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Orbitofrontal activation restores insight lost after cocaine use.

Lucantonio F, Takahashi YK, Hoffman AF, Chang CY, Bali-Chaudhary S, Shaham Y, Lupica CR, Schoenbaum G - Nat. Neurosci. (2014)

Bottom Line: 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.As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

View Article: PubMed Central - PubMed

Affiliation: 1] National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland, USA. [2] Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

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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Related in: MedlinePlus

Conditioned responding and cue-evoked activity summates at the start of compoundtraining in sucrose but not cocaine-trained ratsa–b. Conditioned responding in sucrose (a)and cocaine-trained (b) rats at the end of conditioning (CP 1/2) and throughcompound training (CP 2/2 and CP2-CP4). Error bars indicate S.E.M. A 3-factor ANOVA (cue Xphase X treatment) showed a significant interaction between treatment, cue and phase (F1, 18 = 16.7, p = 0.0007), due to a significant increase inresponding to A1 when it was paired with V in sucrose (*; p < 0.05) but notcocaine-trained (ns) rats. c–f. Population activityacross all cue-responsive neurons to A1, V (c, d) and A2 (e, f)during the compound probe session; dark and light lines illustrate activity during theconditioning and compound phases of the session, respectively. Gray shading indicatesS.E.M, and gray horizontal bars indicate the period of cue presentation. Two-factorANOVA’s (treatment X phase) showed significant effects of treatment on the patternof firing to A1 (F 1, 102 = 7.9, p = 0.0059) but not A2 (F1, 102 = 1.17, p = 0.28), due to a significant increase infiring to A1 in the sucrose but not the cocaine group at the start of compound training(*; p < 0.05). g–j. Distribution of summationindex scores for firing to A1 (g, i) and A2 (h, j) in thecompound probe. Index scores were computed for each neuron based on the change in meannormalized firing to the relevant cue between conditioning and compound training, usingthe 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 wasstatistically significant (t-test, p < 0.05). In sucrose-trained rats, the distributionof the scores for A1 shifted significantly above zero and was significantly different fromthe unshifted distribution for A2; A1 also differed significantly between groups(Mann-Whitney U test, p’s < 0.01). No shifts were observed in the scores fromcocaine-trained rats. k–l. Scatter plots showingrelationship between the change in behavior and neural activity to A1 in the compoundprobe session. Neural summation index scores were computed for firing to A1 as describedabove; behavioral summation index scores were computed similarly, for each session inwhich a cue-responsive neuron was recorded, but using conditioned responding instead offiring. Neural summation was correlated with behavioral summation in sucrose(k) but not cocaine-trained (l) rats.m–n. Line plots showing the ratio between normalizedfiring to A1 and A2 during each compound training session (CP – CP4). N’sindicate number of cue-responsive neurons in each session. Error bars indicate S.E.M. A2-factor ANOVA revealed a significant effect of treatment on the A1/A2 ratios (F 4,412 = 13.8, p < 0.0001), which increased significantly in the compoundphase of the probe and then gradually decreased in sucrose (m) but notcocaine-trained rats (n). A similar effect was evident across trials withinthe compound probe session (inset, F 5,505 = 2.4, p = 0.036).*p < 0.05.
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Figure 2: Conditioned responding and cue-evoked activity summates at the start of compoundtraining in sucrose but not cocaine-trained ratsa–b. Conditioned responding in sucrose (a)and cocaine-trained (b) rats at the end of conditioning (CP 1/2) and throughcompound training (CP 2/2 and CP2-CP4). Error bars indicate S.E.M. A 3-factor ANOVA (cue Xphase X treatment) showed a significant interaction between treatment, cue and phase (F1, 18 = 16.7, p = 0.0007), due to a significant increase inresponding to A1 when it was paired with V in sucrose (*; p < 0.05) but notcocaine-trained (ns) rats. c–f. Population activityacross all cue-responsive neurons to A1, V (c, d) and A2 (e, f)during the compound probe session; dark and light lines illustrate activity during theconditioning and compound phases of the session, respectively. Gray shading indicatesS.E.M, and gray horizontal bars indicate the period of cue presentation. Two-factorANOVA’s (treatment X phase) showed significant effects of treatment on the patternof firing to A1 (F 1, 102 = 7.9, p = 0.0059) but not A2 (F1, 102 = 1.17, p = 0.28), due to a significant increase infiring to A1 in the sucrose but not the cocaine group at the start of compound training(*; p < 0.05). g–j. Distribution of summationindex scores for firing to A1 (g, i) and A2 (h, j) in thecompound probe. Index scores were computed for each neuron based on the change in meannormalized firing to the relevant cue between conditioning and compound training, usingthe 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 wasstatistically significant (t-test, p < 0.05). In sucrose-trained rats, the distributionof the scores for A1 shifted significantly above zero and was significantly different fromthe unshifted distribution for A2; A1 also differed significantly between groups(Mann-Whitney U test, p’s < 0.01). No shifts were observed in the scores fromcocaine-trained rats. k–l. Scatter plots showingrelationship between the change in behavior and neural activity to A1 in the compoundprobe session. Neural summation index scores were computed for firing to A1 as describedabove; behavioral summation index scores were computed similarly, for each session inwhich a cue-responsive neuron was recorded, but using conditioned responding instead offiring. Neural summation was correlated with behavioral summation in sucrose(k) but not cocaine-trained (l) rats.m–n. Line plots showing the ratio between normalizedfiring to A1 and A2 during each compound training session (CP – CP4). N’sindicate number of cue-responsive neurons in each session. Error bars indicate S.E.M. A2-factor ANOVA revealed a significant effect of treatment on the A1/A2 ratios (F 4,412 = 13.8, p < 0.0001), which increased significantly in the compoundphase of the probe and then gradually decreased in sucrose (m) but notcocaine-trained rats (n). A similar effect was evident across trials withinthe compound probe session (inset, F 5,505 = 2.4, p = 0.036).*p < 0.05.

