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Psychedelic 5-HT2A receptor agonism alters neurovascular coupling and differentially affects neuronal and hemodynamic measures of brain function

Nature Neuroscience volume 28, pages 2330–2343 (2025)Cite this article

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Abstract

Human neuroimaging studies report that psychedelics induce serotonin-2A receptor-dependent changes in functional brain reorganization, presumably reflecting neuromodulation. However, these studies often overlook the potent vasoactive effects of serotonin. Here we identified psilocybin-induced alterations in hemodynamic response functions during human functional magnetic resonance imaging, suggesting potential disruptions in neurovascular coupling. We then used wide-field optical imaging in awake Thy1-jRGECO1a mice to determine whether psychedelic-induced changes in hemodynamics arise from neuronal, vascular or neurovascular effects. Exposure to the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) differentially altered coupling between cortical excitatory neuronal versus hemodynamic activity, both during whisker stimulation and in the resting state. Furthermore, DOI resulted in discordant changes between neuronal-based versus hemodynamic-based assessments of functional connectivity. A selective serotonin-2A receptor antagonist (MDL100907) reversed many of the effects of DOI. Our results demonstrate a dissociation between DOI-induced neuronal and hemodynamic signals, indicating a need to consider neurovascular effects of psychedelics when interpreting blood-based measures of brain function.

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Fig. 1: Measuring the effect of 5HT2AR agonism on cortical neuronal and hemodynamic activity.
Fig. 2: Hallucinogenic 5-HT2AR agonism differentially alters stimulus-evoked calcium and hemodynamic activity.
Fig. 3: Hallucinogenic 5-HT2AR agonism alters stimulus-evoked NVC.
Fig. 4: Hallucinogenic 5-HT2AR agonism differentially alters regional resting-state neuronal and hemodynamic activity.
Fig. 5: Hallucinogenic 5HT2AR agonism alters NVC at local and global scales.
Fig. 6: Calcium and hemodynamic activity report differing accounts of RSFC changes arising from hallucinogenic 5-HT2AR agonism.

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Data availability

The Allen Mouse Brain Atlas was downloaded from https://alleninstitute.github.io/AllenSDK/reference_space.html. Processed WFOI data are available via Zenodo at https://doi.org/10.5281/zenodo.15857641 (ref. 155). Raw HTR data are available via Zenodo at https://doi.org/10.5281/zenodo.15857233 (ref. 156). All other data supporting the findings of this study will be made available upon request.

Code Availability

MATLAB processing code is available via GitHub at https://github.com/BauerLabCodebase/WFOI-Textbook-Chapter.

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Acknowledgements

We thank R. Raut, T. Laumann and R. Reneau (Washington University in St. Louis) for helpful discussions and advice. We would also like to express our sincere gratitude to the mice for their vital contributions to this study, which were essential for the findings presented in this paper. We also invite readers to view the bioRxiv version of this manuscript, where the absence of citation limits allowed us to more fully acknowledge the many additional authors, laboratories and scientific contributions that helped shape this work. Finally, we would like to acknowledge the Osage Nation, Missouria, Illinois Confederacy and many other tribes as the ancestral, traditional and contemporary custodians of the land where this work was conducted. This work was supported by National Institutes of Health grants R01NS126326 (A.Q.B.), R01NS102870 (A.Q.B.), RF1AG07950301 (A.Q.B.), R01NS117899 (J.G.M.), R01NS135401 (J.G.M.), F99NS139512 (J.A.P.-C.), T32EB014855 (J.A.P.-C.), T32NS121881 (O.J.K.). This work was also supported by the Center for Holistic Interdisciplinary Research in Psychedelics (CHIRP), a Here and Next Transcend Initiative funded by Washington University in St. Louis.

