A role for reward valuation in the serotonergic modulation of impulsivity

Rationale Impulsive behavior is a deleterious component of a number of mental health disorders but has few targeted pharmacotherapies. One contributing factor to the difficulty in understanding the neural substrates of disordered impulsivity is the diverse presentations of impulsive behavior. Defining the behavioral and cognitive processes which contribute to different subtypes of impulsivity is important for understanding the neural underpinnings of dysregulated impulsive behavior. Methods Using a mouse model for disordered impulsivity, our goal was to identify behavioral and cognitive processes that are associated with increased impulsivity. Specifically, we were interested in the facets of impulsivity modulated by serotonin signaling. We used mice lacking the serotonin 1B receptor (5-HT1BR) and measured different types of impulsivity as well as goal-directed responding, extinction, habitual-like behavior, cue reactivity, and reward reactivity. Results Mice lacking expression of 5-HT1BR had increased levels of impulsive action, goal-directed responding, and motivation, with no differences seen in rate of extinction, development of habitual behavior, delay discounting, or effort-based discounting. Interestingly, mice lacking 5-HT1BR expression also showed an overall increase in the choice of higher value rewards, increased hedonic responses to sweet rewards, and responded more for cues that predict reward. We developed a novel paradigm to demonstrate that increasing anticipated reward value could directly increase impulsive action. Furthermore, we found that 5-HT1BR KO-induced impulsivity could be ameliorated by decreasing the reward value relative to controls, suggesting that the increased 5-HT1BR-associated impulsive action may be a result of increased reward valuation. Conclusions Taken together, these data show that the effects of serotonin on impulsive action are mediated through the modulation of hedonic value, which may alter the reward representations that motivate action. Overall, this data supports a role for reward value as an important substrate in impulsive action which may drive clinically relevant increases in impulsivity.

Heritable variation in locomotion, reward sensitivity and impulsive behaviors in a genetically diverse inbred mouse panel

Drugs of abuse, including alcohol and stimulants like cocaine, produce effects that are subject to individual variability, and genetic variation accounts for at least a portion of those differences. Notably, research in both animal models and human subjects point towards reward sensitivity and impulsivity as being trait characteristics that predict relatively greater positive subjective responses to stimulant drugs. Here we describe use of the eight Collaborative Cross (CC) founder strains and multiple CC strains to examine the heritability of reward sensitivity and impulsivity traits, as well as genetic correlations between these measures and existing addiction-related phenotypes. Methods. Strains were all tested for activity in an open field and reward sensitivity (intake of chocolate BOOST®). Mice were then divided into two counterbalanced groups and underwent reversal learning (impulsive action and waiting impulsivity) or delay discounting (impulsive choice). Results. CC and founder mice demonstrate significant heritability for impulsive action, impulsive choice, waiting impulsivity, locomotor activity, and reward sensitivity, with each impulsive phenotype determined to be non-correlating, independent traits. This research was conducted within the broader, inter-laboratory effort of the Center for Systems Neurogenetics of Addiction (CSNA) to characterize CC and DO mice for multiple, cocaine abuse related traits. These data will facilitate the discovery of genetic correlations between predictive traits, which will then guide discovery of genes and genetic variants that contribute to addictive behaviors.

Inhibition of impulsive action by projection-defined prefrontal pyramidal neurons

The prefrontal cortex (PFC) plays a critical role in curbing impulsive behavior, but the underlying circuit mechanism remains incompletely understood. Here we show that a subset of dorsomedial PFC (dmPFC) layer 5 pyramidal neurons, which project to the subthalamic nucleus (STN) of the basal ganglia, play a key role in inhibiting impulsive responses in a go/no-go task. Projection-specific labeling and calcium imaging showed that the great majority of STN-projecting neurons were preferentially active in no-go trials when the mouse successfully withheld licking responses, but lateral hypothalamus (LH)-projecting neurons were more active in go trials with licking; visual cortex (V1)-projecting neurons showed only weak task-related activity. Optogenetic activation and inactivation of STN-projecting neurons reduced and increased inappropriate licking, respectively, partly through their direct innervation of the STN, but manipulating LH-projecting neurons had the opposite effects. These results identify a projection-defined subtype of PFC pyramidal neurons as key mediators of impulse control.