The psychedelic DOI decreases the modularity of the cortical network by increasing cortico-cortical and thalamo-cortical functional influence
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Curated by eLife
eLife Assessment
This important study combines cortex-wide activity imaging and optogenetics to characterize large-scale changes in functional connectivity following administration of the psychedelic DOI, as well as the circuit mechanisms underlying them. It provides solid evidence that DOI reduces the modularity of cortical networks and has concurrent effects on both cortico-cortical and cortico-thalamic functional connectivity. The study will be of broad interest to basic scientists working on the circuit mechanisms of psychedelics, as well as to researchers studying humans who may wish to reverse-translate their findings into mice.
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Abstract
Psychedelics are powerful modulators of conscious perception, hypothesized to exert their effects by reorganizing large-scale brain functional connectivity. The circuit mechanisms underlying this reorganization remain unknown. Here, using widefield calcium imaging in awake mice, we found that the psychedelic DOI, in a 5-HT2A-dependent manner, acutely decreased the modularity of the cortical network by increasing correlations between anterolateral (AL) and posteromedial (PM) cortical domains. Functional influence measurements revealed that DOI increased both thalamo-cortical and long-range cortico-cortical influence onto the AL domain. We speculate that these increases in functional influence are driving the DOI-induced increase in the coupling between cortical domains. Our results provide a mouse correlate of the network reorganization seen under psychedelics in human neuroimaging and identify thalamo-cortical and cortico-cortical changes as candidate circuit mechanisms for this reorganization.
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eLife Assessment
This important study combines cortex-wide activity imaging and optogenetics to characterize large-scale changes in functional connectivity following administration of the psychedelic DOI, as well as the circuit mechanisms underlying them. It provides solid evidence that DOI reduces the modularity of cortical networks and has concurrent effects on both cortico-cortical and cortico-thalamic functional connectivity. The study will be of broad interest to basic scientists working on the circuit mechanisms of psychedelics, as well as to researchers studying humans who may wish to reverse-translate their findings into mice.
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Reviewer #1 (Public review):
Summary:
Doronin et al. performed wide-field calcium imaging to investigate the cortex-wide activity dynamics in mice after the administration of the psychedelic DOI.
Strengths:
The lab has extensive experience with this approach. The analyses are not trivial, but here the authors progressively step through the rich data to identify salient effects. The observed effects at the level of cortical networks will be of great interest to the field, both for basic scientists interested in circuit mechanisms of psychedelics and for human researchers who may want to reverse translate from humans to mice.
Weaknesses:
The analyses were extensive, but the choices made for the analyses are quite specific, and there are places where other analyses may be more appropriate and logical. For example, instead of comparing …
Reviewer #1 (Public review):
Summary:
Doronin et al. performed wide-field calcium imaging to investigate the cortex-wide activity dynamics in mice after the administration of the psychedelic DOI.
Strengths:
The lab has extensive experience with this approach. The analyses are not trivial, but here the authors progressively step through the rich data to identify salient effects. The observed effects at the level of cortical networks will be of great interest to the field, both for basic scientists interested in circuit mechanisms of psychedelics and for human researchers who may want to reverse translate from humans to mice.
Weaknesses:
The analyses were extensive, but the choices made for the analyses are quite specific, and there are places where other analyses may be more appropriate and logical. For example, instead of comparing activity with serotonergic axonal density, compare with Htr2a transcript because the receptor is the drug target. Moreover, data were combined for day 1 and day 5 for an unclear reason. Furthermore, a few statements in the text did not seem fully supported by the results and may be over-interpreted.
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Reviewer #2 (Public review):
Summary:
In this paper, the authors report a quantitative change in the functional connectivity between cortical domains in mice, due to the influence of the psychedelic, DOI. Additionally, they report that specific cell types (and circuits) within the brain may be involved in the changes in the observed functional connectivity. This will have important implications - both for basic neuroscience and with potential translational implications.
Strengths:
This is a fascinating result - especially since the work on psychedelics has predominantly been focused on humans - and therefore a deeper understanding of cell-type-specific responses due to psychedelics has remained poorly studied. Given that psychedelics result in a variety of distinct changes within the circuit - both affecting plasticity and the …
Reviewer #2 (Public review):
Summary:
In this paper, the authors report a quantitative change in the functional connectivity between cortical domains in mice, due to the influence of the psychedelic, DOI. Additionally, they report that specific cell types (and circuits) within the brain may be involved in the changes in the observed functional connectivity. This will have important implications - both for basic neuroscience and with potential translational implications.
Strengths:
This is a fascinating result - especially since the work on psychedelics has predominantly been focused on humans - and therefore a deeper understanding of cell-type-specific responses due to psychedelics has remained poorly studied. Given that psychedelics result in a variety of distinct changes within the circuit - both affecting plasticity and the steady-state dynamics - it is critical to characterize these changes within a system where we can measure changes in individual cell types.
