Ventral striatum dopamine release encodes unique properties of visual stimuli in mice

  1. L Sofia Gonzalez
  2. Austen A Fisher
  3. Shane P D'Souza
  4. Evelin M Cotella
  5. Richard A Lang
  6. J Elliott Robinson

  • Curated by eLife

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    In this manuscript, Gonzalez et al investigated the dynamics of dopamine signals in the lateral shell of the nucleus accumbens (LNAc) in response to different types of carefully defined visual stimuli. Contrary to reigning theories of dopamine signaling, the authors presented convincing evidence that LNAcc dopamine transients tracked visual sensory transitions rather than any immediately apparent motivational variable. These important findings based on compelling evidence point to a potentially new role for dopamine signaling in the ventral striatum.

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Abstract

The mesolimbic dopamine system is an evolutionarily conserved set of brain circuits that play a role in attention, appetitive behavior, and reward processing. In this circuitry, ascending dopaminergic projections from the ventral midbrain innervate targets throughout the limbic forebrain, such as the ventral striatum/nucleus accumbens (NAc). Dopaminergic signaling in the NAc has been widely studied for its role in behavioral reinforcement, reward prediction error encoding, and motivational salience. Less well characterized is the role of dopaminergic neurotransmission in the response to surprising or alerting sensory events. To address this, we used the genetically encoded dopamine sensor dLight1 and fiber photometry to explore the ability of striatal dopamine release to encode the properties of salient sensory stimuli in mice, such as threatening looming discs. Here, we report that lateral NAc (LNAc) dopamine release encodes the rate and magnitude of environmental luminance changes rather than the visual stimulus threat level. This encoding is highly sensitive, as LNAc dopamine could be evoked by light intensities that were imperceptible to human experimenters. We also found that light-evoked dopamine responses are wavelength-dependent at low irradiances, independent of the circadian cycle, robust to previous exposure history, and involve multiple phototransduction pathways. Thus, we have further elaborated the mesolimbic dopamine system’s ability to encode visual information in mice, which is likely relevant to a wide body of scientists employing light sources or optical methods in behavioral research involving rodents.

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  1. Version published to 10.7554/elife.85064 on eLife
  2. eLife

    Author Response

    Reviewer #1 (Public Review):

    In this manuscript, Gonzalez et al investigated the dynamics of dopamine signals, measured with optophysiological methods in the lateral shell of the nucleus accumbens (LNAc), in response to different types of visual stimuli. Contrary to most current theories of dopamine signaling, the authors found that LNAc dopamine transients tracked sensory transitions in visual stimulation rather than any immediately apparent motivational variable. This unorthodox finding is of potential interest to the field, as it suggests that dopamine in this particular area of the striatum supports a very different, albeit unclear behavioral function than what has been previously attributed to this neuromodulator. Many of the approaches used by the authors were very elegant, like the careful selection of visual stimuli parameters and the use of Gnat1/2 KO mice to demonstrate that the dopamine responses were directly dependent on the visual stimulation of rods and cones. That said, the authors did not discuss how their findings relate to much previously published work, many of which offer potential alternative explanations for their results. It is also not clear from the manuscript text which mice were used for which experiments, and how testing history might affect the results.

    We would like to thank the reviewer for their careful review of our manuscript. In our revised manuscript, we reworked our Materials and Methods to better detail the experimental workflow, which is highlighted in yellow. We have also added new data in stimulus-naïve animals to better examine the effect of exposure history on the dopaminergic response to light. To provide validation of our recording sites, we have included a new figure (Figure 1-Figure Supplement 1) that contains a representative histological image showing the location of the optical fiber/virus expression, as well as a schematic demonstrating optical fiber placements. Finally, the reviewer’s point about discussing the current results in the context of previous literature is well taken, and we have added three new paragraphs of text in the Discussion to highlight these findings.

