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Vestibular neurons link motion sickness, behavioural thermoregulation and metabolic balance in mice

Nature Metabolism volume 7, pages 742–758 (2025)Cite this article

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Abstract

Motion sickness is associated with thermoregulation and metabolic control, but the underlying neural circuitry remains largely unknown. Here we show that neurons in the medial vestibular nuclei parvocellular part (MVePC) mediate the hypothermic responses induced by motion. Reactivation of motion-sensitive MVePC neurons recapitulates motion sickness in mice. We show that motion-activated neurons in the MVePC are glutamatergic (MVePCGlu), and that optogenetic stimulation of MVePCGlu neurons mimics motion-induced hypothermia by signalling to the lateral parabrachial nucleus (LPBN). Acute inhibition of MVePC-LPBN circuitry abrogates motion-induced hypothermia. Finally, we show that chronic inhibition of MVePCGlu neurons prevents diet-induced obesity and improves glucose homeostasis without suppressing food intake. Overall, these findings highlight MVePCGlu neurons as a potential target for motion-sickness treatment and obesity control.

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Fig. 1: Establishment of a mouse motion-sickness model in the laboratory.
Fig. 2: Reactivation of motion-specific MVePC neurons recapitulates motion sickness in female mice.
Fig. 3: Optogenetic stimulation of the MVePCGlu→LPBN neural circuit recapitulates motion sickness in female mice.
Fig. 4: Inhibition of the MVePCGlu→LPBN neural circuit alleviates motion sickness in female mice.
Fig. 5: Chronic inhibition of MVePCGlu neurons prevented diet-induced obesity in female mice.

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Data availability

All data generated or analysed during this study are included in this published article. No third-party materials were included in this paper. Further information and requests for resources and reagents should be directed to and will be fulfilled by Y.X. (yongx@bcm.edu). Source data are provided with this paper.

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Acknowledgements

The investigators are supported by grants from the NIH (P01DK113954, R01DK115761, R01DK117281, R01DK125480 and R01DK120858 to Y.X.; R01DK104901 and R01DK12665 to M.F.; R01MH117089 to M.X.); USDA/CRIS (51000-064-01S to Y.X.; 51000-064-02S to M.F.; 3092-51000-062-04(B)S to C.W.; 1F32DK13868501A1 to X.F.); the McKnight Foundation to M.X.; and an American Heart Association Postdoctoral Fellowship (2020AHA000POST000204188 to L.T.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.

Author information

Author notes

  1. These authors jointly supervised this work: Longlong Tu, Yong Xu.

Authors and Affiliations

  1. Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Longlong Tu, Xing Fang, Yongjie Yang, Meng Yu, Hailan Liu, Hesong Liu, Na Yin, Jonathan C. Bean, Kristine M. Conde, Mengjie Wang, Yongxiang Li, Olivia Z. Ginnard, Qingzhuo Liu, Yuhan Shi, Junying Han, Yi Zhu, Makoto Fukuda, Yang He, Chunmei Wang & Yong Xu

  2. Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA

    Qingchun Tong

  3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Benjamin Arenkiel & Mingshan Xue

  4. Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA

    Mingshan Xue

  5. The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, USA

    Mingshan Xue

  6. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Yong Xu

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Contributions

L.T. was involved in experimental design and most procedures, data acquisition and analyses and writing the paper. X.F. conducted electrophysiological experiments and data analysis. Y.Y., M.Y., Hailan Liu, Hesong Liu, N.Y., J.C.B., K.M.C., M.W., Y.L., O.Z.G., Q.L., Y.S., J.H., Y.Z., M.F., Q.T., B.A., M.X., Y.H. and C.W. contributed to the generation of study mice and data analysis. Y.X. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Longlong Tu or Yong Xu.

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Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editors: Jean Nakhle and Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Motion elicits c-fos expression in the brain.

(a, b) Representative photomicrographs illustrating c-fos immunostaining in NTS, RPa, LC, CeA, αBNST and MPA from 8 for male/sham (a), 9 for male/motion (a), 7 for female/sham (b) and 8 for female/motion (b) mice. (c) Quantification of c-fos cells in NTS, RPa, LC, CeA, αBNST and MPA elicited by motion. n = 8 for male/sham, 9 for male/motion, 7 for female/sham and 8 for female/motion, two-sided student t test within the same sex. Data are expressed as mean ± standard errors of the mean. (Relative to Fig. 1).

