Replicability in measures of attentional set-shifting task performance predicting chronic heavy drinking in rhesus monkeys

Highlights

• The improvement in performance on a self-pacing attentional set-shifting task was replicated in a separate cohort of rhesus monkeys, demonstrating that acquiring proficiency in the task is a stable feature of this population of monkeys.

• Future categorical drinking levels were robustly predicted by rate of improvement on the set-shifting task in a replicate cohort.

• When cohorts were combined, low rates of performance improvement robustly predicted future status as a chronic heavy alcohol drinker.

Abstract

This study was designed to replicate and extend a previous report that the increase in performance of an attentional set-shifting task (ASST) in rhesus monkeys predicted their future alcohol drinking status as a heavy drinker (HD) or non-heavy drinker (NHD). A cohort of 6 young adult male monkeys was trained and tested under the same ASST and then underwent a alcohol self-administration protocol that maintained open-access (22 hours/day) choice of alcohol or water 7 days/week for approximately 6 months. The average improvement in performance in the ASST, as measured by a performance index, was replicated in the cohort of 6 monkeys when compared to the increase in the task performance in a previous cohort of 9 male monkeys. The alcohol self-administration protocol was then used to determine the drinking status (HD: n = 4 or NHD: n = 2) of the replicate cohort, which was accurately predicted by the performance on the ASST. Finally, individuals from both cohorts could be combined based on future drinking status of HD (n = 8) or NHD (n = 7), and the association with pre-alcohol ASST performance remained. Specifically, monkeys that had lower rates of PI improvement were more likely to become HDs. To our knowledge, this is the first study to replicate that deficits in the set-shifting performance can predict chronic heavy alcohol drinking in primates.

Introduction

The Attentional Set-Shifting Task (ASST) is a variant of the Wisconsin Card Sorting Task that reflects sensory-motor and associative processes and has been used to assess behavioral flexibility (Brown & Tait, 2016; Miyake et al., 2000; Nyhus & Barceló, 2009). The wide use of this procedure across many species, (including rodents, non-human primates, and humans) provides an opportunity for identifying fundamental mechanisms of control over repetitive behavioral patterns that are integral to many public health problems, such as addiction and obsessive-compulsive disorders (for example, Kim et al., 2017).

A novel ASST was developed to identify individual differences in behavioral flexibility of rhesus monkeys (Shnitko, Allen, Gonzales, Walter, & Grant, 2017). This ASST task is based on a visual discrimination of one of two geometrical objects presented on a touchscreen. Subjects advance at their own pace through a sequence of up to eight sets, with sets differentiated on intra-dimensional, extra-dimensional, and reversal shifts in the correct choice (Shnitko et al., 2017). Uniquely, all monkeys housed in the same room (i.e., a cohort) are presented with the task in their housing cages at the same time. Each session began with a simple discrimination regardless of the performance during the previous session. This approach minimizes differential training across individuals but increases task-extraneous stimuli primarily from viewing and hearing other monkeys engaging in the task. The application of the ASST in rhesus monkeys revealed rates of improvement in the performance over 30 consecutive sessions and predicted future chronic alcohol drinking status (Shnitko, Gonzales, & Grant, 2019; cohort 14). Specifically, low rates of performance improvement (slopes <2.4) were significantly associated with future status as a heavy drinker.

Chronic heavy drinking is defined as >20% of days with 22-hour access to alcohol or water, consuming more than 3.0 g/kg of alcohol per day (Baker, Farro, Gonzales, Helms, & Grant, 2014). This definition was derived using a mathematical modeling approach and applied to the pattern of alcohol drinking in daily 22-hour sessions, over 12 consecutive months of daily sessions from 31 monkeys from 4 cohorts 6–12 (Baker et al., 2014) and confirmed with subsequent cohorts (Baker et al., 2017; Moore et al., 2019). Ultimately, the ability to use the ASST and alcohol self-administration protocols to identify brain circuity underlying the risk for heavy drinking with in vivo brain imaging or genomic measures of brain function requires a large population of subjects characterized under standard conditions. A key aspect of adding subjects is showing the reliability of the measures within and across cohorts over time. Therefore, the object of this study was to assess the reliability of performance on the novel ASST itself and in predicting future heavy drinking in a new cohort of monkeys.