Abstract

A critical area of inquiry in the neurobiology of alcohol abuse is the mechanisms by which cues gain the ability to elicit alcohol use. Previously, we found that cue-evoked activity in rat ventral pallidum (VP) robustly encodes the value of sucrose cues trained under both Pavlovian and instrumental contingencies, despite a stronger relationship between cue-evoked activity and behavioral latency after instrumental training (Richard et al., 2018). Here, we assessed 1) VP representations of Pavlovian versus instrumental cues trained with alcohol reward, and 2) the impact of non-associative alcohol exposure on VP representations of sucrose cues. Decoding of cue identity based on VP firing was blunted for the Pavlovian alcohol cue in comparison to both the instrumental cue trained with alcohol and either cue type trained with sucrose. Further, non-associative alcohol exposure had opposing effects on VP encoding of sucrose cues trained on instrumental versus Pavlovian associations, enhancing decoding accuracy for an instrumental discriminative stimulus and reducing decoding accuracy for a Pavlovian conditioned stimulus. These findings suggest that alcohol exposure can drive biased engagement of specific reward-related signals in the VP.


  • POST-PUBLICATION REVIEW
  • pre-publication peer review (FINAL ROUND)
    Decision Letter
    2019/07/15

    EJN-2019-04-26338.R1 Recruitment and disruption of ventral pallidal cue encoding during alcohol seeking

    Dear Dr. Richard,

    We are pleased to inform you that your manuscript has been accepted for publication in EJN. Please communicate directly with the office about the minor corrections for Figure 5 (see comment below from the reviewer).

    'Only one minor point - in the new Fig. 5 the top pie charts are not aligned with the bottom pie charts (in 5E the bottom chart seems off to the right, in 5F they seem off to the left). Also the numbers in 5E (11% and 15%) could be moved a bit to make them clearer. '

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    Reviewer report
    2019/06/30

    The authors have addressed most of my concerns. I agree that some of the points I raised will be better addressed as separate full studies (associative vs non-associative effects of alcohol on VP activity, males vs females, etc.) and I hope the authors will address them in the future.

    Only one minor point - in the new Fig. 5 the top pie charts are not aligned with the bottom pie charts (in 5E the bottom chart seems off to the right, in 5F they seem off to the left). Also the numbers in 5E (11% and 15%) could be moved a bit to make them clearer.

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  • pre-publication peer review (ROUND 1)
    Decision Letter
    2019/05/24

    Manuscript Number:EJN-2019-04-26338 Recruitment and disruption of ventral pallidal cue encoding during alcohol seeking

    Dear Dr. Richard,

    Your manuscript has been reviewed by two external reviewers as well as by the Section Editor, Dr. Serge Schiffmann, and ourselves.

    As you can see below, the reviewers found your study and findings to be very interesting but both identified a number of issues and questions that will need to be addressed in a revised version of the manuscript. To tackle their concerns, we consider that a successful revision will require to present more accurately the results by showing some additional data as behavioural data for the non-associative alcohol exposure task or from a group of alcohol reward but without pre-exposure to alcohol. Please carefully respond to each of the points that they have raised.

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    Reviews:

    Reviewer: 1

    Comments to the Author I’ll start with this – I love the recent body of work by the Janak group trying to understand how ventral pallidum (VP) firing dynamics may be linked to the encoding of reward-seeking behavior. The current manuscript is an extension of this work, examining how alcohol affects VP encoding of instrumental vs Pavlovian cues. They show that alcohol pre-exposure impairs the ability of VP firing to predict cue identity in a Pavlovian but not instrumental task when the reward is sucrose. They also show that when the reward itself is alcohol (after pre-exposure to alcohol), prediction of cue identity by VP firing is effective in the instrumental task and not the Pavlovian task. The work is of high technical quality, complies with author guidelines and is relevant to the scope of EJN. As their previous papers, I think this is an interesting work and I definitely recommend it for publication. Having said that (no manuscript is perfect, you know :-) ), there are several points that I am still curious about that could potentially add to the general message of this paper, especially in light of the previous work from this group.

