A novel strategy for dissecting goal-directed action and arousal components of motivated behavior with a progressive hold-down task

Abstract

Motivation serves 2 important functions: It guides actions to be goal-directed, and it provides the energy and vigor required to perform the work necessary to meet those goals. Dissociating these 2 processes with existing behavioral assays has been a challenge. In this article, we report a novel experimental strategy to distinguish the 2 processes in mice. First, we characterize a novel motivation assay in which animals must hold down a lever for progressively longer intervals to earn each subsequent reward; we call this the progressive hold-down (PHD) task. We find that performance on the PHD task is sensitive to both food deprivation level and reward value. Next, we use a dose of methamphetamine (METH) 1.0 mg/kg, to evaluate behavior in both the progressive ratio (PR) and PHD tasks. Treatment with METH leads to more persistent lever pressing for food rewards in the PR. In the PHD task, we found that METH increased arousal, which leads to numerous bouts of hyperactive responding but neither increases nor impairs goal-directed action. The results demonstrate that these tools enable a more precise understanding of the underlying processes being altered in manipulations that alter motivated behavior.

Figure 1

Relationship between Progressive Ratio performance and locomotor activity. Data for both PR performance and locomotor activity is expressed as a log ratio of treatment condition (transgenic or drug treated) divided by control condition (Wildtype or Vehicle), [e.g. log(DAT KD PR performance/WT PR performance)]. (Bold = genetic manipulation; Italics = pharmacological manipulation). Data for PR performance re-plotted from: DAT KD (Cagniard et al., 2006), SERT KD (Sanders et al., 2007), Fluoxetine (Sanders et al., 2007), Amphetamine (Mayorga et al., 2000), D2R-OE (Simpson et al., 2011), Haloperidol (Aberman et al., 1998), Raclopride (Aberman et al., 1998), MSX-3 (Randall et al., 2012). Data for locomotor activity re-plotted from: DAT KD (Zhuang et al., 2001), SERT KD (Sanders et al., 2007), Fluoxetine (Sanders et al., 2007), Amphetamine (Hall et al., 2008), D2R-OE (Kellendonk et al., 2006), Haloperidol (Simón et al., 2000), Raclopride (Simón et al., 2000), MSX-3 (Antoniou et al., 2005).

Figure 2

Characterization of baseline behavior in the PHD task. (A) Representative performance of pressing for a single subject throughout an single PHD session. Shows both successful presses (orange) and unsuccessful presses (green). (B–C) There is a positive linear relationship between the number of presses made on the correct lever (B) and session duration (C) with the number of rewards earned. In (B–C) each point represents a single subject’s average over 5 days of baseline PHD testing.

Figure 3

Food Restriction effects on PHD task performance. (A) Mean (± SEM) lever presses in the PHD task under ad lib and restricted feeding conditions. (B) Mean (± SEM) number of rewards earned in the PHD task under ad lib and restricted feeding conditions. (C) Mean (± SEM) duration (sec) of all lever presses longer than 2 seconds under ad lib and restricted feeding conditions. (D) Mean (± SEM) number of lever presses made which were shorter than 2 sec under ad lib and restricted feeding conditions. In (A–D) each point represents a subjects performance averaged over 3 days of Ad Lib and restricted feeding conditions. ^**p < .01.

Figure 4

Reward value effects on PHD performance. (A) Mean (± SEM) number of lever presses for different sucrose concentrations in the PHD task; Tukey’s HSD test. (B) Mean (± SEM) number of rewards earned for different sucrose concentrations in the PHD task; Tukey’s HSD test. (C) Mean (± SEM) duration (sec) of all lever presses longer than 2 seconds for different sucrose concentrations in the PHD task; Tukey’s HSD test. (D) Mean (± SEM) number of lever presses made which were shorter than 2 sec for different sucrose concentrations in the PHD task. In (A–D) each point represents a subjects performance averaged over 2 days of PHD testing at each sucrose concentration. **p < .01.

Figure 5

Methamphetamine increases responding in a PR. (A) Relationship between number of presses required and reward number for the PR 4 × 1.18 schedule. (B) Mean (± SEM) number of lever presses in the PR. (C) Mean (± SEM) number of rewards earned in the PR. (D) Mean (+ SEM) press rate (responses/min) in the PR. For (B – D) each point represents a single subject’s performance averaged over 4 days of vehicle or METH treatment. **p < .01.

Figure 6

Methamphetamine increases amount lever pressing in the PHD task. (A) Shows a representative press record of the first 100 presses for a single subject tested on the PHD task following treatment with vehicle (white) and METH (grey). (B) Mean (± SEM) number of lever presses on the correct lever. (C) Mean (± SEM), number of rewards earned. (D) Mean (± SEM) duration (sec) of all lever presses longer than 2 seconds. (E–F) There is a significant positive relationship between the number of presses and the number of rewards earned during vehicle treatment (E), whereas there is a significant negative relationship between these measures during METH treatment (F). (G) Shows the distribution of the durations of unsuccessful holds, Mean (± SEM). (G) Mean (± SEM) number of lever presses made which were shorter than 2 seconds. In (B–E, G) each point represents a single subject’s performance averaged across 4 days of each treatment condition. **p < .01.

Figure 7

Methamphetamine increases hyperactive responses in the PHD task. (A) The mean (± SEM) efficiency (proportion of successful responses on the active lever until the last rewarded press). (B) Mean efficiency as a function of the required hold duration (sec) in the PHD session. (C) Mean time (sec) it takes subjects to complete a required hold duration (sec). (D–E) The mean cumulative number of failed presses on the active and inactive lever as a function of the trial number during vehicle (D) and METH (E) treatment. (F) The Mean (± SEM) difference in the number of trials between the first failed press on the active lever and the first press on the inactive lever. In (A, F) each point represents a single subject’s performance averaged across the 4 days of each treatment condition. In (B–C), each point represents the treatment condition average of all subjects at each given hold requirement. In (D–E), each point represents the treatment condition average of all subjects for each trial number. ** p < .01.