Author information

Author notes

  1. These authors contributed equally: Oliver J. Krentzman, Chao-Cheng Kuo.

  2. These authors jointly supervised this work: Joshua S. Siegel, Jordan G. McCall, Adam Q. Bauer.

Authors and Affiliations

  1. Imaging Science Program, Washington University in St. Louis, St. Louis, MO, USA

    Jonah A. Padawer-Curry & Adam Q. Bauer

  2. Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA

    Jonah A. Padawer-Curry, Xiaodan Wang, Annie R. Bice, Abraham Z. Snyder & Adam Q. Bauer

  3. Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, USA

    Oliver J. Krentzman, Chao-Cheng Kuo & Jordan G. McCall

  4. Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA

    Xiaodan Wang & Adam Q. Bauer

  5. Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA

    Ginger E. Nicol & Joshua S. Siegel

  6. Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA

    Abraham Z. Snyder

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Contributions

J.A.P.-C., J.S.S., J.G.M. and A.Q.B. developed project conceptualization and experimental design. J.A.P.-C., O.J.K., C.-C.K., X.W., J.G.M. and A.Q.B. provided technical resources. J.A.P.-C., O.J.K, C.-C.K. and A.R.B. managed animal preparation and surgeries. J.A.P.-C., O.J.K. and C.-C.K. acquired data. J.A.P.-C., O.J.K., C.-C.K., J.S.S., J.G.M. and A.Q.B. analyzed the data. J.S.S., J.G.M. and A.Q.B. supervised the project. J.A.P.-C, A.Z.S., J.S.S., J.G.M. and A.Q.B. wrote the original manuscript. J.A.P.-C, O.J.K, C.-C.K., X.W., A.R.B., G.E.N., A.Z.S., J.S.S., J.G.M. and A.Q.B. reviewed and approved the final manuscript. J.A.P.-C., G.E.N., J.S.S., J.G.M. and A.Q.B. provided financial support.

Corresponding authors

Correspondence to Joshua S. Siegel, Jordan G. McCall or Adam Q. Bauer.

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Competing interests

J.S.S. has received consulting fees from Forbes Manhattan. G.E.N. has received research support from Usona Institute (drug only). In the past 36 months, G.E.N. has received salary support from institutional grants supported by the National Center for Translational Sciences (NCATS) and the National Institute of Digestive and Diabetes and Kidney Diseases (NIDDK); research support from the National Institute of Mental Health (NIMH), the Health Resources and Services Administration (HRSA), the Taylor Family Institute for Innovative Psychiatric Research and the Center for Holistic Interdisciplinary Research on Psychedelics (CHIRP) at Washington University. She has served as a Coinvestigator or Principal Investigator for studies funded by COMPASS Pathways, LB Pharmaceuticals, Inc. and Usona Institute. These potential conflicts of interest have been reviewed and are managed by Washington University School of Medicine. The other authors declare no competing interests.

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Nature Neuroscience thanks Boris Heifets and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Psychedelics alter hemodynamic response functions (HRFs) in humans as reported by BOLD-fMRI.

a) Previously published functional magnetic resonance imaging (fMRI) data were analyzed from humans undergoing a simple auditory-visual matching task during acute exposure to psilocybin, methylphenidate, or no compound. Generalized linear models were computed for task-evoked activity in left and right visual cortex, left hand, left and right auditory cortex, and left language. HRFs were fit using double Gamma basis functions and characterized by three-parameters: Peak Value (P), Dispersion (D), and Time to Peak (T). Data are presented as mean ± SEM. b) Quantified changes in human hemodynamic response functions. Statistical differences for each parameter across conditions were assessed via 2-way ANOVA; significant effects were evaluated post-hoc via two-sided t-tests. p-values are indicated such that #<0.05, ##<0.01, ###<0.001. Data are presented as quantiles and all outliers (>99.3rd percentile) were excluded for visualization purposes only. Top panel: Peak value decreased in left and right visual regions under psilocybin conditions (ANOVA, p=0.030 and p=0.020, respectively). Middle panel: Time-to-peak decreased in all regions except the right visual region (ANOVA, left visual, p=0.03 left hand, p=0.006; left auditory, p=0.002; right auditory, p=0.044; left language, p=0.007). Bottom panel: Dispersion decreased in the left and right visual regions, and left and right auditory regions (ANOVA, p=0.007, p=0.004, p=0.021, p=0.022, respectively).

Extended Data Fig. 2 Mouse body movements and pupil dynamics do not differ across experimental conditions.