Source data

Extended Data Fig. 2 Validation of the mouse motion sickness model with the anti-motion sickness drug scopolamine.

(a) Effect of scopolamine on food intake in the presence or absence of motion. n = 6 mice, two-way ANOVA followed by Bonferroni post hoc test. (b–e) Effect of scopolamine on distance traveled (b), velocity (c), central zone duration (d) and representative heat-maps (e) in an open field test in the presence or absence of motion. n = 6 mice, one-way ANOVA followed by Bonferroni post hoc test. Data are expressed as mean ± standard errors of the mean. (Relative to Fig. 1).

Source data

Extended Data Fig. 3 Validation of ‘TRAP’ed motion-specific neurons via c-fos immunostaining.

(a) Schematic timeline of TRAP protocol coupled with c-fos immnuostaining. (b) In the left panel, tdTomato-labeled neurons refer to ‘TRAP’ed motion-specific neurons, and c-fos positive cells indicate neurons were activated after mice being subjected to a second-round of motion. Percentage of colocalization between tdTomato-labeled neurons and c-fos positive cells in each specific brain region was shown in the right panel. n = 3 mice. Data are expressed as mean ± standard errors of the mean. Arrows point to co-localized cells between tdTomato and c-fos positive cells. (Relative to Fig. 2).

Source data

Extended Data Fig. 4 Re-activation of motion-specific PVH neurons.

(a–d) Re-activation of motion-specific PVH neurons did not affect body temperature (a-b) or locomotor activity (c-d). n = 6 for control, and n = 7 for TRAP mice. (e–g) Re-activation of motion-specific PVH neurons inhibited food intake in fasting mice (e), but did not affect preferred ambient temperature (f-g). n = 6 for control, and n = 7 for TRAP mice, two-way ANOVA followed by Bonferroni post hoc test for (e). (h–k) Distance traveled (h), velocity (i), central zone duration (j), and representative heat-maps (k) in an open field test after motion-specific PVH neurons were re-activated via CNO injection. n = 6 for control, and n = 7 for TRAP mice. (l, m) Expression of hM3Dq-mCherry in the PVH that was validated by c-fos immunostaining after CNO injection, and quantification of c-fos cells (m). n = 6 for control, and n = 7 for TRAP mice, two-sided student t text for (m). Data are expressed as mean ± standard errors of the mean. (Relative to Fig. 2).

Source data

Extended Data Fig. 5 Re-activation of motion-specific LPBN neurons.

(a–d) Re-activation of motion-specific LPBN neurons slightly decreased body temperature (a-b), but did not influence locomotor activity (c-d). n = 6 mice, one-way ANOVA followed by Bonferroni post hoc test for (b). (e–g) Re-activation of motion-specific LPBN neurons inhibited food intake in fasting mice (e), but did not affect preferred ambient temperature (f-g). n = 6 mice, two-way ANOVA followed by Bonferroni post hoc test for (e). (h–k) Distance traveled (h), velocity (i), central zone duration (j), and representative heat-maps (k) in an open field test after motion-specific LPBN neurons were re-activated via CNO injection. n = 6 mice, one-way ANOVA followed by Bonferroni post hoc test for (h) and (i). (l, m) Expression of hM3Dq-mCherry in the LPBN that was validated by c-fos immunostaining after CNO injection, and quantification of c-fos cells (m). n = 6 mice, two-sided student t text for (m). Data are expressed as mean ± standard errors of the mean. (Relative to Fig. 2).

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Extended Data Fig. 6 Effect of scopolamine on electrical responses of motion-specific MVePC neurons.

(a–d) Experimental illustration of a recorded motion-specific MVePC neuron that was labeled by hM3Dq-mCherry (a), scopolamine attenuated CNO-induced increase in firing frequency and membrane potential (b-c), and raw traces of a recorded hM3Dq-mCherry-expressing neuron among different treatments (d). n = 8 neurons from 2 mice, two-tail paired t test for (b) and (c). (e–g) After washout of scopolamine, CNO induced increase in firing frequency and membrane potential of hM3Dq-mCherry-expressing neurons (e-f), and raw traces of a recorded hM3Dq-mCherry-expressing neuron in response to CNO after scopolamine washout (g). n = 6 neurons from 2 mice, two-tail paired t test for (e) and (f). (h, i) Representative photomicrographs illustrating c-fos immunostaining and number of c-fos cells in the MVePC following scopolamine treatment against motion in female mice. n = 6 mice in each group, one-way ANOVA followed by Bonferroni post hoc test. Data are expressed as mean ± standard errors of the mean. (Relative to Fig. 2).

