Mice with impaired synaptic facilitation exhibit deficits in cognitive flexibility

Abstract

Behavioral flexibility is crucial to animal survival in dynamic environments, and a failure to update actions in response to recent outcomes is a hallmark of many neuropsychiatric disorders. However, the cellular and circuit mechanisms in the brain that support behavioral flexibility remain poorly understood. Forms of short-term plasticity such as synaptic facilitation have been theorized to transiently maintain information in neural circuits, and flexibly modulate how circuits process information depending on recent activity. Despite theoretical support, there is no direct experimental evidence linking synaptic facilitation to flexible decision-making. Recently, the presynaptic calcium sensor Synaptotagmin-7 (Syt7) has been shown to be required for synaptic facilitation at many synapses in the mammalian brain. Here, we assess operant learning in male and female Syt7 KO mice to determine how facilitation contributes to learning both stable and dynamic reward contingencies. We find that Syt7 KO mice acquired stable contingencies similarly to wild-type controls. However, KO mice were impaired in learning dynamic contingencies, showed more perseverative responding, and were delayed in applying a new task rule to all trial types following reversal. Behavioral modeling revealed a reduced influence of recent trial history on decisions in KO mice compared to wild-type controls. The behavioral deficits could not be explained by differences in motivation or memory. These results suggest that synaptic facilitation supports adaptive decision-making and that disruptions of short-term plasticity impair animals ability to use recent outcomes to update behavior.