Weaknesses:
The authors attempt to model the types of analyses that have been performed in humans within mice. Perhaps because of their attempt to translate from one system to another, the quantitative justification for each of the specific analyses that have been performed appears unclear within the mouse system. This makes some of their analyses, as currently structured, appear incomplete, and we have detailed the resulting questions in the following comments:
(1) The concept of a "cortical domain" is used in the abstract and is a fundamental component of the paper. We were not familiar with the concept prior to its use in this paper and, given the importance of the concept, it would be helpful to clearly delineate what the authors define as a domain at the outset, so that readers can build their expectations. Further, both AL and PM have been used as acronyms for secondary visual areas (which the authors are very familiar with). This leads to further confusion for the reader. As such, it would be helpful to clearly delineate that these are distinct acronyms for a distinct class of spatial feature within the brain - even within the abstract.
(2) The authors define the AL and PM cortical domains through the use of a threshold on the seed correlation maps. They chose a threshold of 35%, but it's not clear why that threshold was chosen - and what would occur if the authors used a different threshold instead. Would the boundaries change significantly, and would the rest of their results then be affected by this change?
(3) The authors report that the behavioral events that show a maximally distinguishable response in the PM and AL domains are behavioral fidgets. However, the authors do not define either (a) the set of all possible behavioral events which they compared against (and how those behavioral events were assayed), and (b) the quantitative definition of fidgets that was used. This is particularly critical since the authors use the fidget response as a metric of responsiveness in the rest of the paper.
(4) The authors report that the AL and PM domains correlate with the projection patterns of specific neuromodulatory systems. Given the (apparently) arbitrary threshold used in the definition of the AL and PM domains, and the fact that the authors mention that they examined "some of the major neuromodulatory systems", it is unclear how to interpret this result.
(5) The authors claim that the DOI-induced increase in the correlation between the cortical domains is 5-HT2A dependent, and their evidence for this depends on a block of the 5-HT2A receptor via ketanserin, in the presence of DOI. However, the result that they report from ketanserin is a decrease in the correlations below baseline, and not simply a removal of the effect observed in DOI. This suggests that the effect of DOI on the network cannot be simplistically explained through 5-HT2A dependence, and requires some further characterization and / or explanation.
(6) The authors introduce the concept of "amplitude of activity variation". However, they do not define the specific quantification that they are using in the text. Additionally, their justification for the use of the concept is also unclear. Why should the activity of input variation change "on first approximation"? If this is a quantifiable prediction, what is the approximation? Increasing the precision of their introduction of the concept would greatly aid the reader in interpreting the results in Figure 4.
(7) The authors report that EEG responses do not directly reflect the opposing responses observed via widefield calcium imaging. They conclude that "the opposing effects we observe in calcium activity are difficult to relate to psychedelic-induced EEG effects in humans". However, their apparent effects are also not observed in mouse EEG recordings. As such, their claim is unclear - are they reporting that calcium recordings are not reflected in EEG responses, or is there a specific effect present in mice that is absent in humans?
(8) The authors compare the widefield response resulting from stimulation of specific populations of cortical and subcortical neurons prior to and under the influence of DOI. They claim that the resulting changes provide "candidate circuit mechanisms" for the effects observed during DOI. However, the observed changes due to stimulation do not match the specific changes observed during DOI, making it hard to justify their claim. Indeed, one could hypothesize that the observed changes are only due to downstream effects in a secondary population, only indirectly stimulated through the authors' paradigm. As such, clarification of their results and increased precision of their claims would be helpful. As one example, the authors could provide a model for how the specific changes that they observe during stimulation may directly result in the domain-specific changes observed due to DOI.
(9) Following up on question (8), it would also be helpful for the authors to characterize the space of stimulation paradigms within the selected neuronal populations. How specific are the changes that they observe to the specific stimulation paradigm used? Are these stimulation paradigms biologically plausible? And, if not, what precisely do we learn through this stimulation?
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In short, DOI blurs the distinction between the two main domains in the mouse cortex and increases both cortico-cortical and thalamo-cortical functional influence, which could explain this cortical reorganization. Check out the full paper for details! www.biorxiv.org/content/10.6... 10/10
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The psychedelic DOI decreases the modularity of the cortical network by increasing cortico-cortical and thalamo-cortical functional influence https://www.biorxiv.org/content/10.64898/2026.07.20.739656v1
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The psychedelic DOI decreases the modularity of the cortical network by increasing cortico-cortical and thalamo-cortical functional influence https://www.biorxiv.org/content/10.64898/2026.07.20.739656v1
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