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Extended Data Fig. 7 Electrical responses of MVePC neurons exposed to different ambient temperatures.

(a) Experimental illustration of a recorded non-motion-specific MVePC neuron from 2 female TRAP2/Rosa26-LSL-tdTomato mice. (b–d) Firing frequency and membrane potential of non-motion-specific MVePC neurons during different ambient recording temperatures (b-c), and representative raw traces of one recorded non-motion-specific MVePC neuron (d). n = 7 neurons from 2 mice. (e, f) Membrane potential of motion-specific MVePC neurons during different ambient recording temperatures in the presence of a cocktail of synaptic blockers (TTX, CNQX, D-AP5 and bicuculline), and representative raw trace of one recorded neuron in this condition. n = 13 neurons from 2 mice. One-way ANOVA followed by Bonferroni tests for (e). (g, h) Membrane potential of non-motion-specific MVePC neurons during different ambient recording temperatures in the presence of a cocktail blockers of synaptic blockers (TTX, CNQX, D-AP5 and bicuculline), and representative raw trace of one recorded neuron in this condition. n = 6 neurons from 2 mice. Data are expressed as mean ± standard errors of the mean. (Relative to Fig. 2).

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Extended Data Fig. 8 Compound C abolishes excitation of MVePC neurons elicited by high ambient temperature.

(a, b) Firing frequency and membrane potential of motion-specific MVePC neurons exposed to different ambient temperatures in the presence of compound C (10 µM). n = 8 neurons from 2 mice. (c) Representative raw traces of one recorded neuron. Data are expressed as mean ± standard errors of the mean. (Relative to Fig. 2).

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Extended Data Fig. 9 Validation of hChR2 expression and real-time place preference test.

(a–d) Representative image showing fiber position and hChR2 (H134R)-EFYP expression in the MVePCGlu neurons (a), and time spent, velocity and distance travelled in each respective chamber that was coupled with MVePCGlu stimulation during the real-time place preference test (b-d). n = 7 mice, two-tail paired t test for (b). (e–h) Representative image showing fiber position and hChR2 (H134R)-EFYP expression in the MVePCVgat neurons (e), and time spent, velocity and distance travelled in each respective chamber that was coupled with MVePCVgat stimulation during the real-time place preference test (f-h). n = 7 mice, two-tail paired t test. (i–l) Representative image showing fiber position and terminals of hChR2 (H134R)-EFYP expression in the LPBN (i), and time spent, velocity and distance travelled in each respective chamber that was coupled with stimulation of terminals of MVePCGlu in the LPBN during the real-time place preference test (j-l). n = 6 mice, two-tail paired t test for (j). Data are expressed as mean ± standard errors of the mean. (Relative to Fig. 3).

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Extended Data Fig. 10 MVePCGlu neurons modulates BAT thermogenesis in female mice.

(a, b) Motion decreased BAT temperature in female mice. n = 6 mice, two-way ANOVA followed by Bonferroni tests for (a), and two-sided student t test for (b). (c, d) Experimental illustration of PRV-mediated retrograde polysynaptic tracing in BAT (c), and representative images showing RFP+ neurons in MVePC, RPa, PVH, but not LPBN (d) from 3 mice. (e–g) Activation of MVePCGlu neurons via blue light delivery decreased BAT temperature. n = 6 mice, two-way ANOVA followed by Bonferroni tests for (e), and two-tail paired t test for (g). (h–j) Inhibition of MVePCGlu neurons via CNO injection increased BAT temperature. n = 6 mice, two-way ANOVA followed by Bonferroni tests for (i), and student t test for (j). Data are expressed as mean ± standard errors of the mean. (Relative to Fig. 4).

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Tu, L., Fang, X., Yang, Y. et al. Vestibular neurons link motion sickness, behavioural thermoregulation and metabolic balance in mice. Nat Metab 7, 742–758 (2025). https://doi.org/10.1038/s42255-025-01234-9

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