Mentions: At the end of conditioning, rats were trained in a compound probe session (CP inFig. 1a). This session consisted of additionalconditioning (CP 1/2) followed by compound training (CP 2/2), in which A1 and V werepresented concurrently (A1V) followed by the same reward as in initial conditioning. A2,A3 and V were presented individually throughout compound training, followed by the samereward, as in initial conditioning. The sucrose-trained rats showed a significant increasein responding to A1 when it was presented in compound with V (Fig. 2a). The increase was evident over the entire session, andalso when only the first trial of compound training was considered (Fig. S3a). This effect was not evident incocaine-trained rats, which responded the same amount to A1 alone and in compound with V(Figs. 2b and S3b). Notably, the increased responding to theA1V compound cue in the sucrose-trained group was specific to the compound cue; neithergroup showed any change in responding to the A2 control cue between the two phases.


Orbitofrontal activation restores insight lost after cocaine use.

Lucantonio F, Takahashi YK, Hoffman AF, Chang CY, Bali-Chaudhary S, Shaham Y, Lupica CR, Schoenbaum G - Nat. Neurosci. (2014)

Conditioned responding and cue-evoked activity summates at the start of compoundtraining in sucrose but not cocaine-trained ratsa–b. Conditioned responding in sucrose (a)and cocaine-trained (b) rats at the end of conditioning (CP 1/2) and throughcompound training (CP 2/2 and CP2-CP4). Error bars indicate S.E.M. A 3-factor ANOVA (cue Xphase X treatment) showed a significant interaction between treatment, cue and phase (F1, 18 = 16.7, p = 0.0007), due to a significant increase inresponding to A1 when it was paired with V in sucrose (*; p < 0.05) but notcocaine-trained (ns) rats. c–f. Population activityacross all cue-responsive neurons to A1, V (c, d) and A2 (e, f)during the compound probe session; dark and light lines illustrate activity during theconditioning and compound phases of the session, respectively. Gray shading indicatesS.E.M, and gray horizontal bars indicate the period of cue presentation. Two-factorANOVA’s (treatment X phase) showed significant effects of treatment on the patternof firing to A1 (F 1, 102 = 7.9, p = 0.0059) but not A2 (F1, 102 = 1.17, p = 0.28), due to a significant increase infiring to A1 in the sucrose but not the cocaine group at the start of compound training(*; p < 0.05). g–j. Distribution of summationindex scores for firing to A1 (g, i) and A2 (h, j) in thecompound probe. Index scores were computed for each neuron based on the change in meannormalized firing to the relevant cue between conditioning and compound training, usingthe 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 wasstatistically significant (t-test, p < 0.05). In sucrose-trained rats, the distributionof the scores for A1 shifted significantly above zero and was significantly different fromthe unshifted distribution for A2; A1 also differed significantly between groups(Mann-Whitney U test, p’s < 0.01). No shifts were observed in the scores fromcocaine-trained rats. k–l. Scatter plots showingrelationship between the change in behavior and neural activity to A1 in the compoundprobe session. Neural summation index scores were computed for firing to A1 as describedabove; behavioral summation index scores were computed similarly, for each session inwhich a cue-responsive neuron was recorded, but using conditioned responding instead offiring. Neural summation was correlated with behavioral summation in sucrose(k) but not cocaine-trained (l) rats.m–n. Line plots showing the ratio between normalizedfiring to A1 and A2 during each compound training session (CP – CP4). N’sindicate number of cue-responsive neurons in each session. Error bars indicate S.E.M. A2-factor ANOVA revealed a significant effect of treatment on the A1/A2 ratios (F 4,412 = 13.8, p < 0.0001), which increased significantly in the compoundphase of the probe and then gradually decreased in sucrose (m) but notcocaine-trained rats (n). A similar effect was evident across trials withinthe compound probe session (inset, F 5,505 = 2.4, p = 0.036).*p < 0.05.
