Brief cognitive training interventions in young adulthood promote long-term resilience to drug-seeking behavior

Abstract

Environmental stress and deprivation increase vulnerability to substance use disorders in humans and promote drug-seeking behavior in animal models. In contrast, experiences of mastery and stability may shape neural circuitry in ways that build resilience to future challenges. Cognitive training offers a potential intervention for reducing vulnerability in the face of environmental stress or deprivation. Here, we test the hypothesis that brief cognitive training can promote long-term resilience to one measure of drug-seeking behavior, cocaine conditioned place preference (CPP), in mice. In young adulthood, mice underwent cognitive training, received rewards while exploring a training arena (i.e. yoked control), or remained in their home cages. Beginning 4 weeks after cessation of training, we conditioned mice in a CPP paradigm and then tested them weekly for CPP maintenance or daily for CPP extinction. We found that a brief 9-day cognitive training protocol reduced maintenance of cocaine CPP when compared to standard housed and yoked conditions. This beneficial effect persisted long after cessation of the training, as mice remained in their home cages for 4 weeks between training and cocaine exposure. When mice were tested for CPP on a daily extinction schedule, we found that all trained and yoked groups that left their home cages to receive rewards in a training arena showed significant extinction of CPP, while mice kept in standard housing for the same period did not extinguish CPP. These data suggest that in early adulthood, deprivation may confer vulnerability to drug-seeking behavior and that brief interventions may promote long-term resilience.

Keywords: Addiction; Cocaine; Cognitive training; Conditioned place preference; Resilience.

Conflict of interest statement

Disclosures

The authors declare no conflict of interest.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Fig. 1. Schematic of cognitive training paradigm

Each subfigure (A–I) shows 1 day of training, with 9 total days. The mouse is shown in the start compartment of the training arena. Digging pots are shown by filled rectangles (B–H) or filled circles (I). The digging pot containing an accessible cereal reward is indicated by a check mark and green color on the relevant exemplar, while incorrect choices are indicated by an “x” and red color on the relevant exemplar. Irrelevant exemplars are shown in gray. O1-12 refer to the 12 odors used to scent the digging medium; T1-8 refer to the 8 textures used to cover the digging pots. To control for odor, all texture pairs were of the same material with discriminable textures on opposing sides (e.g. sand paper, reverse sandpaper). The location of each odor/texture combination was pseudorandomized between trials. (A) Day 1 (habituation): mice were exposed to cereal pieces in the arena. (B) Day 2 (shaping): mice learned to dig in wood shavings for cereal rewards. (C) Day 3 (compound discrimination): 1 of 2 odors was rewarded, while 2 textures were irrelevant (20 trials). (D) Day 4 (overtraining): the same rule used on Day 3 was repeated for 30 additional trials. (E) Day 5 (reversal 1): the same odors/textures were used as on days 3 and 4. The rule used on days 3 and 4 was repeated for the first 10 trials, after which the opposite odor was rewarded for 40 trials. (F) Day 6 (intradimensional shift and reversal 2): for the first 20 trials, an odor-based rule was employed with 2 novel odors and 2 novel textures. For last 35 trials, the opposite odor was rewarded. (G) Day 7 (extradimensional shift, texture): a texture-based rule was employed with 2 novel odors and 2 novel textures (30 trials). (H) Day 8 (extradimensional shift, spatial): a spatial rule was employed with 2 novel odors and 2 novel textures. One location (i.e. the digging pot on the left side) was rewarded, regardless of odor and texture (25 trials). (I) Day 9 (4-choice discrimination and reversal 3): 4 novel odors were used. One odor was rewarded for the first 20 trials, and a different odor was rewarded for the last 25 trials.

Fig. 2. Schematic of experimental groups for Experiment 2

Mice are shown in the home cage (A) or in a training arena (B–D). Digging pots containing scented bedding are shown by filled rectangles. The digging pot containing an accessible cereal reward is indicated by a check mark and green color on the relevant exemplar, while incorrect choices are indicated by an “x” and red color on the relevant exemplar. Irrelevant exemplars are shown in gray. O1 and O2 refer to the 2 odors used to scent the digging medium; T1 and T2 refer to the 2 textures used to cover the digging pots. To control for odor, texture pairs were of the same material with discriminable textures on opposing sides (e.g. velvet, reverse velvet). (A) Standard Housed (SH) mice remained in their home cages with no training or cereal rewards. (B) Each yoked mouse was paired with one mouse that underwent single rule training (SRT). The yoked mouse explored an identical arena adjacent to the SRT mouse and received a cereal reward each time the SRT mouse earned a cereal reward. (C) On days 1–3 of training, single rule trained (SRT) mice underwent habituation, shaping, and compound discrimination (CD) as described in Fig. 1A–C. On days 4–9 of training, SRT mice repeated the compound discrimination task with no rule changes. The location of each odor/texture combination was pseudorandomized between trials. (D) Trained mice underwent the same procedures shown in Fig. 1A–I, including set-shifts and reversals. The location of each odor/texture combination was pseudorandomized between trials.

