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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

In vivo optogenetic activation of OFC neurons reverses thebehavioral deficit in cocaine-trained ratsa. Timeline for the optogenetic experiment. Approximately 3 weeks after theend of self-administration (7 weeks post-virus injection), rats were trained in aPavlovian over-expectation task illustrated in Figure1. b. Locations of cannula tracks in ChR2 (left) and eYFP (right)rats. c. left panel: approximate location (box) of confocal fluorescenceimage (right panel) showing expression of ChR2-eYFP (yellow) ~8 weeks after virusinjection into OFC in a representative brain slice. d. Sample traces (left)and mean data (right) of synaptic currents evoked by a 5–ms 473 nm light pulseinto the OFC in vitro, in AAV-CAMKII-ChR2-YFP (n = 4 cells) and AAV-CAMKII-YFP (n= 4 cells) injected rats. Light-evoked currents were only observed in theAAV-CAMKII-Chr2-YFP-injected group, and they were abolished by NBQX (10 μM), anAMPA\kainate receptor antagonist. Dashed lines represent time of initiation oflight stimulations. e–h. Conditioned responding incocaine-trained rats as a percentage of time in the food cup during each cue at the end ofcompound training (PB 1/2) and during the 8 trials of extinction (Trial 1–8 andbar graph showing means) in ChR2-CS (e), and eYFP-CS (f),ChR2-ITI (g), and eYFP-ITI (h) groups. Error bars indicateS.E.M., (*p < 0.05). Three-factor ANOVA’s (cue X trial X treatment)revealed significant interactions between treatment and cue for both CS (F 2,30 = 3.84, p = 0.032) and ITI stimulation (F 2, 30= 4.02, p = 0.028). Subsequent analyses showed that this was due tosignificant declines in responding to A1 when it was separated from V in ChR2 (*;p < 0.05) but not eYFP (ns) rats.
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Figure 5: In vivo optogenetic activation of OFC neurons reverses thebehavioral deficit in cocaine-trained ratsa. Timeline for the optogenetic experiment. Approximately 3 weeks after theend of self-administration (7 weeks post-virus injection), rats were trained in aPavlovian over-expectation task illustrated in Figure1. b. Locations of cannula tracks in ChR2 (left) and eYFP (right)rats. c. left panel: approximate location (box) of confocal fluorescenceimage (right panel) showing expression of ChR2-eYFP (yellow) ~8 weeks after virusinjection into OFC in a representative brain slice. d. Sample traces (left)and mean data (right) of synaptic currents evoked by a 5–ms 473 nm light pulseinto the OFC in vitro, in AAV-CAMKII-ChR2-YFP (n = 4 cells) and AAV-CAMKII-YFP (n= 4 cells) injected rats. Light-evoked currents were only observed in theAAV-CAMKII-Chr2-YFP-injected group, and they were abolished by NBQX (10 μM), anAMPA\kainate receptor antagonist. Dashed lines represent time of initiation oflight stimulations. e–h. Conditioned responding incocaine-trained rats as a percentage of time in the food cup during each cue at the end ofcompound training (PB 1/2) and during the 8 trials of extinction (Trial 1–8 andbar graph showing means) in ChR2-CS (e), and eYFP-CS (f),ChR2-ITI (g), and eYFP-ITI (h) groups. Error bars indicateS.E.M., (*p < 0.05). Three-factor ANOVA’s (cue X trial X treatment)revealed significant interactions between treatment and cue for both CS (F 2,30 = 3.84, p = 0.032) and ITI stimulation (F 2, 30= 4.02, p = 0.028). Subsequent analyses showed that this was due tosignificant declines in responding to A1 when it was separated from V in ChR2 (*;p < 0.05) but not eYFP (ns) rats.

Mentions: Previously we have shown that optogenetically inhibiting OFC activity during thecompound cue prevents learning 6. Giventhe reduction in the synaptic efficacy at pyramidal neurons in OFC, observed both in vivoand ex vivo in cocaine-trained rats, we conducted a final experiment to test whetherartificially activating OFC pyramidal neurons would restore normal learning incocaine-trained rats (Fig. 5a). Rats receivedbilateral infusions of either AAV-CaMKIIa-ChR2-eYPF (N = 9) or AAV-CaMKII-eYFP(control, N = 8) into the OFC and had fiber optic assemblies implanted immediatelyabove the injection sites. The CaMKII promoter was used to target cortical neurons withinthe OFC 24, 25; expression and light-dependent activation of OFC neurons was laterconfirmed using ex vivo recording (Fig.5c–d).


