Abstract
Genetic variation in the human serotonin transporter (5-HTT) has been linked to altered fear learning but the data are inconsistent and the mechanism is unclear. The present study investigated conditioned aversive learning in 5-HTT knockout (KO) mice while simultaneously recording neural network activity (theta oscillations) and hemodynamic responses (tissue oxygen delivery) from the amygdala, a brain region necessary for forming fearful memories. Conditioned aversive learning was measured using a discrimination learning task in which one auditory cue was paired with foot-shock, whereas a second auditory cue was not. Compared with wild-type mice, 5-HTTKO mice exhibited faster discrimination learning. This effect was associated with stronger theta frequency oscillations and greater hemodynamic changes in the amygdala in response to both the emotionally relevant cues and the unconditioned foot-shock stimulus. Furthermore, hemodynamic responses to the unconditioned stimulus predicted behavioral discrimination performance the following day. Acute pharmacological 5-HTT blockade in wild-type mice produced a similar effect, to the extent that administration of citalopram during the fear conditioning sessions enhanced fear memory recall. Collectively, our data argue that loss of 5-HTT function enhances amygdala responsivity to aversive events and facilitates learning for emotionally relevant cues.
Highlights
The serotonin transporter (5-HTT) regulates serotonin (5-HT) availability at the synapse, and is the target of selective serotonin reuptake inhibitors (SSRIs), which are currently the mainline treatment for depression and anxiety disorders
To clarify the impact of 5-HTT loss on emotional learning, the present study investigated conditioned aversive learning and amygdala activity in 5-HTT knockout (5-HTTKO) mice using a discriminative fear learning paradigm rather than the “single-cue” fear paradigm used in previous investigations of 5-HTTKO rodents
Analysis of Δfreezing scores (ANOVA model: genotype2 × sex2 × day2 × CS type2 × trial[5], n = 60 mice) revealed greater freezing evoked by the CS+ than CS– (main effect of CS type: F(1, 56) = 23.4, p < 0.001) and superior discrimination in 5-HTTKO compared with WT mice (genotype × CS type interaction: F(1, 56) = 7.6, p = 0.01)
Summary
The serotonin transporter (5-HTT) regulates serotonin (5-HT) availability at the synapse, and is the target of selective serotonin reuptake inhibitors (SSRIs), which are currently the mainline treatment for depression and anxiety disorders. A substantial research effort has examined the influence of variation in the human 5-HTT gene on the risk for developing anxiety and depression, as well as other aspects of emotional function These studies have focused on the 5HTT gene-linked polymorphic region (5-HTTLPR), which is an insertion/deletion polymorphic site that generates long and short alleles. The risk of psychiatric disorders associated with reduced 5-HTT expression is thought to be underpinned by elevated amygdala responsivity to fearful stimuli as detected in functional Magnetic Resonance Imaging (fMRI) Blood Oxygen Level Dependent (BOLD) studies[4,5].
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