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Article Published: 14 December 2022

A microbiome-dependent gut–brain pathway

regulates motivation for exercise
Lenka Dohnalová, Patrick Lundgren, Jamie R. E. Carty, Nitsan Goldstein, Sebastian L. Wenski, Pakjira
Nanudorn, Sirinthra Thiengmag, Kuei-Pin Huang, Lev Litichevskiy, Hélène C. Descamps, Karthikeyani
Chellappa, Ana Glassman, Susanne Kessler, Jihee Kim, Timothy O. Cox, Oxana Dmitrieva-Posocco,
Andrea C. Wong, Erik L. Allman, Soumita Ghosh, Nitika Sharma, Kasturi Sengupta, Belinda Cornes,
Nitai Dean, Gary A. Churchill, … Christoph A. Thaiss   Show authors

Nature  612, 739–747 (2022) Cite this article

53k Accesses 16 Citations 1732 Altmetric Metrics

Abstract
Exercise exerts a wide range of beneficial effects for healthy physiology1. However, the
mechanisms regulating an individual’s motivation to engage in physical activity remain
incompletely understood. An important factor stimulating the engagement in both
competitive and recreational exercise is the motivating pleasure derived from prolonged
physical activity, which is triggered by exercise-induced neurochemical changes in the
brain. Here, we report on the discovery of a gut–brain connection in mice that enhances
exercise performance by augmenting dopamine signalling during physical activity. We find
that microbiome-dependent production of endocannabinoid metabolites in the gut
stimulates the activity of TRPV1-expressing sensory neurons and thereby elevates
dopamine levels in the ventral striatum during exercise. Stimulation of this pathway
improves running performance, whereas microbiome depletion, peripheral
endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine
blockade abrogate exercise capacity. These findings indicate that the rewarding properties
of exercise are influenced by gut-derived interoceptive circuits and provide a microbiome-
dependent explanation for interindividual variability in exercise performance. Our study
also suggests that interoceptomimetic molecules that stimulate the transmission of gut-
derived signals to the brain may enhance the motivation for exercise.

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Data availability
Raw sequencing data for this study are publicly available under accession numbers
PRJNA865937, PRJNA866511 and GSE210906. Source data are provided with this paper.

References
1. Neufer, P. D. et al. Understanding the cellular and molecular mechanisms of physical
activity-induced health benefits. Cell Metab. 22, 4–11 (2015).

Article  CAS  Google Scholar 

2. Hawley, J. A., Hargreaves, M., Joyner, M. J. & Zierath, J. R. Integrative biology of exercise.
Cell 159, 738–749 (2014).

Article  CAS  Google Scholar 

3. Churchill, G. A., Gatti, D. M., Munger, S. C. & Svenson, K. L. The diversity outbred mouse
population. Mamm. Genome 23, 713–718 (2012).

PDF Article  Google Scholar 

4. Kelly, S. A. & Pomp, D. Genetic determinants of voluntary exercise. Trends Genet. 29, 348–
357 (2013).

Article  CAS  Google Scholar 

5. Scheiman, J. et al. Meta-omics analysis of elite athletes identifies a performance-

enhancing microbe that functions via lactate metabolism. Nat. Med. 25, 1104–1109
(2019).

PDF Article  CAS  Google Scholar 

6. Okamoto, T. et al. Microbiome potentiates endurance exercise through intestinal acetate

production. Am. J. Physiol. Endocrinol. Metab. 316, E956–E966 (2019).

Article  CAS  Google Scholar 

7. Hsu, Y. J. et al. Effect of intestinal microbiota on exercise performance in mice. J. Strength.

Cond. Res. 29, 552–558 (2015).

Article  Google Scholar 

8. Nay, K. et al. Gut bacteria are critical for optimal muscle function: a potential link with
glucose homeostasis. Am. J. Physiol. Endocrinol. Metab. 317, E158–E171 (2019).

Article  CAS  Google Scholar 

9. Lundberg, S. M. et al. From local explanations to global understanding with explainable

AI for trees. Nat. Mach. Intell. 2, 56–67 (2020).

