Ventromedial striatal dopamine dynamically integrates motivated action and reward proximity
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eLife Assessment
This manuscript describes a series of studies using four different Go/No Go task variants in combination with fast-scan cyclic voltammetry to determine the role of dopamine release in the ventromedial striatum in action selection, controllability of reward pursuit, effort, and reward approach. The authors conclude that dopamine signals in the ventromedial striatum integrate the invigoration of action initiation with continuous estimation of spatial, but not temporal, proximity to rewards. There are, however, a number of concerns regarding methodology that could affect the interpretation of the results. Thus, while the findings are useful, they are considered incomplete, with the primary claims only partially supported.
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Abstract
Dopamine release in the ventromedial striatum (VMS) both invigorates actions and encodes reward-related information, yet how these functions are integrated remains under active debate. To investigate this further, we designed four different versions of a rat Go/No-go task, where we systematically manipulated response requirements, temporal task demands, and controllability of reward pursuit. Dopamine release increased reliably during action initiation (Go) but was delayed during action suppression (No-go), and was insensitive to augmented response demands or controllability. Following response completion, dopamine rose gradually until animals arrived at the reward location, irrespective of reward-delivery timing, prior action demands, or controllability. This proximity dopamine-signal was exaggerated after animals exhibited Pavlovian consummatory behavior during No-go trials, revealing a motivational signal component. Together, these findings indicate that in reward contexts, VMS-dopamine signals successively integrate the invigoration of action initiation with the continuous estimation of spatial – but not temporal – proximity to rewards.
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eLife Assessment
This manuscript describes a series of studies using four different Go/No Go task variants in combination with fast-scan cyclic voltammetry to determine the role of dopamine release in the ventromedial striatum in action selection, controllability of reward pursuit, effort, and reward approach. The authors conclude that dopamine signals in the ventromedial striatum integrate the invigoration of action initiation with continuous estimation of spatial, but not temporal, proximity to rewards. There are, however, a number of concerns regarding methodology that could affect the interpretation of the results. Thus, while the findings are useful, they are considered incomplete, with the primary claims only partially supported.
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Reviewer #1 (Public review):
Summary:
Poh and colleagues investigate dopamine signaling in the nucleus accumbens (ventromedial striatum) in rats engaged in several forms of Go/No Go tasks, which differed in reward controllability (self-initiated reward seeking or cue-evoked/quasi-pavlovian), and in the specific timing of the action-reward contingencies. They analyze dopamine recordings made with fast scan cyclic voltammetry, and find that dopamine signals vary most consistently to cues that signal a required action (Go cues) vs cues signaling action withholding (No Go cues). Through various analyses, they report that dopamine signals align most clearly with action initiation and with the approach to the reward-delivery location. Collectively, these data support aspects of a variety of frameworks related to accumbens dopamine signaling …
Reviewer #1 (Public review):
Summary:
Poh and colleagues investigate dopamine signaling in the nucleus accumbens (ventromedial striatum) in rats engaged in several forms of Go/No Go tasks, which differed in reward controllability (self-initiated reward seeking or cue-evoked/quasi-pavlovian), and in the specific timing of the action-reward contingencies. They analyze dopamine recordings made with fast scan cyclic voltammetry, and find that dopamine signals vary most consistently to cues that signal a required action (Go cues) vs cues signaling action withholding (No Go cues). Through various analyses, they report that dopamine signals align most clearly with action initiation and with the approach to the reward-delivery location. Collectively, these data support aspects of a variety of frameworks related to accumbens dopamine signaling in movement, action vigor, approach, etc.
Strengths:
These studies use several task variants that consolidate a few different components of dopamine signal functions and allow for a broad comparison of many psychological and behavioral aspects. The behavioral analysis is detailed. These results touch on many previous findings, largely showing consistent results with past studies.
Weaknesses:
The paper could heavily benefit from some revision to increase clarity of the figures, the methods, and the analysis. The inclusion of many tasks is a strength, but also somewhat overshadows specific points in the data, which could be improved with some revision/reworking.
Some conclusions are not fully justified. As shown, support for the conclusion "dopamine reflects action initiation but not controllability or effort" is lacking without more analyses and additional context. Further, the notion that the dopamine signals reported here reflect spatial information could be justified more strongly.