Two cameras were placed in front of the mouse to monitor body movement and pupil dynamics. Image sequences of mouse movement and pupil dynamics were time locked to WFOI. a) Motion monitoring using optical flow. (i) Optical flow (OF) estimates were generated using the Lucas-Kanade method (ii); OF yields a spatiotemporal series of vectors, with each pixel in each frame assigned a vector that reflects local spatiotemporal gradients. At each pixel, the vector magnitude provides a scalar measure of motion, with higher values corresponding to larger movements (iii). The temporal variance of vector magnitudes is shown, with yellow colors indicating larger variance, and demonstrates OF sensitivity to the motion of the felt pouch supporting the mouse (which moves when the mouse moves). (iv) The vector magnitude was computed at each pixel; higher values correspond to larger movement. (v) The root-sum square across all frames was computed to yield a single time trace of estimated movement. b) Distributions of OF-derived movement measures. No differences were observed between conditions (\(n=8\) mice per condition, as assessed by differences between post- minus pre- injection; Kruskal-Wallis: p=0.262). c) Simplified schematic of the automated pupil segmentation algorithm. d) Example of a user-annotated pupil segmentation and the automated pupil segmentation using our algorithm. As demonstrated, user-guided segmentation matches well with automated segmentation. e) Automated outlier detection. Large spatial deviations in the likelihood distributions of the pupil mask’s center-of-mass are attributed to artifact due to the slow rate of pupil diameter fluctuations compared to the imaging frame rate. Outlier frames, along with the frames immediately before and after, were manually labeled and appended to the original training dataset to increase robustness of the algorithm. f) Example frames and time course of pupil area change during imaging. g) Changes in pupil area before and after compound injection. Distributions of pupil area changes did not differ before and after injection of any compound (saline, DOI (4mg/kg), MDL (0.1mg/kg), DOI+MDL, \(n=8\) mice per condition).

Extended Data Fig. 3 5-HT2AR-mediated action potential-independent increase in global calcium signal.

Ex vivo recordings of global calcium signals in acute brain slices upon DOI (10μM) and TTX (1μM) application (\(n=6\) mice). a) Experimental arrangement. Global imaging and cell-attached recordings were conducted on prefrontal cortical region (for example, cingulate, prelimbic and infralimbic cortex) and pyramidal cells within these regions, respectively. b) Subthreshold effects led by direct activation of 5-HT2AR. Representative cell-attached recordings demonstrate lack of spontaneous activity of cortical pyramidal cells in acute brain slice preparation. Application of NMDA, but not DOI or DOI+TTX, resulted in burst firing in recorded cells (aCSF only: 3 cells, NMDA: 5 cells, DOI: 6 cells, DOI upon TTX: 4 cells). c) Tonic, TTX-resistant global calcium increases upon DOI application. Representative traces corrected for photobleaching show a small but steady increase of global calcium signal led by DOI application, which was not affected by TTX pretreatment. (1.55±0.96 vs. 0.87±0.78%, two-way, t-test: p=0.314). d) Elimination of 5-HT2AR-mediated action potential-independent tonic calcium signal by temporal filtering. Representative filtered traces from the same recordings shown in panel c (0.01-5Hz) demonstrate complete removal of action potential-independent DOI-mediated calcium increase (aCSF: 0.00±0.01 vs. 0.01±0.03%, two-sided, Wilcoxon rank-sum test: p=0.343). Abbreviations: aca, anterior commissure (anterior part); AI, anterior insular cortex; Cg1, cingulate cortex (area 1); IL, infralimbic cortex; M1, primary motor cortex; M2, secondary motor cortex; PrL, prelimbic cortex.

Extended Data Fig. 4 5-HT2AR activation does not contribute to calcium fluctuations in electrically-evoked neural activity.