PDF Article  Google Scholar 

10. Lahiri, S. et al. The gut microbiota influences skeletal muscle mass and function in mice.
Sci. Transl. Med. 11, eaan566 (2019).

Article  Google Scholar 

11. Almagro, B. J., Saenz-Lopez, P., Fierro-Suero, S. & Conde, C. Perceived performance,
intrinsic motivation and adherence in athletes. Int. J. Environ. Res. Public Health 17, 9441
(2020).

Article  Google Scholar 

12. Friend, D. M. et al. Basal ganglia dysfunction contributes to physical inactivity in

obesity. Cell Metab. 25, 312–321 (2017).

Article  CAS  Google Scholar 

13. Fernandes, M. F. et al. Leptin suppresses the rewarding effects of running via STAT3
signaling in dopamine neurons. Cell Metab. 22, 741–749 (2015).

Article  CAS  Google Scholar 

14. Tong, J. et al. Brain monoamine oxidase B and A in human parkinsonian dopamine
deficiency disorders. Brain 140, 2460–2474 (2017).

PDF Article  Google Scholar 

15. Cryan, J. F. et al. The microbiota-gut-brain axis. Physiol. Rev. 99, 1877–2013 (2019).

Article  CAS  Google Scholar 

16. Cavanaugh, D. J. et al. Distinct subsets of unmyelinated primary sensory fibers mediate
behavioral responses to noxious thermal and mechanical stimuli. Proc. Natl Acad. Sci.
USA 106, 9075–9080 (2009).

Article  ADS  CAS  Google Scholar 

17. Diepenbroek, C. et al. Validation and characterization of a novel method for selective
vagal deafferentation of the gut. Am. J. Physiol. Gastrointest. Liver Physiol. 313, G342–
G352 (2017).

Article  CAS  Google Scholar 

18. Tellez, L. A. et al. A gut lipid messenger links excess dietary fat to dopamine deficiency.
Science 341, 800–802 (2013).

Article  ADS  CAS  Google Scholar 

19. Chang, F. Y. et al. Gut-inhabiting clostridia build human GPCR ligands by conjugating
neurotransmitters with diet- and human-derived fatty acids. Nat. Microbiol. 6, 792–805
(2021).

PDF Article  CAS  Google Scholar 

20. Sharma, N. et al. The emergence of transcriptional identity in somatosensory neurons.

Nature 577, 392–398 (2020).

PDF Article  ADS  CAS  Google Scholar 

21. Muller, C., Morales, P. & Reggio, P. H. Cannabinoid ligands targeting TRP channels.
Front. Mol. Neurosci. 11, 487 (2018).

Article  CAS  Google Scholar 

22. Dubreucq, S., Koehl, M., Abrous, D. N., Marsicano, G. & Chaouloff, F. CB1 receptor
deficiency decreases wheel-running activity: consequences on emotional behaviours
and hippocampal neurogenesis. Exp. Neurol. 224, 106–113 (2010).

Article  CAS  Google Scholar 

23. Cluny, N. L. et al. A novel peripherally restricted cannabinoid receptor antagonist,

AM6545, reduces food intake and body weight, but does not cause malaise, in rodents.
Br. J. Pharmacology 161, 629–642 (2010).

Article  CAS  Google Scholar 

24. Bull, F. C. et al. World Health Organization 2020 guidelines on physical activity and
sedentary behaviour. Br. J. Sports Med. 54, 1451–1462 (2020).

Article  Google Scholar 

25. Teixeira, P. J., Carraca, E. V., Markland, D., Silva, M. N. & Ryan, R. M. Exercise, physical
activity, and self-determination theory: a systematic review. Int. J. Behav. Nutr. Phys. 9,
78 (2012).

Article  Google Scholar 

26. Fuss, J. et al. A runner’s high depends on cannabinoid receptors in mice. Proc. Natl Acad.
Sci. USA 112, 13105–13108 (2015).

Article  ADS  CAS  Google Scholar 

27. Su, Z., Alhadeff, A. L. & Betley, J. N. Nutritive, post-ingestive signals are the primary
regulators of AgRP neuron activity. Cell Rep. 21, 2724–2736 (2017).

