Unilateral caudate inactivation increases motor impulsivity in rhesus monkeys

Abstract

Impulsivity, the tendency to react quickly and without consideration of consequences, is correlated with asymmetry in the volume of the caudate nucleus in human patients. In this study, we sought to determine whether the induction of functional asymmetry in the caudate nucleus of monkeys would produce phenomenologically comparable behavior. We found that unilateral suppression of the ventral caudate nucleus increases impulsive behavior in rhesus monkeys. Impulsivity was modeled by the subjects' inability to maintain hold of a touch-sensitive bar until presentation of an imperative signal. Two methods were used to suppress activity in the caudate region. First, muscimol was locally infused. Second, a viral construct expressing the hM₄Di DREADD (designer receptor exclusively activated by designer drug) was injected at the same site. Clozapine N-oxide and deschloroclozapine activate the DREADD to suppress neuronal activity. Both methods of suppression, pharmacological and chemogenetic, increased the rate of early bar releases, a behavior we interpret to indicate impulsivity. Thus, we demonstrate a causal relationship between caudate asymmetry and impulsivity.

Graphical abstract

Fig. 1

Reward-delay task (a) Task schematic: subjects initiated a trial by pressing a bar, and released the bar during one of two subsequent intervals to accept or reject the current offer indicated by the background cue (see Methods for details). (b) Set of cues used to indicate the reward and delay to reward available for completion of the trial.

Fig. 2

DREADD injection site Illustration of intended injection site for muscimol and DREADDs. Location of DREADD injection as identified by Gd/Mn in a post-virus injection MRI for Monkey F (a) and Monkey B(b). The larger region of hypersignal corresponding to virus injection for Monkey F is due to the greater concentration of the contrast agent injected, and is not representative of the comparative spread of the virus.

Fig. 3

Effect of muscimol on early errors, completed trials, reaction time and fixation errors Cumulative early errors by individual test sessions for Monkey B (a) and Monkey F (b) following a muscimol (blue) or vehicle (yellow) injection. Mean early errors as a percent of total trials for Monkey B (c) and Monkey F (d) for trial across sessions. Mean number of total trials per session for Monkey B (e) and Monkey F (f). Mean reaction time of bar release for correct trials for Monkey B (g) and Monkey F (h) following an injection of muscimol (blue) or vehicle (yellow). Mean fixation errors as a percent of total trials for Monkey B (i) and Monkey F(j). Error bars are s. e.m., (*) indicates significance of p < 0.05. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

Effect of DCZ and CNO on early errors, completed trials, reaction time and fixation errors Cumulative early errors by individual test sessions for Monkey B following DCZ (green) or vehicle injections (yellow) (a) and for Monkey F following CNO (red) or vehicle injections (yellow) (b). Mean early errors as a percent of total trials for Monkey B (c) and Monkey F (d). Mean number of total trials per session for Monkey B (e) and Monkey F (f). Mean reaction time of bar release for correct trials for Monkey B following DCZ (green) or vehicle injections (yellow) (g) and for Monkey F following CNO (red) or vehicle injections (h). Mean fixation errors as a percent of total trials for Monkey B (i) and Monkey F(j). Error bars are s. e.m., (*) indicates significance of p < 0.05. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)