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 signaling in the NAc. Here, we studied the regulation of impulsive behavior by fast-spiking interneurons (FSIs), a strong source of gamma-aminobutyric acid–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 to measure both impulsive action and sustained attention. During the 5-choice serial reaction time task, 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-choice serial reaction time task, NAc FSIs showed sustained activity on trials ending with correct responses, but FSI activity 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 gamma-aminobutyric acid–mediated synaptic inhibition of medium spiny projection neurons. Our findings may provide insight into the pathophysiology of disorders associated with impulsivity and may inform the development of circuit-based therapeutic interventions.
Bibliographical noteFunding Information:
This work was supported by the University of Minnesota's MnDRIVE (Minnesota's Discovery, Research and Innovation Economy) initiative (to MTP, BHT, and PER), National Institutes of Health Grant Nos. F32MH118794 (to MTP) and R00DA037279 (to PER), the Whitehall Foundation (to PER), a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (to PER), and an MQ Fellows Award (to PER). The University of Minnesota MnDRIVE Optogenetics Core provided technical support for fiber photometry experiments. Some of the viral vectors used in this study were generated by the University of Minnesota Viral Vector and Cloning Core, as well as the Stanford University Gene Virus and Vector Core. We thank Justin Lines for fiber photometry analysis troubleshooting; Eshaan Iyer for early piloting of the 5-choice serial reaction time task; Sowmya Narayan and Sumyuktha Vijay for assistance with behavioral experiments; Drs. Rocio Gomez-Pastor and Esther Krook-Magnuson for sharing advice and reagents; and Carlee Toddes and Dieter Brandner for helpful discussion of the manuscript. A preprint version of this manuscript is available on bioRxiv (https://doi.org/10.1101/516609). The authors report no biomedical financial interests or potential conflicts of interest.
This work was supported by the University of Minnesota’s MnDRIVE (Minnesota’s Discovery, Research and Innovation Economy) initiative (to MTP, BHT, and PER), National Institutes of Health Grant Nos. F32MH118794 (to MTP) and R00DA037279 (to PER), the Whitehall Foundation (to PER), a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (to PER), and an MQ Fellows Award (to PER).
© 2019 Society of Biological Psychiatry
- Fiber photometry
- Nucleus accumbens