    1) The main question I still don’t know the answer to is whether the differences between VP encoding of instrumental vs Pavlovian alcohol cues is because that’s how the VP encodes alcohol reward or because of the pre-exposure to alcohol. Is the VP really more tuned to action value when the reward is alcohol (and if so, should show the differences even without pre-exposure to alcohol) or is goal-tracking of alcohol more sensitive to outcome devaluation (and if so, maybe without pre-exposure to alcohol VP encoding of Pavlovian alcohol cues is similar to the instrumental ones)? Adding a group of alcohol reward but without pre-exposure to alcohol could clarify this. 2) The general theme in the paper is that VP neurons increase their firing rate when presented with a cue predicting reward. However, in Fig. 2C it seems that the majority of the neurons are actually inhibited when presented with the instrumental reward-predicting cue. Are these inhibited neurons particularly important for the DS task? They were not discussed further even though the effect of alcohol on their activity was mostly significant. 3) In previous papers, the authors examined the link between VP firing and response latency and found that VP firing predicts response latency to sucrose cues. Is this the same for alcohol cues? Does alcohol pre-exposure impair the link between VP neuron firing and response latency? 4) Latencies of the changes in firing rate relative to cue presentation are also not examined. In their previous papers, the authors showed nicely that VP neurons responding to reward (sucrose) cues respond before the accumbens, meaning that their action is not merely a downstream response to accumbens activity. Are the latencies here comparable to the previous findings? At least in the suc(alc) groups, did alcohol pre-exposure change the latencies? 5) The data was taken from both male and female rats. In light of the recent “shocking” realization that males and females are different (even in rats!), did the authors see any differences between males and females in their VP encoding of DS or CS cues? 6) Page 13, 2nd paragraph, lines 5-6 – the words “we used” are written twice written twice. 7) Loved the 1st summary paragraph of the discussion. 8) In the cumulative probability plots (ie Fig. 3I, 4E, etc.) the authors should indicate in the legends what the vertical lines represent. 9) Figure 5 – In the text the authors talk about the proportions of neurons excited/inhibited in the suc(alc) task. I think it would be good to also include pie charts (as those given in Fig. 2) of these proportions in Fig. 5.

    Reviewer: 2

    Comments to the Author This study uses a combination of elegant behaviour, in vivo recording and modelling to show that alcohol differentially effects the encoding of VP cue related activity in instrumental and Pavlovian conditions. This work builds on previous reports and now adds important information about how pre-treatment with alcohol effects reward-related signals in the VP.

    Overall the study is well designed and the experiments are clearly described. I have no major concerns but I have a few minor points.

    1. As the activity of the VP is tightly linked to behaviour I think it would be useful for the authors to show the behavioural data for the non-associative alcohol exposure task. This would help the readers appreciate if the changes in neural activity are correlated with changes in the behaviour.
    2. In the Pavlovian task the port entry probability is lower and the port entry is lower compared with the instrumental task. If the authors took trials where the latency to port entry was the same in the Pavlovian and instrumental task would they still be able to decode more accurately the cue identity in the instrumental task? This would be important as it would show how tightly the VP activity is related to behaviour.
    3. I think it would be easier to read if the decoding accuracy plots (Figure 4E, F and 6B, C) had decoding accuracy was plotted on the same axis.

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    Reviewer report
    2019/05/19

    This study uses a combination of elegant behaviour, in vivo recording and modelling to show that alcohol differentially effects the encoding of VP cue related activity in instrumental and Pavlovian conditions. This work builds on previous reports and now adds important information about how pre-treatment with alcohol effects reward-related signals in the VP.

    Overall the study is well designed and the experiments are clearly described. I have no major concerns but I have a few minor points.

