Dopamine in the dorsal bed nucleus of stria terminalis signals Pavlovian sign-tracking and reward violations

  1. Utsav Gyawali
  2. David A Martin
  3. Fangmiao Sun
  4. Yulong Li
  5. Donna Calu

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    Authors investigated the role of dopamine (DA) release via GRABDA in the dorsal bed nucleus of the stria terminalis (dBNST) in sign and goal tracking behavior, in response to systemic fentanyl, and to fentanyl self-administration. The behavioral experiments were well-conducted and provide novel information about BNST DA in theories of learning and reinforcement. Identified limitations had to do with acknowledgment and discussion of divergent sources of DA innervation, the low sample size in fentanyl experiments with the exclusion of a large number of animals, and a need for additional analyses of the photometry data and/or control recordings to rule out spontaneous transients in this region.

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Abstract

Midbrain and striatal dopamine signals have been extremely well characterized over the past several decades, yet novel dopamine signals and functions in reward learning and motivation continue to emerge. A similar characterization of real-time sub-second dopamine signals in areas outside of the striatum has been limited. Recent advances in fluorescent sensor technology and fiber photometry permit the measurement of dopamine binding correlates, which can divulge basic functions of dopamine signaling in non-striatal dopamine terminal regions, like the dorsal bed nucleus of the stria terminalis (dBNST). Here, we record GRAB DA signals in the dBNST during a Pavlovian lever autoshaping task. We observe greater Pavlovian cue-evoked dBNST GRAB DA signals in sign-tracking (ST) compared to goal-tracking/intermediate (GT/INT) rats and the magnitude of cue-evoked dBNST GRAB DA signals decreases immediately following reinforcer-specific satiety. When we deliver unexpected rewards or omit expected rewards, we find that dBNST dopamine signals encode bidirectional reward prediction errors in GT/INT rats, but only positive prediction errors in ST rats. Since sign- and goal-tracking approach strategies are associated with distinct drug relapse vulnerabilities, we examined the effects of experimenter-administered fentanyl on dBNST dopamine associative encoding. Systemic fentanyl injections do not disrupt cue discrimination but generally potentiate dBNST dopamine signals. These results reveal multiple dBNST dopamine correlates of learning and motivation that depend on the Pavlovian approach strategy employed.

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  1. Version published to 10.7554/elife.81980 on eLife
  2. Version published to 10.1101/2022.06.21.497039v3 on bioRxiv
  3. eLife

    eLife assessment

    Authors investigated the role of dopamine (DA) release via GRABDA in the dorsal bed nucleus of the stria terminalis (dBNST) in sign and goal tracking behavior, in response to systemic fentanyl, and to fentanyl self-administration. The behavioral experiments were well-conducted and provide novel information about BNST DA in theories of learning and reinforcement. Identified limitations had to do with acknowledgment and discussion of divergent sources of DA innervation, the low sample size in fentanyl experiments with the exclusion of a large number of animals, and a need for additional analyses of the photometry data and/or control recordings to rule out spontaneous transients in this region.

  4. eLife

    Reviewer #1 (Public Review):

    This manuscript investigates the role of dopamine (DA) release in the dorsal bed nucleus of the stria terminalis (dBNST) investigating sign and goal tracking behavior, response to systemic fentanyl, and to fentanyl self-administration. The studies are largely well conducted and interesting, and the conclusions are justified by the data. The behavioral experiments are elegant and well-conceived, and good thought has been put into how they fit with current theories of learning and reinforcement. As written, however, it is hard to know how much of this data is novel as compared to what is known about DA release in the nucleus accumbens (NAc) which partially comes from similar sources (ventral tegmental area/VTA) but the BNST also receives DA from divergent sources (periaquaductal gray/PAG). The anatomy of DA innervation in the BNST is somewhat distinct and it is doubtful that the optical fiber has the spatial resolution to distinguish between areas that are innervated more by the VTA, which seems more restricted to the juxtacapsular subnucleus, vs. the PAG which more broadly innervates the dlBNST and the oval subnucleus. Further, the release of DA by these two areas may be differentially governed and that is not considered.

  5. eLife

    Reviewer #2 (Public Review):

    In addition to the nucleus accumbens, the bed nucleus stria terminalis (BNST; part of the extended amygdala) is also a recipient of dopamine release from VTA and other regions. While nucleus accumbens dopamine signaling has been heavily implicated in individual differences in the attribution of incentive salience towards a reward predictive cue and reward learning, it is still unclear whether dopamine signaling in extended amygdala is involved in this process.

    Here, Gyawali et al. use GRABDA sensors to record dopamine signaling in the dorsal BNST (dBNST) during Pavlovian and instrumental cue-evoked reward tasks. During a Pavlovian lever autoshaping task, they observed individual differences in dopamine signaling in response to a reward CS, with sign-tracking rats showing heightened dopamine response compared to goal-tracking rats. dBNST dopamine signaling also bidirectionally encoded violations in reward prediction, as well as outcome-specific satiety. Finally, they show that fentanyl self-administration-associated cues also elevate dBNST dopamine signaling.

    The manuscript is very well written, includes appropriate controls, use of statistical analyses, and conclusions were generally justified by their results. In some instances, larger group sizes would allow authors to more powerfully assert their claims. Although causal manipulations would further solidify the necessity of cue-evoked dopamine signaling in the BNST, these are a very interesting and thorough set of experiments that importantly highlight the role of endogenous dopamine dynamics in BNST in cue-related reward motivation. Not only are these findings important in defining a role for BNST in appetitive motivation (in addition to its more famous role in aversive motivation), but they are also likely to impact future important work that causally delineates sources of dopamine to BNST.

  6. eLife

    Reviewer #3 (Public Review):

    Gyawali et al. make use of fiber photometry methods with a dopamine biosensor to monitor dopamine signaling in the BNST, where it has received much less attention compared to striatal regions. They use a Pavlovian conditioned approach paradigm to assess the encoding of associative learning, finding that, similar to the striatum, BNST dopamine responds to violations of expectation. Further, BNST dopamine responses to Pavlovian cues and outcomes vary according to individual differences in conditioned approach behaviors. In other studies, they demonstrate that BNST dopamine tracks sensory-specific satiety, and is amplified following fentanyl self-administration. Overall these are interesting and well done studies that make great use of new sensor technology. This work represents a foray into monitoring learning-related dopamine signals in non-striatal areas. A primary critique pertains to the analysis and interpretations of the reward prediction error manipulations, which I do not think bidirectional reward prediction error encoding is definitely demonstrated.

  7. Version published to 10.1101/2022.06.21.497039v2 on bioRxiv
  8. Version published to 10.1101/2022.06.21.497039v1 on bioRxiv