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Figure 2: Conditioned responding and cue-evoked activity summates at the start of compoundtraining in sucrose but not cocaine-trained ratsa–b. Conditioned responding in sucrose (a)and cocaine-trained (b) rats at the end of conditioning (CP 1/2) and throughcompound training (CP 2/2 and CP2-CP4). Error bars indicate S.E.M. A 3-factor ANOVA (cue Xphase X treatment) showed a significant interaction between treatment, cue and phase (F1, 18 = 16.7, p = 0.0007), due to a significant increase inresponding to A1 when it was paired with V in sucrose (*; p < 0.05) but notcocaine-trained (ns) rats. c–f. Population activityacross all cue-responsive neurons to A1, V (c, d) and A2 (e, f)during the compound probe session; dark and light lines illustrate activity during theconditioning and compound phases of the session, respectively. Gray shading indicatesS.E.M, and gray horizontal bars indicate the period of cue presentation. Two-factorANOVA’s (treatment X phase) showed significant effects of treatment on the patternof firing to A1 (F 1, 102 = 7.9, p = 0.0059) but not A2 (F1, 102 = 1.17, p = 0.28), due to a significant increase infiring to A1 in the sucrose but not the cocaine group at the start of compound training(*; p < 0.05). g–j. Distribution of summationindex scores for firing to A1 (g, i) and A2 (h, j) in thecompound probe. Index scores were computed for each neuron based on the change in meannormalized firing to the relevant cue between conditioning and compound training, usingthe 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 wasstatistically significant (t-test, p < 0.05). In sucrose-trained rats, the distributionof the scores for A1 shifted significantly above zero and was significantly different fromthe unshifted distribution for A2; A1 also differed significantly between groups(Mann-Whitney U test, p’s < 0.01). No shifts were observed in the scores fromcocaine-trained rats. k–l. Scatter plots showingrelationship between the change in behavior and neural activity to A1 in the compoundprobe session. Neural summation index scores were computed for firing to A1 as describedabove; behavioral summation index scores were computed similarly, for each session inwhich a cue-responsive neuron was recorded, but using conditioned responding instead offiring. Neural summation was correlated with behavioral summation in sucrose(k) but not cocaine-trained (l) rats.m–n. Line plots showing the ratio between normalizedfiring to A1 and A2 during each compound training session (CP – CP4). N’sindicate number of cue-responsive neurons in each session. Error bars indicate S.E.M. A2-factor ANOVA revealed a significant effect of treatment on the A1/A2 ratios (F 4,412 = 13.8, p < 0.0001), which increased significantly in the compoundphase of the probe and then gradually decreased in sucrose (m) but notcocaine-trained rats (n). A similar effect was evident across trials withinthe compound probe session (inset, F 5,505 = 2.4, p = 0.036).*p < 0.05.
Mentions: At the end of conditioning, rats were trained in a compound probe session (CP inFig. 1a). This session consisted of additionalconditioning (CP 1/2) followed by compound training (CP 2/2), in which A1 and V werepresented concurrently (A1V) followed by the same reward as in initial conditioning. A2,A3 and V were presented individually throughout compound training, followed by the samereward, as in initial conditioning. The sucrose-trained rats showed a significant increasein responding to A1 when it was presented in compound with V (Fig. 2a). The increase was evident over the entire session, andalso when only the first trial of compound training was considered (Fig. S3a). This effect was not evident incocaine-trained rats, which responded the same amount to A1 alone and in compound with V(Figs. 2b and S3b). Notably, the increased responding to theA1V compound cue in the sucrose-trained group was specific to the compound cue; neithergroup showed any change in responding to the A2 control cue between the two phases.

Bottom Line: 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.As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

View Article: PubMed Central - PubMed

Affiliation: 1] National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland, USA. [2] Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

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.

Show MeSH
Related in: MedlinePlus