    1. As the activity of the VP is tightly linked to behaviour I think it would be useful for the authors to show the behavioural data for the non-associative alcohol exposure task. This would help the readers appreciate if the changes in neural activity are correlated with changes in the behaviour.

    2. In the Pavlovian task the port entry probability is lower and the port entry is lower compared with the instrumental task. If the authors took trials where the latency to port entry was the same in the Pavlovian and instrumental task would they still be able to decode more accurately the cue identity in the instrumental task? This would be important as it would show how tightly the VP activity is related to behaviour.

    3. I think it would be easier to read if the decoding accuracy plots (Figure 4E, F and 6B, C) had decoding accuracy was plotted on the same axis.

    Cite this review
    Endorsed by
    Ongoing discussion (0 comments - click to toggle)
    Reviewer report
    2019/05/06

    I’ll start with this – I love the recent body of work by the Janak group trying to understand how ventral pallidum (VP) firing dynamics may be linked to the encoding of reward-seeking behavior. The current manuscript is an extension of this work, examining how alcohol affects VP encoding of instrumental vs Pavlovian cues. They show that alcohol pre-exposure impairs the ability of VP firing to predict cue identity in a Pavlovian but not instrumental task when the reward is sucrose. They also show that when the reward itself is alcohol (after pre-exposure to alcohol), prediction of cue identity by VP firing is effective in the instrumental task and not the Pavlovian task. The work is of high technical quality, complies with author guidelines and is relevant to the scope of EJN. As their previous papers, I think this is an interesting work and I definitely recommend it for publication. Having said that (no manuscript is perfect, you know :-) ), there are several points that I am still curious about that could potentially add to the general message of this paper, especially in light of the previous work from this group.

    1) The main question I still don’t know the answer to is whether the differences between VP encoding of instrumental vs Pavlovian alcohol cues is because that’s how the VP encodes alcohol reward or because of the pre-exposure to alcohol. Is the VP really more tuned to action value when the reward is alcohol (and if so, should show the differences even without pre-exposure to alcohol) or is goal-tracking of alcohol more sensitive to outcome devaluation (and if so, maybe without pre-exposure to alcohol VP encoding of Pavlovian alcohol cues is similar to the instrumental ones)? Adding a group of alcohol reward but without pre-exposure to alcohol could clarify this.

    2) The general theme in the paper is that VP neurons increase their firing rate when presented with a cue predicting reward. However, in Fig. 2C it seems that the majority of the neurons are actually inhibited when presented with the instrumental reward-predicting cue. Are these inhibited neurons particularly important for the DS task? They were not discussed further even though the effect of alcohol on their activity was mostly significant.

    3) In previous papers, the authors examined the link between VP firing and response latency and found that VP firing predicts response latency to sucrose cues. Is this the same for alcohol cues? Does alcohol pre-exposure impair the link between VP neuron firing and response latency?

    4) Latencies of the changes in firing rate relative to cue presentation are also not examined. In their previous papers, the authors showed nicely that VP neurons responding to reward (sucrose) cues respond before the accumbens, meaning that their action is not merely a downstream response to accumbens activity. Are the latencies here comparable to the previous findings? At least in the suc(alc) groups, did alcohol pre-exposure change the latencies?

    5) The data was taken from both male and female rats. In light of the recent “shocking” realization that males and females are different (even in rats!), did the authors see any differences between males and females in their VP encoding of DS or CS cues?

    6) Page 13, 2nd paragraph, lines 5-6 – the words “we used” are written twice written twice.

    7) Loved the 1st summary paragraph of the discussion.

    8) In the cumulative probability plots (ie Fig. 3I, 4E, etc.) the authors should indicate in the legends what the vertical lines represent.

    9) Figure 5 – In the text the authors talk about the proportions of neurons excited/inhibited in the suc(alc) task. I think it would be good to also include pie charts (as those given in Fig. 2) of these proportions in Fig. 5.

    Cite this review
    Endorsed by
    Ongoing discussion (0 comments - click to toggle)