Article  CAS  Google Scholar 

28. Goldstein, N. et al. Hypothalamic detection of macronutrients via multiple gut-brain

pathways. Cell Metab. 33, 676–687 e675 (2021).

Article  CAS  Google Scholar 

29. Lin, Y. T. & Chen, J. C. Dorsal root ganglia isolation and primary culture to study
neurotransmitter release. J. Vis. Exp. https://doi.org/10.3791/57569 (2018).

Article  Google Scholar 

30. Loro, E. et al. Effect of interleukin-15 receptor alpha ablation on the metabolic
responses to moderate exercise simulated by in vivo isometric muscle contractions.
Front. Physiol. 10, 1439 (2019).

Article  Google Scholar 

31. Habib, N. et al. Massively parallel single-nucleus RNA-seq with DroNc-seq. Nat. Methods
14, 955–958 (2017).

PDF Article  CAS  Google Scholar 

32. Hafemeister, C. & Satija, R. Normalization and variance stabilization of single-cell RNA-
seq data using regularized negative binomial regression. Genome Biol. 20, 296 (2019).

PDF Article  CAS  Google Scholar 

33. Gokce, O. et al. Cellular taxonomy of the mouse striatum as revealed by single-cell RNA-
seq. Cell Rep. 16, 1126–1137 (2016).

Article  CAS  Google Scholar 

34. Wang, L., Liu, J., Harvey-White, J., Zimmer, A. & Kunos, G. Endocannabinoid signaling via
cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline
in mice. Proc. Natl Acad. Sci. USA 100, 1393–1398 (2003).

Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements
We thank the members of the Thaiss and Betley labs for valuable discussions and input. We
acknowledge D. Kobuley and M. Albright for germ-free animal caretaking, M. Tetlak for
technical assistance and L. Micha for mouse husbandry. We thank N. Yucel and Z. Arany
(University of Pennsylvania) for access to running wheel cages, G. Kunos (National Institute
of Health) for CB1-deficient mice, M. Abt (University of Pennsylvania) for bacterial strains,
the Rodent Metabolic Phenotyping Core (S10-OD025098) for metabolic cage
measurements and S. Cherry and J. Henao-Mejia for critical support. P.L. was supported by
the NIH (F31HL160065), N.G. by NSF GFRP (DGE-1845298) and J.K. by a Boehringer
Ingelheim MD Fellowship. A.D.P. was supported by NIH grant no. S10-OD021750. J.N.B. is
supported by NIH grant no. P01DK119130 and R01DK115578, and by a Klingenstein-Simons
Fellowship. C.A.T. is a Pew Biomedical Scholar and a Kathryn W. Davis Aging Brain Scholar
and is supported by the NIH Director’s New Innovator Award (grant no. DP2AG067492), NIH
grant no. R01-DK-129691, the Edward Mallinckrodt, Jr Foundation, the Agilent Early Career
Professor Award, the Global Probiotics Council, the Mouse Microbiome Metabolic Research
Program of the National Mouse Metabolic Phenotyping Centers and grants by the IDSA
Foundation, the Thyssen Foundation, the Human Frontier Science Program (HFSP), the
Penn Center for Musculoskeletal Disorders (grant no. P30-AR-069619), the PennCHOP
Microbiome Program, the Penn Institute for Immunology, the Penn Center for Molecular
Studies in Digestive and Liver Diseases (grant no. P30-DK-050306), the Penn Skin Biology
and Diseases Resource-based Center (grant no. P30-AR-069589), the Penn Diabetes
Research Center (grant no. P30-DK-019525), the Penn Institute on Aging and the Dean’s
Innovation Fund of the University of Pennsylvania Perelman School of Medicine.