    Reviewer #2 (Public Review):

    In this elegant work, the authors investigated dopamine release (measured by dLight sensor fiber photometry) in the nucleus accumbens shell, in response to salient luminance change. They show that abrupt visual stimuli - including stimuli not detectable by the human eye - can evoke robust dopamine release in the accumbens shell.

    The fact that dopamine signals can be evoked by salient sensory stimuli is not itself novel, but the paper manages to make several important and new findings:

    1. The authors show that the dopamine signal is not related to the level of threat evoked by the visual stimuli.
    1. They provide important detail about the stimuli parameters relevant to dopamine release. For instance, they show that the rate of luminance change (or abruptness) is a key factor in evoking dopamine responses.
    1. They show that robust dopamine responses can be evoked by visual stimuli of low intensity, including stimuli not perceptible by the human eye.
    1. They show that these dopamine responses can be evoked by all wavelengths in the visible spectrum (with some higher sensitivity at certain wavelengths).
    1. Finally, by recording dopamine responses in two knockout mice strains, the authors show that the light-evoked dopamine release critically relies on rod and cone photoreceptors, but not melanopsin phototransduction.

    These results add to a series of recent findings showing that dopamine signals are not restricted to the encoding of reward prediction error, but instead contribute to signaling environmental changes more broadly. The study has been skillfully executed, the results are clear and appropriately analyzed, and the manuscript is very well written. Although the work did not include control mice lacking the dLight sensor, the fact that light-evoked dopamine responses were not observed in mice lacking cone + rod phototransduction is strong evidence that the fiberphotometry signals were not due to direct light artifacts.

    We would like to thank the reviewer for taking their valuable time over the holidays to review our manuscript. We appreciate their feedback and have responded to their concerns below.

    Comment/concerns are minor:

    1. The authors show that the dopamine response evoked by a brief visual stimulus is drastically reduced when the visual stimulus is repeated in rapid succession (stimulus train). The authors interpret this as evidence for the HABITUATION of this light-evoked dopamine release. An alternative explanation is that it is the prediction of the stimulus that is responsible for canceling the dopamine response (i.e. sensory prediction error). The authors should discuss this alternative explanation for this finding.

    This is a valid point, which we have now addressed in the revised Discussion section (Paragraph 3).

    1. Although the study largely focuses on dopamine responses to visual stimuli, the results are largely consistent with previous studies showing dopamine signals encoding value-neutral changes in sensory inputs (i.e. sensory prediction errors) in different modalities (taste or odors; cf. Takahashi et al., 2017, Neuron; Howard & Kahnt, 2018, Nat. Comm.). The authors might want to cite those papers (note that I am not affiliated with those papers).

    This is similar to the point brought up by Reviewer 1, namely that several key pieces of literature were not discussed in the original manuscript. We agree that this was an oversight and hope we have remedied it in the revised Discussion, as detailed in the response to Reviewer 1. We have included both citations in the new text.

  3. eLife

    eLife assessment

    In this manuscript, Gonzalez et al investigated the dynamics of dopamine signals in the lateral shell of the nucleus accumbens (LNAc) in response to different types of carefully defined visual stimuli. Contrary to reigning theories of dopamine signaling, the authors presented convincing evidence that LNAcc dopamine transients tracked visual sensory transitions rather than any immediately apparent motivational variable. These important findings based on compelling evidence point to a potentially new role for dopamine signaling in the ventral striatum.

  4. eLife

    Reviewer #1 (Public Review):

    In this manuscript, Gonzalez et al investigated the dynamics of dopamine signals, measured with optophysiological methods in the lateral shell of the nucleus accumbens (LNAc), in response to different types of visual stimuli. Contrary to most current theories of dopamine signaling, the authors found that LNAcc dopamine transients tracked sensory transitions in visual stimulation rather than any immediately apparent motivational variable. This unorthodox finding is of potential interest to the field, as it suggests that dopamine in this particular area of the striatum supports a very different, albeit unclear behavioral function than what has been previously attributed to this neuromodulator. Many of the approaches used by the authors were very elegant, like the careful selection of visual stimuli parameters and the use of Gnat1/2 KO mice to demonstrate that the dopamine responses were directly dependent on the visual stimulation of rods and cones. That said, the authors did not discuss how their findings relate to much previously published work, many of which offer potential alternative explanations for their results. It is also not clear from the manuscript text which mice were used for which experiments, and how testing history might affect the results.

