorphism. Nevertheless, findings in this area of research have been equivocal. Thus, we examined the influence of the val66met polymorphism on fear conditioning, extinction, and extinction memory testing. One hundred and twenty healthy participants completed differential fear conditioning in a fear-potentiated startle paradigm, followed by extinction and extinction memory testing 24 and 48 hr later, respectively. Participants were genotyped for the val66met polymorphism and divided into met allele carriers and non-carriers. Results revealed that, although both met-carriers and non-carriers developed conditioned fear, met-carriers exhibited significantly weaker fear acquisition than non-carriers. This difference persisted throughout extinction and extinction memory testing and, during these last two days of testing, was primarily evident in females. These results are consistent with previous work demonstrating that this polymorphism is associated with impaired amygdala-dependent fear learning and extend such findings by demonstrating that females may be more sensitive to such effects.

Behavioral and Neurobiological Assessments of Predator-Based Fear Conditioning and Extinction

Shock, immobilization, and exposure to predator-related stimuli have all been used to study fear conditioning in rodents, but they have never been used in conjunction in a single study. Experiment 1 compared the effects of these three reinforcers, alone and in various combinations, on the expression of long-term conditioned fear memory and extinction in adult male rats. Whereas foot shock conditioning, alone, was rapidly extinguished;the combination of immobilization and cat exposure, or all 3 stimuli together, produced a significant increase in the magnitude of fear conditioning and greater resistance to extinction, which persisted for at least 5 weeks post-training (p < 0.05). Experiment 2 assessed the role of the hippocampus in predator-based context and cued fear conditioning. Pharmacological suppression of hippocampal activity during fear conditioning produced a selective impairment of contextual, but not cued, fear memory. Experiment 3 investigated the effects of sleep deprivation prior to fear conditioning on the expression of fear memory. This experiment demonstrated that pre-training sleep deprivation blocked the expression of contextual (hippocampal-dependent), but not cued (hippocampal-independent), fear memory. Overall, this series of experiments has extended the use of predator exposure in conjunction with conventional reinforcers, such as foot shock and immobilization, to advance our understanding of the neurobiology of traumatic memory.