Author information
Authors and Affiliations
Department of Microbiology, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA
Lenka Dohnalová, Patrick Lundgren, Lev Litichevskiy, Hélène C. Descamps, Ana
Glassman, Susanne Kessler, Jihee Kim, Timothy O. Cox, Oxana Dmitrieva-Posocco, Andrea
C. Wong, Maayan Levy & Christoph A. Thaiss

Institute for Immunology, Perelman School of Medicine, University of Pennsylvania,

Philadelphia, PA, USA
Lenka Dohnalová, Patrick Lundgren, Lev Litichevskiy, Hélène C. Descamps, Ana
Glassman, Susanne Kessler, Jihee Kim, Timothy O. Cox, Oxana Dmitrieva-Posocco, Andrea
C. Wong, Maayan Levy & Christoph A. Thaiss

Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine,

University of Pennsylvania, Philadelphia, PA, USA
Lenka Dohnalová, Patrick Lundgren, Lev Litichevskiy, Hélène C. Descamps, Karthikeyani
Chellappa, Ana Glassman, Susanne Kessler, Jihee Kim, Timothy O. Cox, Joseph A. Baur, J.
Nicholas Betley & Christoph A. Thaiss

Institute for Molecular Bio Science, Goethe University Frankfurt, and LOEWE Center
for Translational Biodiversity Genomics, Frankfurt, Germany
Lenka Dohnalová, Sebastian L. Wenski, Pakjira Nanudorn, Sirinthra Thiengmag & Eric J. N.
Helfrich

Department of Biology, University of Pennsylvania, Philadelphia, PA, USA

Jamie R. E. Carty, Nitsan Goldstein & J. Nicholas Betley

Monell Chemical Senses Center, Philadelphia, PA, USA

Kuei-Pin Huang & Amber L. Alhadeff

Department of Physiology, Perelman School of Medicine, University of Pennsylvania,

Philadelphia, PA, USA
Karthikeyani Chellappa, Kasturi Sengupta, Tejvir S. Khurana & Joseph A. Baur

Department of Biochemistry and Molecular Biology and Department of Veterinary

and Biomedical Sciences, the Pennsylvania State University, University Park, PA, USA
Erik L. Allman & Andrew D. Patterson

Department of Systems Pharmacology and Translational Therapeutics, Perelman

School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Soumita Ghosh & Garret A. FitzGerald

Institute for Translational Medicine and Therapeutics, Perelman School of Medicine,

University of Pennsylvania, Philadelphia, PA, USA
Soumita Ghosh & Garret A. FitzGerald

Department of Radiology, Perelman School of Medicine, University of Pennsylvania,

Philadelphia, PA, USA
Nitika Sharma & Mark A. Sellmyer

Pennsylvania Muscle Institute, Perelman School of Medicine, University of

Pennsylvania, Philadelphia, PA, USA
Kasturi Sengupta & Tejvir S. Khurana

The Jackson Laboratory, Bar Harbor, ME, USA

Belinda Cornes & Gary A. Churchill

Hoss Technology, New York, NY, USA

Nitai Dean

Department of Neuroscience, Perelman School of Medicine, University of

Pennsylvania, Philadelphia, PA, USA
Amber L. Alhadeff

Contributions
L.D. performed and analysed all experiments, interpreted the results and wrote the
manuscript. P.L. performed experiments and computational analysis. J.R.E.C. and N.G.
performed surgeries and neural recordings. S.L.W., P.N. and S.T. performed metabolomics
analysis and bacterial genetics. K.-P.H. performed and analysed surgeries. L.L., H.C.D., B.C.
and N.D. performed computational analysis. K.C., A.G., S.K., J.K., T.O.C., O.D.-P. and A.C.W.
performed in vivo experiments. E.L.A., S.G. and N.S. performed metabolomics analysis. K.S.
performed ex vivo experiments. G.A.C., T.S.K., M.A.S., G.A.F., A.D.P., J.A.B., A.L.A., E.J.N.H.,
M.L. and J.N.B. supervised the experiments and analysis. C.A.T. conceived the project,
mentored the participants, interpreted the results and wrote the manuscript.

Corresponding author
Correspondence to Christoph A. Thaiss.

Ethics declarations
Competing interests
The authors declare no competing interests.

Peer review
Peer review information
Nature thanks Aleksandar Kostic and the other, anonymous, reviewer(s) for their
contribution to the peer review of this work.

Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Prediction of exercise performance in diversity-outbred
mice.
a, Ranking of diversity-outbred (DO) mice by time spent on treadmill until exhaustion. b,
Wheel turn recording of DO mice over two consecutive days. c, Kinship matrix of DO mice.
d, GWAS for time spent on treadmill during endurance exercise of DO mice. d, (D)
Heritability (h2) calculated for distance, time, and energy spent on treadmills. f,
Classification of serum metabolomes of DO mice. g, Taxonomies based on 16S rDNA
sequencing of DO mice. h-o, Recording traces (h, j, l, n) and quantification (i, k, m, o) of
horizontal movement (h, i), respiratory exchange ratio ( j, k), energy expenditure (l, m), and
food intake (n, o) of DO mice. p, q, Algorithm-predicted versus measured treadmill time (p)
and energy (q) based on a model including all assessed non-genetic features. r, Explained
variability for “metagroups” of non-genetic variables used for prediction. s-w, Algorithm-
predicted versus measured treadmill distance (s), time (t, v), and energy (u, w) based on a
model including the serum metabolome (s-u), and microbiota features (v, w). x-z,
Correlation of food intake (x), energy expenditure (y), and spontaneous locomotion (z)
with treadmill distance. Error bars indicate means ± SEM. Exact n and p-values are
presented in Supplementary Table 2.

Source Data

Extended Data Fig. 2 The microbiome impact on exercise performance.

a, Ranked plot of treadmill distance of DO mice, with and without antibiotic (Abx)
treatment. b-d, Kaplan-Meier plots for distance (b) and time (c) to exhaustion, and time
quantification (d) for treadmill exercise of DO mice, with and without Abx treatment. e-h,
Quantifications (e, g, h) and Kaplan-Meier plot (f) of treadmill distance (e), time (f, g) and
energy (h) of antibiotics (Abx)-treated female mice. i, Wheel running quantification of Abx-
treated mice. j-m, Quantifications ( j, l, m) and Kaplan-Meier plot (k) of treadmill distance
( j), time (k, l) and energy (m) of germ-free (GF) mice. n, Wheel running quantification of GF
mice. o-s, Kaplan-Meier plots (o, q) and quantifications (p, r, s) of treadmill distance (o, p),
time (q, r) and energy (s) of Abx-treated male mice. t-w, Kaplan-Meier plots (t, v) and
quantifications (u, w) of distance (t, u) and time (v, w) on treadmill of Abx-treated mice or
mice after Abx cessation (ex-Abx). x-aa, Kaplan-Meier plots (x, z) and quantifications (y, aa)
of distance (x, y) and time (z, aa) on treadmill of GF mice and conventionalized (ex-GF) mice.
Error bars indicate means ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Exact n
and p-values are presented in Supplementary Table 2.

Source Data

Extended Data Fig. 3 Taxonomic analysis of microbiome features associated

with exercise performance.
a, b, Recording (a) and quantification (b) of free horizontal movement measured in
metabolic cages for two consecutive days in Abx-treated mice and controls. c-e, Open field
locomotion (c), distance quantification (d) and velocity quantification (e) of Abx-treated
mice and controls. f-i, Kaplan-Meier plots (f, h) and quantifications (g, i) of distance (f, g)
and time (h, i) on treadmill of mice treated with either absorbable (Abs) or non-absorbable
(Non-abs) antibiotics, or a broad-spectrum mixture (Abx). j-n, Body weight ( j), Kaplan-
Meier plot (k) and quantification (l) of time on treadmill, averaged hourly distance (m) and
quantification (n) of voluntary wheel activity of mice treated with the indicated antibiotics.
Inset shows representative recording traces. o-s, Kaplan-Meier plots (o, q), and
quantifications (p, r, s) of treadmill distance (o, p), time (q, r) and energy (s) of GF mice
colonized with microbiome samples from conventional (SPF), neomycin-treated (Neo) or
ampicillin-treated (Amp) mice. t, Phylum-level taxonomic microbiome composition of
neomycin- and ampicillin-treated mice. u, SHAP-value ranking of all microbiota features
contributing to prediction of exercise performance in DO mice. v, w, Relative abundance of
Erysipelotrichaceae in neomycin- and ampicillin-treated mice (v) and GF mice receiving
their microbiome samples (w). x-aa, Bacterial load (x), taxonomic composition (y),
treadmill distance, Kaplan-Meier plot (z) and quantification (aa) of SPF mice, GF mice, and
GF mice mono-colonized with the indicated bacterial species. Error bars indicate means ± 
SEM. * n.s. not significant, * p < 0.05, ** p < 0.01, *** p<0.001, **** p < 0.0001. Exact n and p-
values are presented in Supplementary Table 2.