Fig. 3. Cognitive training reduces maintenance of cocaine CPP without altering locomotor sensitization or initial CPP levels

(A) Experiment timeline. “Cog. train.” is cognitive training, “Hab. & cond.” is habituation and conditioning (i.e. habituation to CPP chambers followed by cocaine conditioning, see Methods 2.3.4). Mice were ages p55–p77 at the start of cognitive training (day 0 on the timeline). (B) Cognitive training did not alter locomotor activity recorded during 15-minute sessions after saline injections. N=11 trained mice (1 mouse excluded due to equipment failure), N=9 yoked to trained (YT) mice, N=9 standard housed (SH) mice. (C) Cognitive training did not alter locomotor activity recorded during 15-minute sessions after cocaine injections. All groups showed increased locomotor activity across successive cocaine injections, consistent with sensitization. N=12 trained mice, N=9 YT mice, N=9 SH mice. (D) Cognitive training did not alter the initial establishment of cocaine CPP, as measured by seconds in the cocaine-paired chamber minus seconds in the saline-paired chamber. CPP is shown before and after cocaine conditioning (i.e. on habituation day and on test day 1). N=12 trained mice, N=9 YT mice, N=9 SH mice. (E) Cognitive training reduced maintenance of CPP over a 28-day testing period. CPP values on test days were normalized to each mouse’s CPP value on habituation day. N=12 trained, N=9 YT mice, N=9 SH mice. *p<0.05; **p<0.01 for trained compared to YT or SH animals. #p<0.05 for YT compared to SH animals. All bars represent means; all error bars represent SEM.

Fig. 4. Trained and yoked mice show extinction of CPP, while standard housed mice show no extinction of CPP

(A) Experimental timeline. “Hab. & cond.” is habituation and conditioning (i.e. habituation to CPP chambers followed by cocaine conditioning). (B) Cognitive training did not alter locomotor activity recorded during 15-minute sessions after saline injections. “SH” is standard housed. “SRT” is single rule trained. “YS” is yoked to single rule trained. N=6 SH mice, N=10 YS mice, N=10 SRT mice, N=7 trained mice. (C) Cognitive training did not alter locomotor activity recorded during 15-minute sessions after cocaine injections. All groups showed increased locomotor activity with successive cocaine injections, consistent with sensitization. N=6 SH mice, N=10 YS mice, N=10 SRT mice, N=7 trained mice. (D) Cognitive training did not alter the initial establishment of cocaine CPP, as measured by seconds in the cocaine-paired chamber minus seconds in the saline-paired chamber. CPP is shown before and after cocaine conditioning (i.e. on habituation day and on test day 1). N=6 SH mice, N=10 YS mice, N=10 SRT mice, N=7 trained mice. (E) Trained, SRT, and YS animals showed significant within-group reductions in CPP across the 11-day CPP extinction period, while SH animals showed no reduction in CPP. Statistics for within-group comparisons across time are shown in H. N=6 SH mice, N=10 YS mice, N=10 SRT mice, N=7 trained mice (F) Cognitive training did not affect reinstatement, as measured by CPP on reinstatement day minus CPP on habituation day. N=6 SH mice, N=10 YS mice, N=9 SRT mice (1 outlier excluded), N=7 trained mice. (G) Cognitive training did not affect reinstatement, as measured by CPP on reinstatement day minus CPP on test day 11. N=6 SH mice, N=10 YS mice, N=9 SRT mice (1 outlier excluded), N=7 trained mice. (H) Trained, SRT, and YS animals showed extinction of CPP, as evidenced by significant reductions in CPP from day 1 to later test days. SH animals did not show extinction of CPP. Asterisks indicate significance levels for Holm-Sidak adjusted p values. N=6 SH mice, N=10 YS mice, N=10 SRT mice, N=7 trained mice. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. All bars represent means; all error bars represent SEM.