Ex vivo recordings of electrical stimulation-evoked calcium signal in acute brain slice upon DOI (10μM) application (\(n=4\) mice). a-b) Experimental arrangement. Simultaneous cell-attached recordings and calcium imaging was conducted on layer V pyramidal cells in prefrontal cortical region (for example, cingulate, prelimbic and infralimbic cortices) with a stimulation electrode placed in layer II/III. c) Direct activation of 5-HT2AR does not affect the number of evoked action potentials. (top) Representative cell-attached recordings demonstrate evoked action potentials in both baseline and DOI administration. (bottom) Summarized plot showing the input-output relationship between stimulation intensity and the number of evoked action potentials. Note that all representative traces in c-e are from recordings with 50% of stimulation intensity. d) Activation of 5-HT2AR does not affect the evoked calcium fluctuation in recorded cell. (top) Representative stimulus-evoked traces (solid: mean; pale: individual) demonstrate evoked calcium fluctuation in recorded cells shown in b. (bottom) Summarized plot showing the input-output relationship between stimulation intensity and evoked calcium fluctuation. e) Activation of 5-HT2AR does not affect the evoked calcium fluctuation in recorded slices. (top) Representative peri-stimulus traces (solid: mean; pale: individual) demonstrate evoked calcium fluctuation in the whole FOV. (bottom) Summarized plot showing the input-output relationship between stimulation intensity and evoked calcium fluctuation. f) Activation of 5-HT2AR does not affect the evoked calcium fluctuation under blockade of synaptic transmission. (upper left) Global calcium imaging recording was conducted on layer V pyramidal cells in prefrontal cortices with stimulation electrode locally placed in layer V under kynurenic acid (5mM) and picrotoxin (100μM). (lower left) Representative peri-stimulus traces (solid: mean; pale: individual) demonstrate evoked global calcium fluctuation. (right) No significant difference in evoked calcium fluctuation. Abbreviations: aca, anterior commissure (anterior part); AI, anterior insular cortex; AP, action potential; Cg1, cingulate cortex (area 1); IL, infralimbic cortex; M1, primary motor cortex; M2, secondary motor cortex; PrL, prelimbic cortex.

Extended Data Fig. 5 Hallucinogenic 5-HT2A receptor agonism alters resting-state activity.

Global (that is, regionally averaged) PSDEs were integrated over double-octave bins and compared between compounds (saline, DOI (4mg/kg), MDL (0.1mg/kg), DOI+MDL, \(n=8\)) for both calcium (a) and hemodynamic (b) activity. The lowest frequency bin was limited by the lower limit of 0.02Hz due to the window length used to segment resting-state from stimulus-evoked data. All measures were averaged over the cortex and comparisons were made between pre- and post-injection (post- minus pre-) and across compounds using two-sided t-tests (*<0.05, **<0.01, and ***<0.001) and one-way ANOVAs with post-hoc, two-sided, t-tests (#<0.05, ##<0.01, ###<0.001), respectively. Multiple comparisons were corrected for using the Bonferroni method. c) Fractional changes in broad-band activity attributed to hallucinogenic 5-HT2A receptor agonism. Fractional changes in regional power spectra are displayed as the ratio of post-injection values divided by pre-injection values and regions are organized from anterior-to-posterior and from left-to-right. DOI differentially affected the spectral content of calcium (left) and hemodynamic (right) activity in a region-dependent manner. ISA: DOI increased calcium ISA power in frontal, cingulate, and motor cortices while hemodynamic ISA activity increased primarily in somatosensory regions. Intermediate: Calcium activity decreased in all cortical regions excluding frontal and cingulate. In contrast, hemodynamic activity decreased in frontal and cingulate cortex. Delta: Both calcium and hemodynamic activity exhibited increased delta band activity in nearly every cortical region examined with the largest increases occurring at ~0.8Hz hemodynamic activity. Across all frequencies examined, MDL largely reversed the effects of DOI. Saline and MDL minimally altered hemodynamics and calcium spectral content. Average fractional changes over the cortex are visualized on top of each column and plotted as mean ± std across mice.

Extended Data Fig. 6 Hallucinogenic 5-HT2A receptor agonism alters resting-state neurovascular coupling.

a) Neurovascular coupling parameterization and quantification. Regional hemodynamic response functions (HRFs) were characterized by their peak value (peak), time to peak amplitude (TTP), and full width at half maximum (FWHM). These parameters were averaged across regions and compared across compounds (saline, DOI (4mg/kg), MDL (0.1mg/kg), DOI+MDL, \(n=8\)). Predicted hemodynamic activity was calculated by convolving each region’s solved HRF with its corresponding measured calcium signal. Model fit was assessed via Pearson’s r between predicted and measured hemodynamic activity. Band-limited frequency transduction was calculated over three frequency bands: infraslow activity band (ISA, 0.03-0.08Hz), intermediate activity band (0.08-0.50Hz), and delta activity band (0.5-4.0Hz). The lowest frequency bin of the TF (that is, 0.03Hz) was determined by the 30s long window used for estimating HRFs. All global measures were averaged over the cortex and comparisons were made between pre- and post-injection and across compounds (post- minus pre-) using two-tailed t-tests (*<0.05, **<0.01, and ***<0.001) and one-way ANOVAs evaluated post-hoc via two-tailed t-test (#<0.05, ##<0.01, ###<0.001), respectively. Multiple comparisons were corrected for using the Bonferroni method. b) Hallucinogenic 5-HT2A receptor agonism alters region-specific NVC. Estimated HRFs were averaged across mice for each region and compound. Regions are organized from anterior-to-posterior and from left-to-right. Prior to compound injection, NVC differed (parameterized in Fig. 5c) across the cortex. For instance, somatosensory and parietal regions exhibited the strongest coupling (for example, large peak value), while frontal and cingulate regions exhibited more modest coupling. DOI caused a zero-lag notch across the entire cortex (that is, the acausal feature seen in Fig. 5a, black arrow), strongest motor, retrosplenial, and visual regions. Additionally, DOI increased coupling in the somatosensory and parietal regions. These effects were dampened when DOI was administered with MDL. Cortical-averaged HRFs are visualized above each column and plotted as mean +/- std across mice. The color axis has units of \(\Delta \mu\)Mol/\(\Delta\)F/F(%).

