Orbitofrontal activation restores insight lost after cocaine use

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  • An Erratum to this article was published on 26 August 2014

Abstract

Addiction is characterized by a lack of insight into the likely outcomes of one's behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

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Figure 1: Experimental timeline, task design and recording sites for in vivo recording experiment.
Figure 2: Conditioned responding and cue-evoked activity summates at the start of compound training in sucrose-trained, but not cocaine-trained, rats.
Figure 3: Conditioned responding and cue-evoked activity spontaneously declined at the start of extinction training in sucrose-trained, but not cocaine-trained, rats.
Figure 4: Reduced excitatory transmission in OFC pyramidal neurons in cocaine-trained rats.
Figure 5: In vivo optogenetic activation of OFC neurons reverses the behavioral deficit in cocaine-trained rats.

Change history

  • 28 July 2014

    In the version of this article initially published, author Chun Yun Chang's name was given as Chun Chang. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors would like to thank K. Deisseroth (Stanford University) and the Gene Therapy Center at the University of North Carolina at Chapel Hill core for providing viral reagents, and B. Harvey of the NIDA Optogenetic and Transgenic Core for technical advice on their use. This work was supported by funding from the National Institute on Drug Abuse (NIDA). The opinions expressed in this article are the authors' own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Author information

F.L. and G.S. conceived the behavioral and single-unit experiments with input from Y.S. and Y.K.T., F.L. and C.R.L. conceived the slice physiology work with input from A.F.H. and F.L. carried out the experiments with assistance from Y.K.T., A.F.H., C.Y.C. and S.B.-C. F.L. analyzed the data with assistance from Y.K.T., A.F.H., C.R.L. and G.S. The manuscript was prepared by F.L. and G.S with input from the other authors.

Correspondence to Federica Lucantonio or Geoffrey Schoenbaum.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Self-administration, over-expectation training and phasic neural activity in rats designated for single unit recording.

a and b. Number of reinforcements (triangles) and responses on the active (filled circles) and inactive (open circles) lever during sucrose (a) (n = 12), and cocaine (b) (n = 8) self-administration. The two groups obtained similar amount of reinforcements, and sucrose rats executed more lever presses than rats self-administering cocaine because of more responses in the 40 second time out periods. ANOVA’s (session x lever) revealed significant lever by session interactions (cocaine: F(13, 91) = 2.92, p = 0.0014; sucrose: F(13, 143) = 6.13, p < 0.0001). Separate ANOVA’s also showed significant effects of session on the number of reinforcements in cocaine (F (13, 91) = 37.80, p ˂ 0.0001) and sucrose groups (F (13, 143) = 1.90, p = 0.034). Error bars = SEM. c and d. Plot illustrating increase in conditioned responding in sucrose (c), and in cocaine (d) trained rats. Lines indicate percentage of responding to each of the 4 cues during conditioning. Red diamond: A1, Blue square: A2, green circle: A3, yellow triangle: V. A 3-factor ANOVA (session X cue X reward comparing conditioned responding during cue presentation demonstrated significant main effects of both cue and session (cue: F(3, 64) = 11.42, p < 0.0001; session: F(11, 704) = 25.99, p < 0.0001), as well as a significant interaction between them (F(33, 704) = 5.27, p < 0.0001). However, there were neither significant main effects nor any interactions with reward (F's < 0.32, p's > 0.80). Post-hoc testing also showed that there were no differences in responding to A1 and A2 at any point in training in either group. e and f. Plot illustrating increase in proportions of neurons that were cue-responsive across sessions in sucrose (e), and in cocaine (f) trained rats. Bars indicate percentage of cue-responsive neurons within each pair of sessions. The proportion of neurons that increased firing (white) grew significantly across conditioning (chi-square test), whereas proportion of neurons that decreased firing (black) did not change. A 2-factor ANOVA (session X reward) comparing the number of cue-selective neurons across conditioning days demonstrated significant main effect of session (F (11, 198) = 10.06, p < 0.0001), but no significant main effect nor any interaction with reward (F's < 3.63, p's > 0. 08). In particular, in the sucrose group, cue-evoked activity was present in 20% of OFC neurons recorded in the first two sessions of conditioning. This included 8% that increased firing to at least one of 4 cues and 12.5% that suppressed firing. The proportion of neurons that showed a phasic increase in firing grew steadily across conditioning, reaching 50% by the last two conditioning sessions. In cocaine group, the scenario was similar: cue-evoked activity was present in 35% of OFC neurons recorded in the first two sessions of conditioning, including 10% of neurons that increased firing to at least one of 4 cues and 25% of neurons that suppressed firing, and the proportion of neurons that showed a phasic increase in firing grew across conditioning, reaching 45% by the last two conditioning sessions, a proportion similar to that seen in sucrose group. Interestingly, the proportion of neurons that suppressed firing did not change substantially as the rats learned across training sessions in either group. Thus, all subsequent analyses of associative encoding were conducted on the population of neurons that showed excitatory phasic responses to the cues. **p < 0.01, *p < 0.05.

