Genetic variants related to deficient fear conditioning – a pathway to uncertainty

Great variability exists in learning adaptive responses to threat in a fear conditioning
paradigm. Cognitive and personality variables have been found to play a role in conditioning,
but even in highly educated samples substantial percentages of subjects fail to acquire
a conditioned response. Our previous work has demonstrated that failure to condition to a
specific threat cue results in an increase in conditioned fear to the context because the threat
remains unpredictable. This mechanism may model a pathway to chronic states of anxiety.
Preclinical data from collaborators suggests the interplay between brain serotonin (5HT)
and corticotropin releasing hormone (CRH) systems is crucial in successful fear acquisition.
Subjects underwent a cue and context fear conditioning procedure in a virtual environment
and were genotyped for common polymorphisms within regulatory regions of the
serotonin transporter (5HTTLPR) and the CRH receptor 1 (CRHR1). 5HTTLPR and the
G-allele of CRHR1 have been associated with risk for anxiety/depression and panic
disorder, respectively. Conditioned responses were measured with fear-potentiated startle.
Uninstructed fear acquisition to the threat cue was significantly affected by CRHR1
genotype: G-allele carriers failed to discriminate between threat cue and context. Subjects
carrying the risk-alleles of both genotypes displayed increased contextual conditioned
responses. Hence, genetic variation in these transmitter systems may confer a risk for
maladaptive acquisition of fear associations, which may constitute a pathway to pathological
fear.