Tyrosine Hydroxylase-positive Nucleus Accumbens Neurons Influence Delay Discounting in a Mouse T-maze Task

Abstract

Delay discounting (DD) is a phenomenon where individuals devalue a reward associated with a temporal delay, with the rate of devaluation being representative of impulsive-like behavior. Here we first sought to develop and validate a mouse DD task to study brain circuits involved in DD decision-making within short developmental time windows, given widespread evidence of developmental regulation of impulse control and risk-taking. We optimized a T-maze DD task for mice that enables training and DD trials within two weeks. Mice learned to choose between a large and a small reward located at opposite arms of a T-maze. Once training criteria were met, mice underwent DD whereby the large reward choice was associated with a temporal delay. Task validation showed that adolescent C57BL/6J mice display increased preference for the small reward upon a temporal delay, confirming increased impulsivity compared to adults. We next used this DD task to explore the neural basis of decision-making. We used tyrosine hydroxylase transgenic mice (TH-Cre) to target TH-positive neurons in the nucleus accumbens (NAc) and ventral tegmental area (VTA) with Cre-dependent excitatory or inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Inhibition of transduced neurons in the NAc decreased preference for the small but immediate reward during DD. Inhibition of TH+ neurons in the ventral tegmental area (VTA) did not affect impulsive choice in this DD task. These results uncover a novel role for NAc TH-positive neurons in DD behavior and expand the repertoire of behavioral tasks available for studying decision-making across the lifespan.Significance Statement Delay discounting (DD) tasks are used in rodents to study impulsive choice, whereby subjects display a preference for an immediate, smaller reward when access to a larger reward is contingent on a temporal delay. Research implicates the nucleus accumbens (NAc) brain region in impulsive behavior, with recent evidence of specialization among NAc neuronal subtypes in impulsive choice. Here we interrogated the neural requirements of impulsive choice in mice. We found that inhibition of a subset of NAc neurons expressing tyrosine hydroxylase decreases impulsive choice. We also saw increased impulsive choice in adolescent mice compared to adults, consistent with reported developmental changes in impulsivity. Together, our data identify cell-specific NAc regulation of impulsive choice with important implications for neurodevelopment.