Extended Data Fig. 7 Lagged cross-covariance and coherence between calcium and total hemoglobin recapitulate DOI-induced changes in neurovascular coupling.

a) Global hemodynamic response functions: The global HRF estimated using deconvolution following DOI injection (4mg/kg, \(n=8\), top; Fig. 4a) and the global lagged cross-covariance function (CCF; bottom) between resting-state calcium and hemodynamics. Pre-injection CCFs display a simple, quasi-causal relation (calcium leads hemodynamics). DOI decreased coupling (peak value, -51% [-66%, -13%], pre- vs. post-injection: p=0.039; Kruskal-Wallis: p=0.004; saline vs. DOI: p=0.020; DOI vs. DOI+MDL: p=0.004; DOI vs. MDL (0.1mg/kg): p<0.001). DOI induced a zero-lag notch in the CCF (black arrow). Covariance has units of \(\Delta \mu\)Mol\(\Delta\)F/F(%) and the HRF has units of \(\Delta \mu\)Mol/\(\Delta\)F/F(%). b) DOI-induced alterations in CCF over the cortex. Regional distribution of cross covariance after the injection of DOI reveals a negative-lag peak across the cortex. CCFs for all regions and compounds are displayed in Supplementary Fig. S6a. c) Magnitude Squared Coherence (MSC) between calcium and hemodynamic activity. Before compound injection, MSC exhibited a large 0.2Hz peak, demonstrating the band-limited nature of NVC. After injection of DOI, a coherence peak ~0.8Hz (~0.5Hz half-bandwidth) emerged (0.5-2.0Hz: +170% [110% 230%]; pre- vs. post-injection: p=0.008; Kruskal-Wallis: p=0.004; saline vs. DOI: p=0.009; DOI vs. DOI+MDL: p=0.030; DOI vs. MDL: p=0.025). Moreover, the 0.2Hz peak present before injection largely diminished (<0.5Hz: -47% [-53%, 49%], pre- vs. post-injection: p=0.008). This phenomenon signifies a DOI-induced shift in the coherent frequencies contained in both neuronal and hemodynamic activity. DOI+MDL largely reversed the effects of DOI alone (Supplementary Fig. S6). Coherence for all regions and compounds are displayed in Supplementary Fig. S6b. d) Phase relation between calcium and hemodynamics. Prior to injection, global calcium activity led hemodynamic activity (positive slope at frequencies below ~1Hz; left). After DOI injection, phase relations between calcium and hemodynamic activity flipped sign (for example, from positive to negative slope in primary motor and primary somatosensory hindpaw; right), indicating that hemodynamics precede calcium over these frequencies. Supplementary Fig. S6c reports phase relations for all regions and compounds. All data are presented mean ± std across mice. Significance was determined via Kruskal-Wallis tests and post-hoc, two-sided Wilcoxon’s sign-rank corrected post-hoc using Bonferroni correction.

