Enhanced discriminative aversive learning and amygdala responsivity in 5-HT transporter mutant mice

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.

Effect of selective serotonin reuptake inhibitor discontinuation on anxiety-like behaviours in mice

“…This experiment also examined the possibility that discontinuation from paroxetine would affect fear learning, which is reported to be sensitive to manipulations of the 5-HT transporter (e.g. Lima et al, 2019).…”

“…The present study systematically investigated the effect of SSRI discontinuation on the behaviour of mice, with a focus on anxiety which is a core symptom of SSRI discontinuation in patients. Also, both anxiety and fear are well known to be modulated by pharmacological and genetic manipulations of the 5-HT transporter (Barkus et al, 2014; Handley and McBlane, 1993; Lima et al, 2019; Line et al, 2011). Paroxetine was selected for detailed study since discontinuation from this SSRI is considered particularly problematic in patients (Fava et al, 2015), likely due in part to its short half-life (Price et al, 1996).…”

Effect of SSRI discontinuation on anxiety-like behaviours in mice

“…This experiment also examined the possibility that discontinuation from paroxetine would affect fear-learning, which is reported to be sensitive to manipulations of the 5-HT transporter (e.g. (Lima et al, 2019)). On day 3, neither discontinued mice nor mice receiving continued paroxetine were different from saline controls in terms of either LMA measurements (F(2,33)=0.073, p=0.929) or the time spent in the centre zone of the AOF (Suppl.…”

“…The present study systematically investigated the effect of SSRI discontinuation on the behaviour of mice, with a focus on anxiety which is a core symptom of SSRI discontinuation in patients. Also, both anxiety and fear are well known to be modulated by pharmacological and genetic manipulations of the 5-HT transporter (Handley and McBlane, 1993;Line et al, 2011;Barkus et al, 2014;Lima et al, 2019).…”

“…The present study systematically investigated the effect of SSRI discontinuation on the behaviour of mice, with a focus on anxiety which is a core symptom of SSRI discontinuation in patients. Also, both anxiety and fear are well known to be modulated by pharmacological and genetic manipulations of the 5-HT transporter (Handley and McBlane, 1993; Line et al, 2011; Barkus et al, 2014; Lima et al, 2019). Paroxetine was selected for detailed study since discontinuation from this SSRI is considered particularly problematic in patients (Fava et al, 2015), likely due in part to its short half-life (Price et al, 1996).…”