Additional details on subjects used in each study, analysis details on trialwise vs subjects-wise data, and other context would be helpful for improving the paper.
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Reviewer #2 (Public review):
Here, the authors record dopamine release using fast-scan cyclic voltammetry in the nucleus accumbens/ ventromedial striatum (VMS) while rats perform variants of a Go/No Go task. Two versions are self-paced, in that the rat can initiate a trial by nosepoking at the odor port at any time once the ITI has elapsed, whereas the other two require the rat to wait for a cue-light before responding. Two "long" variants also require either more lever-presses on Go trials, or a longer nosepoke time for No Go trials, and also incorporate "free" trials in which the rat is rewarded for just heading straight to the food tray. The authors find that dopamine levels increase more during the response requirement for Go than No Go trials, indicating a role for invigorating to-be-rewarded actions. Dopamine levels also steadily …
Reviewer #2 (Public review):
Here, the authors record dopamine release using fast-scan cyclic voltammetry in the nucleus accumbens/ ventromedial striatum (VMS) while rats perform variants of a Go/No Go task. Two versions are self-paced, in that the rat can initiate a trial by nosepoking at the odor port at any time once the ITI has elapsed, whereas the other two require the rat to wait for a cue-light before responding. Two "long" variants also require either more lever-presses on Go trials, or a longer nosepoke time for No Go trials, and also incorporate "free" trials in which the rat is rewarded for just heading straight to the food tray. The authors find that dopamine levels increase more during the response requirement for Go than No Go trials, indicating a role for invigorating to-be-rewarded actions. Dopamine levels also steadily increased as rats approached the site of reward delivery, and the authors demonstrate quite elegantly that this was not due to orientation to the food tray, or time-to-reward, or action initiation, but instead reflects spatial proximity to the rewarded location. Contrary to previous reports, the authors did not discern any differences in dopamine dynamics depending on whether the trials were cue- or self-paced, and dopamine release did not scale with effort requirements.
The manuscript is well-written, and the authors use figures to great effect to explain what could otherwise be a hard-to-parse set of data. The authors make good use of the richness of their behavioral data to justify or negate potential conclusions. I have the following comments.
Re: The lack of relationship between effort to acquire reward in the current study and the magnitude of dopamine release, can the authors unpack this a bit more? Why the difference between the Walton and Bouret studies? Were the shifts in effort requirements comparable across the behavioral tasks? What else could be different between the methodologies?
I would argue that the cue- vs self-initiated distinction was pretty minor, given that there was a fixed ITI of 5s. How does this task modification compare to those used previously to show that dopamine release corresponds to behavioral controllability? It would help the reader if the authors could spend more time discussing these disparate findings and looking for points of methodological divergence/ commonality.
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Reviewer #3 (Public review):
Summary:
The manuscript by Poh et al. investigated whether dopamine release in the ventral medial striatum integrates information about action selection, controllability of reward pursuit, effort, and reward approach. Rats were implanted with FSCV probes and trained in four Go/No Go task variants:
(1) trials were self-initiated and had two trial types (Go vs. No Go) that were auditorily cued,
(2) trials were cue-initiated and had two trial types (Go vs. No Go) that were auditorily cued,
(3) trials were self-initiated and had three trial types (Go vs. No Go vs. free reward) that were auditorily cued, and effort was increased,
(4) trials were cue-initiated and had three trial types (Go vs. No Go vs. free reward) that were auditorily cued.
The authors report that dopamine levels rose during Go trials and slowly …
Reviewer #3 (Public review):
Summary:
The manuscript by Poh et al. investigated whether dopamine release in the ventral medial striatum integrates information about action selection, controllability of reward pursuit, effort, and reward approach. Rats were implanted with FSCV probes and trained in four Go/No Go task variants:
(1) trials were self-initiated and had two trial types (Go vs. No Go) that were auditorily cued,
(2) trials were cue-initiated and had two trial types (Go vs. No Go) that were auditorily cued,
(3) trials were self-initiated and had three trial types (Go vs. No Go vs. free reward) that were auditorily cued, and effort was increased,
(4) trials were cue-initiated and had three trial types (Go vs. No Go vs. free reward) that were auditorily cued.