Source Data

Extended Data Fig. 4 The impact of the microbiome on muscle physiology.

a-d, Weight of soleus (a), gastrocnemius (b), tibilias anterior (c), and extensor digitorum
longus (EDL) muscles in Abx-treated mice and controls. e, f, Grip strength of Abx-treated
mice and controls before (e) and after (f) exercise. g-j, Maximum twitch (g), tetanic force
(h), specific twitch force (i), and specific tetanic force ( j) of EDL muscle from Abx-treated
mice and controls. k-n, Decrease in power (k) and specific muscle force (l), force recovery
over time (m) and force recovery quantification (n) of EDL muscle from Abx-treated mice
and controls. o, EDL muscle cross-sectional area in Abx-treated mice and controls. p, q,
Quantification of oxidative phosphorylation and fatty acid oxidation of isolated
mitochondria (p) and whole cell lysates (q) from EDL muscle obtained from either Abx-
treated mice or controls. r, s, PCA plot (r) and heatmap of selected genes (s) from EDL
transcriptomes obtained from Abx-treated mice and controls. NMJ, neuro-muscular
junction. Error bars indicate means ± SEM. ** p < 0.01. Exact n and p-values are presented in
Supplementary Table 2.

Source Data

Extended Data Fig. 5 Single-nucleus sequencing of the striatum.

a, UMAP clustering of all cell types identified in the striatum. b-h, Feature plots for each
cluster-identifying marker. i, UMAP of neuronal subcluster showing expression of Drd1 and
Drd2. j, k, UMAP plots ( j) and quantification (k) of Fos expression in striatal neurons from
control and Abx-treated mice before and during exercise.

Extended Data Fig. 6 The role of microbiome-mediated dopamine responses in

exercise performance.
a, Schematic depicting in vivo fibre photometry of dopamine sensor fluorescence in the
nucleus accumbens of mice during treadmill running. b-d, Fibre photometry recording of
dopamine dynamics at the end of exercise in the ventral striatum (b), the dorsal striatum
(c), and the ventral striatum after different durations of exercise (d). e, f, Glutamate (e) and
acetylcholine (f) levels in the brain of Abx-treated mice and controls, at steady-state and
after endurance exercise. g, Post-exercise dopamine levels in brain tissue of GF mice, and GF
mice colonized with stool from SPF, neomycin- or ampicillin-treated mice. h-k, Kaplan-
Meier plots (h, j) and quantifications (i, k) of distance (h, i) and time ( j, k) on treadmill of
Abx-treated Slc6a3hM4Di mice, with or without CNO treatment. l, m, Averaged hourly
distance (l) and quantification (m) of voluntary wheel activity of Abx-treated Slc6a3hM4Di
mice, with or without CNO treatment. Inset shows representative recording traces. n-r,
Schematic (n), recording traces (o), quantification (p), mean signals (q), and maximum
signals (r) of fibre photometry recording from the VTA of Slc6a3-Cre mice injected with a
GCamp6-expressing virus. Mice were recorded at the end of the exercise protocol. Error
bars indicate means ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p<0.0001. Exact n and p-
values are presented in Supplementary Table 2.

Source Data

Extended Data Fig. 7 Mechanisms of microbiome-mediated control of striatal

dopamine responses.
a-d, Kaplan-Meier plots (a, c) and quantifications (b, d) of distance (a, b) and time (c, d) on
treadmill of Abx-treated mice, with or without leptin injection i.p. or into the VTA. e-h,