Nucleus Accumbens Fast-Spiking Interneurons Constrain Impulsive Action

Background The nucleus accumbens (NAc) controls multiple facets of impulsivity, but is a heterogeneous brain region with diverse microcircuitry. Prior literature links impulsive behavior in rodents to gamma aminobutyric acid (GABA) signaling in the NAc. Here, we studied the regulation of impulsive behavior by fast-spiking interneurons (FSIs), a strong source of GABA-mediated synaptic inhibition in the NAc. Methods Male and female transgenic mice expressing Cre recombinase in FSIs allowed us to identify these sparsely distributed cells in the NAc. We used a 5-choice serial reaction time task (5-CSRTT) to measure both impulsive action and sustained attention. During the 5-CSRTT, we monitored FSI activity with fiber photometry calcium imaging, and manipulated FSI activity with chemogenetic and optogenetic methodology. We used electrophysiology, optogenetics, and fluorescent in situ hybridization to confirm these methods were robust and specific to FSIs. Results In mice performing the 5-CSRTT, NAc FSIs showed sustained activity on trials ending with correct responses, but declined over time on trials ending with premature responses. The number of premature responses increased significantly after sustained chemogenetic inhibition or temporally delimited optogenetic inhibition of NAc FSIs, without any changes in response latencies or general locomotor activity. Conclusions These experiments provide strong evidence that NAc FSIs constrain impulsive actions, most likely through GABA-mediated synaptic inhibition of medium spiny projection neurons. Our findings may provide insight into the pathophysiology of disorders associated with impulsivity, and inform the development of circuit-based therapeutic interventions.