  5. eLife

    Reviewer #2 (Public Review):

    In this elegant work, the authors investigated dopamine release (measured by dLight sensor fiber photometry) in the nucleus accumbens shell, in response to salient luminance change. They show that abrupt visual stimuli - including stimuli not detectable by the human eye - can evoke robust dopamine release in the accumbens shell.

    The fact that dopamine signals can be evoked by salient sensory stimuli is not itself novel, but the paper manages to make several important and new findings:

    1. The authors show that the dopamine signal is not related to the level of threat evoked by the visual stimuli.
    2. They provide important detail about the stimuli parameters relevant to dopamine release. For instance, they show that the rate of luminance change (or abruptness) is a key factor in evoking dopamine responses.
    3. They show that robust dopamine responses can be evoked by visual stimuli of low intensity, including stimuli not perceptible by the human eye.
    4. They show that these dopamine responses can be evoked by all wavelengths in the visible spectrum (with some higher sensitivity at certain wavelengths).
    5. Finally, by recording dopamine responses in two knockout mice strains, the authors show that the light-evoked dopamine release critically relies on rod and cone photoreceptors, but not melanopsin phototransduction.

    These results add to a series of recent findings showing that dopamine signals are not restricted to the encoding of reward prediction error, but instead contribute to signaling environmental changes more broadly. The study has been skillfully executed, the results are clear and appropriately analyzed, and the manuscript is very well written. Although the work did not include control mice lacking the dLight sensor, the fact that light-evoked dopamine responses were not observed in mice lacking cone + rod phototransduction is strong evidence that the fiberphotometry signals were not due to direct light artifacts.

    Comment/concerns are minor:

    1. The authors show that the dopamine response evoked by a brief visual stimulus is drastically reduced when the visual stimulus is repeated in rapid succession (stimulus train). The authors interpret this as evidence for the HABITUATION of this light-evoked dopamine release. An alternative explanation is that it is the prediction of the stimulus that is responsible for canceling the dopamine response (i.e. sensory prediction error). The authors should discuss this alternative explanation for this finding.

    2. Although the study largely focuses on dopamine responses to visual stimuli, the results are largely consistent with previous studies showing dopamine signals encoding value-neutral changes in sensory inputs (i.e. sensory prediction errors) in different modalities (taste or odors; cf. Takahashi et al., 2017, Neuron; Howard & Kahnt, 2018, Nat. Comm.). The authors might want to cite those papers (note that I am not affiliated with those papers).

  6. eLife

    **Reviewer #3 (Public Review):
    **
    Gonzalez and colleagues investigate dopamine signals in response to visual stimuli. This work builds on the longstanding notion that dopamine neurons respond to unexpected sensory stimuli, including visual cues. Using fiber photometry measurements of a fluorescent dopamine sensor, they find that in the lateral ventral striatum, dopamine signals reliably report salient transitions in illuminance. Dopamine signals scale with light intensity and the speed of illuminance changes. They further find that the frequency of illuminance transitions, rather than the number, dictates the extent that dopamine signals habituate. In a number of studies, they characterize dopamine signals to light of different wavelengths, durations, and intensities. These results shed new "light" on the role of dopamine in signaling salience, independent of reward or threat learning. This work is elegantly done and compelling. While the results are potentially specific to this region of the striatum, rather than a broad dopaminergic profile of visual stimulus encoding, this work offers valuable insight into dopamine function, as well as a practical guide and considerations for the implementation of visual stimuli in behavioral tasks that assay dopamine systems.

  7. Version published to 10.1101/2022.09.20.508670v2 on bioRxiv
  8. Version published to 10.1101/2022.09.20.508670v1 on bioRxiv