PMAT enhances sexual dimorphism of fear behaviors and facilitates female mice’s generalized contextual fear extinction

Enhanced signaling of dopamine and/or serotonin during highly arousing situations can be reduced or terminated by monoamine transporters. One such transporter, plasma membrane monoamine transporter (PMAT, Slc29a4 ), attenuates both dopamine and serotonin signaling. An absence of selective pharmacological inhibitors means genetically modified mice constitutively deficient in PMAT remain the best tool with which to study PMAT’s organism-level functional effects. Fear conditioning is a high arousal process. Generalization of fear is an evolutionarily advantageous process, whereby information learned from one experience is applied to other new but similar encounters. Pathological fear generalization, in contrast, is a core feature of most anxiety disorders. Given our previous findings indicating PMAT function reduces male mice’s context fear and enhances extinction of female mice’s cued fear, we hypothesized that PMAT would similarly reduce generalization (i.e., enhance discrimination) of context and cued fear in male and female mice, respectively. Our context and cued fear conditioning experiments in adult PMAT wildtype (+/+) and heterozygous (+/−) male and female mice partially supported our hypotheses. We discovered PMAT functions to facilitate extinction of contextually generalized fear, plus subsequent extinction of context-specific fear, selectively in females. Moreover, when specific fear cues or contexts were temporally presented before cues or contexts that were similar enough to make generalization possible, PMAT enhanced biological sex differences. Growing evidence reports common PMAT polymorphisms elicit measurable effects when PMAT function is reduced. Thus, we suspect future experiments may reveal positive associations between PMAT polymorphisms and risk for anxiety disorder symptoms, particularly in people assigned female at birth. Inclusion of these genetic variations in pharmacogenomic analyses may prove therapeutically beneficial.