Supplementary Figure 2 Distribution of baseline firing rates for OFC neurons recorded in sucrose- and cocaine-treated rats.

Distribution of baseline firing rates in the compound probe (a, b), and in the probe test (c, d). Baseline firing rates were calculated from activity in a 20 second period in the inter-trial interval. Black bars represent all neurons recorded during the session, while gray bars represent only cue-responsive neurons, calculated as previously described (see Figure S2b). The numbers in each panel indicate the average baseline firing rate for all recorded neurons (u, black) and for cue-responsive neurons (u, gray). There were no differences in baseline firing rates between groups in the compound probe and in the extinction probe test sessions (Mann Whitney U test, p’s>0.05).

Supplementary Figure 3 Conditioned responding and cue-evoked activity in the first trial of compound training in sucrose and cocaine group.

a and b. Conditioned responding as a percentage of time in the food cup during each of the 4 cues during the conditioning training (CP 1/2) and the first trial of compound training (1st CP2/2) in sucrose (a) and cocaine (b) groups. Red diamonds indicate A1 in CP 1/2 phase, and A1V in 1st trial of CP 2/2. Blue squares, green circles and yellow triangles indicate A2, A3 and V. * p < 0.05. Error bars = S.E.M. c-f. Population activity across all cue-responsive neurons to A1, V (c,d) and A2 (e,f) during the first trial of the compound probe session; dark and light lines illustrate activity during the conditioning and compound phases of the session, respectively. Gray shading indicates S.E.M, and gray bars indicate the period of cue presentation. Two-factor ANOVA’s (phase X reward) revealed significant effects of reward on the pattern of firing to A1 (F 1, 102 =4.5, p = 0.036) but not A2 (F 1, 102 = 0.98, p = 0.32). Subsequent analyses showed that this was because cocaine-trained rats did not exhibit the significant increase in firing to A1 observed in the sucrose group at the first trail of compound training (*; p < 0.05). g-j. Distribution of summation index scores for firing to A1 (g-i), and A2 (h-j) in the compound probe. The summation index was computed as the average normalized firing of each neuron in the first trial of the second half of the compound probe (CP 2/2) against firing in the first half (CP1/2) of the session. Black bars represent neurons in which the difference in firing was statistically significant (t-test, p < 0.05). The numbers in each panel indicate results of a Wilcoxon signed-rank test (p) on the distribution and the average summation index (u). In sucrose-trained rats, the distribution of the scores for A1 shifted significantly above zero and was significantly different from the unshifted distribution for A2 (Mann-Whitney U test, p’s < 0.01). A1 also differed significantly between groups (Mann-Whitney U test, p’s < 0.01). No shifts were observed in the scores from cocaine-trained rats. k and l. Scatter plots represent relationship between average normalized firing of each neuron to preferred cue in the 1st half and average normalized firing to A1V on the 1st trial in the 2nd half of the session. Distribution plots represent summation index calculated by average normalized firing to preferred cue in the 1st half and average normalized firing to A1V on the 1st trial in the 2nd half of the session.

Supplementary Figure 4 Cue-evoked activity of OFC neurons that showed decreased firing activity during cue presentation in the compound probe in sucrose and cocaine group.

a-d. Population activity to A1, V (a,b) and A2 (c,d) in the compound probe; dark and light lines illustrate activity during the conditioning and compound phases of the session, respectively. Gray shading indicates S.E.M, and gray bars indicate the period of cue presentation. Two-factor ANOVA’s (phase X reward) revealed no significant effects or interactions on the pattern of firing to A1 or A2 (p’s> 0.33). e-h. Distribution of summation index scores for firing to A1 (e-g), and A2 (f-h) in the compound probe. Index scores were computed for each neuron based on the change in mean normalized firing to the relevant cue between conditioning and compound training, using the following formula: (firing CP 2/2 – firing CP 1/2)/(firing CP 2/2 + firing CP 1/2). Black bars represent neurons in which the difference in firing was statistically significant (t-test, p < 0.05). The numbers in each panel indicate results of a Wilcoxon signed-rank test (p) on the distribution and the mean index (u). No shifts were observed in the scores from both sucrose- and cocaine-trained rats.