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)

In vivo optogenetic activation of OFC neurons reverses thebehavioral deficit in cocaine-trained ratsa. Timeline for the optogenetic experiment. Approximately 3 weeks after theend of self-administration (7 weeks post-virus injection), rats were trained in aPavlovian over-expectation task illustrated in Figure1. b. Locations of cannula tracks in ChR2 (left) and eYFP (right)rats. c. left panel: approximate location (box) of confocal fluorescenceimage (right panel) showing expression of ChR2-eYFP (yellow) ~8 weeks after virusinjection into OFC in a representative brain slice. d. Sample traces (left)and mean data (right) of synaptic currents evoked by a 5–ms 473 nm light pulseinto the OFC in vitro, in AAV-CAMKII-ChR2-YFP (n = 4 cells) and AAV-CAMKII-YFP (n= 4 cells) injected rats. Light-evoked currents were only observed in theAAV-CAMKII-Chr2-YFP-injected group, and they were abolished by NBQX (10 μM), anAMPA\kainate receptor antagonist. Dashed lines represent time of initiation oflight stimulations. e–h. Conditioned responding incocaine-trained rats as a percentage of time in the food cup during each cue at the end ofcompound training (PB 1/2) and during the 8 trials of extinction (Trial 1–8 andbar graph showing means) in ChR2-CS (e), and eYFP-CS (f),ChR2-ITI (g), and eYFP-ITI (h) groups. Error bars indicateS.E.M., (*p < 0.05). Three-factor ANOVA’s (cue X trial X treatment)revealed significant interactions between treatment and cue for both CS (F 2,30 = 3.84, p = 0.032) and ITI stimulation (F 2, 30= 4.02, p = 0.028). Subsequent analyses showed that this was due tosignificant declines in responding to A1 when it was separated from V in ChR2 (*;p < 0.05) but not eYFP (ns) rats.
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Figure 5: In vivo optogenetic activation of OFC neurons reverses thebehavioral deficit in cocaine-trained ratsa. Timeline for the optogenetic experiment. Approximately 3 weeks after theend of self-administration (7 weeks post-virus injection), rats were trained in aPavlovian over-expectation task illustrated in Figure1. b. Locations of cannula tracks in ChR2 (left) and eYFP (right)rats. c. left panel: approximate location (box) of confocal fluorescenceimage (right panel) showing expression of ChR2-eYFP (yellow) ~8 weeks after virusinjection into OFC in a representative brain slice. d. Sample traces (left)and mean data (right) of synaptic currents evoked by a 5–ms 473 nm light pulseinto the OFC in vitro, in AAV-CAMKII-ChR2-YFP (n = 4 cells) and AAV-CAMKII-YFP (n= 4 cells) injected rats. Light-evoked currents were only observed in theAAV-CAMKII-Chr2-YFP-injected group, and they were abolished by NBQX (10 μM), anAMPA\kainate receptor antagonist. Dashed lines represent time of initiation oflight stimulations. e–h. Conditioned responding incocaine-trained rats as a percentage of time in the food cup during each cue at the end ofcompound training (PB 1/2) and during the 8 trials of extinction (Trial 1–8 andbar graph showing means) in ChR2-CS (e), and eYFP-CS (f),ChR2-ITI (g), and eYFP-ITI (h) groups. Error bars indicateS.E.M., (*p < 0.05). Three-factor ANOVA’s (cue X trial X treatment)revealed significant interactions between treatment and cue for both CS (F 2,30 = 3.84, p = 0.032) and ITI stimulation (F 2, 30= 4.02, p = 0.028). Subsequent analyses showed that this was due tosignificant declines in responding to A1 when it was separated from V in ChR2 (*;p < 0.05) but not eYFP (ns) rats.
Mentions: Previously we have shown that optogenetically inhibiting OFC activity during thecompound cue prevents learning 6. Giventhe reduction in the synaptic efficacy at pyramidal neurons in OFC, observed both in vivoand ex vivo in cocaine-trained rats, we conducted a final experiment to test whetherartificially activating OFC pyramidal neurons would restore normal learning incocaine-trained rats (Fig. 5a). Rats receivedbilateral infusions of either AAV-CaMKIIa-ChR2-eYPF (N = 9) or AAV-CaMKII-eYFP(control, N = 8) into the OFC and had fiber optic assemblies implanted immediatelyabove the injection sites. The CaMKII promoter was used to target cortical neurons withinthe OFC 24, 25; expression and light-dependent activation of OFC neurons was laterconfirmed using ex vivo recording (Fig.5c–d).

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