Extended Data Fig. 8 Non-hallucinogenic doses of DOI and the non-hallucinogenic, 5-HT2AR agonist, Lisuride do not alter NVC.

a) Head twitch responses (HTRs) recorded during sub-hallucinogenic DOI (low-dose, 0.04mg/kg) and the non-hallucinogenic, psychedelic ligand, Lisuride (0.1mg/kg). No differences in HTRs were observed between groups (Kruskal-Wallis, p>0.99). HTRs were recorded for 30 minutes (\(n=4\)). Significance was determined via Kruskal-Wallis tests and evaluated post-hoc via two-sided Wilcoxon’s sign-rank test corrected for multiple comparisons using Bonferroni correction. a-f) WFOI imaging of non-hallucinogenic ligands. Two groups of Thy1-jRGECO1a mice were imaged under resting-state conditions for 30min before and 30min after injection. Cohort 1 (4M, 5F) received saline and lisuride (0.1mg/kg); cohort 2 (2M, 2F) received saline and a sub-hallucinogenic dose of DOI (low-dose DOI, 0.04mg/kg. b) Hemodynamic response functions before and after injection of low-dose DOI. Low-dose DOI did not alter global estimates of NVC. c) Regional changes NVC following low-dose DOI. Full-width-at-half-maximum (FWHM), time-to-peak (TTP), and peak value are visualized across the cortex. Sub-hallucinogenic doses of DOI did not alter any regional HRF parameters compared to saline. d) Hemodynamic response functions before and after Lisuride injection. No significant changes to global hemodynamic response functions were observed after the injection of lisuride. e) Regional changes NVC following Lisuride. Parameterized hemodynamic response functions reveal no differences in regional NVC after injection of low-dose DOI. f) Global power spectral density estimates before and after injection of lisuride and d) Integrated, band-limited power over double octave frequency bins. Spectra are reported as median and shaded 25th and 75th percentiles. Band-limited power is consistently decreased after injection of both saline and lisuride, like results reported in Extended Data Fig. 5a,b. Lisuride modestly affected power over the 0.32-1.28Hz bin (p=0.009). Band-limited power was tested for significance via Kruskal-Wallis tests and evaluated post-hoc via two-tailed Wilcoxon’s sign-rank corrected for multiple comparisons using Bonferroni correction.

Extended Data Fig. 9 Hallucinogenic 5-HT2A receptor agonism alters inter- vs. intra-network connectivity.

a) Whole-cortex RSFC matrices. Average, pre-injection, whole-cortex RSFC matrices across mice (\(n=8\)) for infralow (ISA; 0.02-0.08Hz) calcium and HbT activity and delta (0.5-4Hz) calcium activity. Matrices represent all pixel-pair comparisons and are organized by network assignment. b) Hierarchical clustering of RSFC. RSFC matrices were hierarchically clustered using Ward’s method and visualized as a dendrogram. c) Resultant clusters at a specific hierarchical level. A distance threshold was selected to create a parcellation containing 13 clusters. These parcels were used to assess inter- and intra-regional relationships. d) Pre-injection Silhouette scores. Silhouette scores were computed at each pixel to assess the ratio between cohesion (intra-cluster distance metric) and separation (inter-cluster metric). Silhouette scores range from -1 to +1, such that +1 indicates a point is well-clustered and far from neighboring clusters (strongly intra-connected, weakly inter-connected), 0 indicates that the point is on, or near, the boundary between two clusters (equally intra- and inter-connected/equally likely to belong to any neighboring cluster), and -1 indicates a point is misclassified and likely should be assigned to a different cluster than its own (weakly intra-connected, strongly inter-connected). i) A graphical demonstration of cohesion (black cluster) and separation to the nearest cluster (red cluster). ii) Pre-injection silhouette scores for each species and frequency band. e) Changes in Silhouette scores after compound injection. DOI (4mg/kg) predominantly decreases ISA calcium silhouette scores everywhere (regions are less intra-connected and more inter-connected), an effect not fully reversed in under DOI+MDL. Importantly, ISA calcium scores in the cingulate and retrosplenial cortices—constellations of the mouse default mode network—showed opposite effects: cingulate scores marginally increased, while retrosplenial scores markedly decreased. This divergence was substantially reduced when scores were computed using infralow hemodynamic activity. Delta calcium activity under DOI suggests that the compound primarily alters network boundaries rather than modulating inter- or intra-network interactions.

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Supplementary Results, Discussion, Table 1, Figs. 1–6 and References.

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Padawer-Curry, J.A., Krentzman, O.J., Kuo, CC. et al. Psychedelic 5-HT2A receptor agonism alters neurovascular coupling and differentially affects neuronal and hemodynamic measures of brain function. Nat Neurosci 28, 2330–2343 (2025). https://doi.org/10.1038/s41593-025-02069-z

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  • DOI: https://doi.org/10.1038/s41593-025-02069-z

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