Supplementary Figure 5 Cue-evoked activity of neurons that showed decreased firing activity during cue presentation at the start of extinction training in sucrose and cocaine-trained rats.

a-d. Population activity to A1, V(a,b) and A2 (c,d) during the extinction probe session; light and dark lines illustrate activity during the compound phase and on the first trial (1T) of extinction during the session, respectively. Gray shading indicates S.E.M, and gray horizontal bars indicate the period of cue presentation. Two-factor ANOVA’s (phase X reward) revealed no significant effects or interactions on the pattern of firing to A1 or A2 (p’s > 0.41). e-h. Distribution of over-expectation index scores for firing to A1 (e, g) and A2 (f, h) in the extinction probe. Index scores were computed for each neuron based on the change in mean normalized firing to the relevant cue between compound training and the first trial of extinction, using the following formula: (firing PB 1T – firing PB 1/2)/(firing PB 1T + firing PB 1/2). Black bars represent neurons in which the difference in firing was statistically significant (t-test, p < 0.05). The numbers in each panel indicate results of a Wilcoxon signed-rank test (p) on the distribution and the mean index (u). No shifts were observed in the scores from sucrose- or cocaine-trained rats.

Supplementary Figure 6 Self-administration and over-expectation training in rats designated for in vitro experiments.

a and b. Number of reinforcements (triangles) and responses on the active (filled circles) and inactive (open circles) lever during sucrose (a) (N = 9), and cocaine (b) (N = 9) self-administration. The two groups obtained similar amount of reinforcements, and sucrose rats executed more lever presses than rats self-administering cocaine because of more responses in the 40 second time out periods. ANOVA’s (session x lever) revealed significant lever by session interactions (cocaine: F(13, 104) = 2.61, p = 0.0035; sucrose: F(13, 104) = 8.06, p < 0.0001). Separate ANOVA’s also showed significant effects of session on the number of reinforcements in cocaine (F (13, 104) = 30.54, p ˂ 0.0001) and sucrose groups (F (13, 104) = 2.33, p = 0.0092). Error bars = SEM. c and d. Percentage of responding to food cup during the cue presentation across 10 days of conditioning and compound training in sucrose (c), and cocaine (d) trained rats. Red diamonds, blue squares, green circles and yellow triangles indicate A1 or A1/V, A2, A3, and V, respectively. Error bars = SEM. There were neither main effects nor any interactions with reward during conditioning or compound training (F’s < 0.65; p’s > 0.23)..

Supplementary Figure 7 Cocaine self-administration and over-expectation training in rats designated for optogenetic experiments.

a and b. Number of reinforcements (triangles) and responses on the active (filled circles) and inactive (open circles) lever during cocaine self-administration, in ChR2 (a) (N = 9), and eYFP (b) (N = 8) groups. The two groups obtained similar amount of reinforcements. ANOVA’s (session x lever) revealed significant lever by session interactions (ChR2: F(13, 104) = 5.10, p ˂ 0.0001; eYFP: F(13, 91) = 3.28, p = 0.0004). Separate ANOVA’s also showed significant effects of session on the number of reinforcements in ChR2 (F (13, 104) = 7.90, p ˂ 0.0001) and eYFP groups (F (13, 91) = 11.55, p < 0.0001). Error bars = SEM. c and d. Percentage of responding to food cup during the cue presentation within each pair of sessions across 12 days of conditioning in ChR2 (a), and eYFP (b) group. Red diamonds, blue squares, green circles and yellow triangles indicate A1, A2, A3, and V, respectively. e and f. Percentage of responding to food cup during each of the 4 cues during the compound probe (CP) and 3 days of compound training (CP2 – CP4) in ChR2 (c), and e YFP (d) group. Red diamonds indicate A1 in CP 1/2 phase, and A1/V in CP 2/2 and CP2 – CP4 phases. Blue squares, green circles, and yellow triangles indicate A2, A3, and V, respectively. In both groups, light was delivered during presentation of A1/V in CP 2/2 and CP2 – CP4 phases. There were neither main effects nor any interactions with reward during conditioning or compound training (F’s < 1.03; p’s > 0.34). Error bars = SEM.

Supplementary Figure 8 In vivo optical stimulation of the OFC is not reinforcing.

a. Mean number of active and inactive lever presses within three consecutive 1-hour sessions in ChR2 (N = 10, blue) and EYFP (N = 7, red). ANOVA (session X lever X group) revealed neither main effects nor any interactions (F’s < 2.62, p’s > 0.13). Error bars = SEM.

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