The authors report that dopamine levels rose during Go trials and slowly rose in No Go trials, but this pattern did not differ across task variants that modified effort and whether trials were cued or initiated. They also report that dopamine levels rose as rats approached the reward location and were greater in rats that bit the noseport while holding during the No Go response.
Strengths:
(1) Interesting task and variants within the task paradigm that would allow the authors to isolate specific behavioral metrics.
(2) The goal of determining precisely what VMS dopamine signals do is highly significant and would be of interest to many researchers.
Weaknesses:
(1) This Go/No-Go procedure is different from the traditional tasks, and this leads to several problems with interpreting the results:
(a) Go/No Go tasks typically require subjects to refrain from doing any action. In this task, a response is still required for the No Go trials (e.g., continue holding the nosepoke). The problem with this modified design is that failure to withhold a response on No Go trials could be because i) rats could not continue holding the response, as holding responses are difficult for rodents, or ii) rats could not suppress the prepotent go response. This makes interpreting the behavior and the dopamine signal in No Go trials very difficult.
(b) Most Go/No Go tasks bias or overrepresent Go trials so that the Go response is prepotent, and consequently, successful suppression of the Go response is challenging. I didn't see any information in the manuscript about how often each trial type was presented or how the authors ensured that No Go responses (or lack thereof) were reflecting a suppression of the Go response.
(2) The authors observe relatively consistent differences in the DA signal between Go and No Go trials after the action-cue onset. However, the response type was not randomized between trial type, so there is a confound between trial type (Go/No Go) and response (lever/nosepoke). The difference in DA signal may have nothing to do with the cue type, but reflects differences in DA signal elicited by levers vs. nosepokes.
(3) Both Go and No Go trials start with the rat having their nose in the noseport. One cue (Go cue) signals the rat to remove their nose from the noseport and make two lever responses in 5 seconds, whereas the other cue (No Go cue) signals the rat to keep their nose in the noseport for an additional 1.7-1.9 s. The authors state that the time between cue onset and reward delivery was kept the same for all trial types, and Figure 1 suggests this is 2 s, so was reward delivered before rats completed the two lever presses? I would imagine reward was only delivered if rats completed the FR requirement, but again, the descriptions in the text and figures are incongruent.
(4) The manuscript is difficult to understand because key details are not in the main text or are not mentioned at all. I've outlined several points below:
(a) The author's description in the manuscript makes it appear as a discrimination task versus a Go/No Go task. I suggest including more details in the main text that clarify what is required at each step in the task. Additionally, providing clarity regarding what task events the voltammetry traces are aligned to would be very useful.
(b) How many subjects were included in each task variant? The text makes it seem like all rats complete each task variant, but the behavioral data suggest otherwise. Moreover, it appears that some rats did more than one version. Was the order counterbalanced? If not, might this influence the DA signal?
(5) There is a major challenge in their design and interpretation of the dopamine signal. Both trial types (Go and No Go) start with the rat having their nose in the noseport. An auditory cue is presented for 2-3 s signaling to the rat to either leave the noseport and make a lever response (Go trial) or to stay in the noseport (No Go trial). The timing of these actions and/or decisions is entirely independent, so it is not clear to me how the authors would ever align these traces to the exact decision point for each trial type. They attempt to do this with the nose-port exit analysis, but exiting the noseport for a Go trial (a rat needs to make 2 lever presses and then get a reward) versus a No Go trial (a rat needs to go retrieve the reward) is very different and not comparable.
(6) The voltammetry analysis did not appear to test the hypotheses the authors outlined in the intro. All comparisons were done within task variants (DA dynamics in Go vs. No Go trials, aligned to different task events), but there were no comparisons across task variants to determine if the DA signal differed in cued vs self-initiated trials.
(7) Classification of No Go behaviors was interesting, but was not well integrated with the rest of the paper and was underdeveloped. It also raised more questions for me than answers. For example:
(a) Was the behavior classification consistent across rats for all No Go trials? If not, did the DA signal change within subjects between biting vs digging vs calm?
(b) If "biting rats" were not always biting rats on every No Go trial, then is it fair to collapse animals into a single measure (Figure 3C).
(c) Some of the classification groups only had 2 or fewer rats in them, making any statistical comparison and inference difficult.
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