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The cerebellum modulates thirst

Abstract

The cerebellum, a phylogenetically ancient brain region, has long been considered strictly a motor control structure. Recent studies have implicated the cerebellum in cognition, sensation, emotion and autonomic function, making it an important target for further investigation. Here, we show that cerebellar Purkinje neurons in mice are activated by the hormone asprosin, leading to enhanced thirst, and that optogenetic or chemogenetic activation of Purkinje neurons induces rapid manifestation of water drinking. Purkinje neuron-specific asprosin receptor (Ptprd) deletion results in reduced water intake without affecting food intake and abolishes asprosin’s dipsogenic effect. Purkinje neuron-mediated motor learning and coordination were unaffected by these manipulations, indicating independent control of two divergent functions by Purkinje neurons. Our results show that the cerebellum is a thirst-modulating brain area and that asprosin–Ptprd signaling may be a potential therapeutic target for the management of thirst disorders.

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Fig. 1: Genetic and pharmacological asprosin inhibition is associated with hypodipsia.
Fig. 2: Asprosin activates cerebellar Purkinje neurons.
Fig. 3: Purkinje neuron activation enhances water intake in mice.
Fig. 4: Purkinje neuron-specific Ptprd deletion leads to hypodipsia.
Fig. 5: Purkinje-specific Ptprd deletion does not affect motor learning and coordination.
Fig. 6: Purkinje neuron-specific Ptprd deletion abolishes water-deprivation-induced Purkinje neuron activation.
Fig. 7: Asprosin activates Purkinje neurons in vivo, and Purkinje neuron-specific Ptprd deletion renders mice unresponsive to the dipsogenic effects of asprosin.

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All data used in the analysis are available to any researcher for the purposes of reproducing or extending the analysis in source data files. Further information and requests for resources and reagents should be directed to and will be fulfilled by the corresponding author. Source data are provided with this paper.

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Acknowledgements

We thank members of the Chopra lab for helpful suggestions and critical reading of the manuscript. This work was supported by the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK130931, DK118290), the NIH National Institute of Neurological Disorders and Stroke (NINDS) (R01NS119301, R01NS127435), the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103555) for use of the Cell and Tissue Pathogenesis Core and In Situ Hybridization Core (the BCM IDDRC) and the Harrington Discovery Institute at University Hospitals, Cleveland, Ohio. The Genotype-Tissue Expression (GTEx) Project is supported by the Common Fund of the Office of the Director of the NIH (additional funds were provided by the National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health and NINDS). The use of the Texas A&M Rodent Preclinical Phenotyping Core is acknowledged for the determination of plasma and urine osmolality. The Cardiovascular Research Institute Mouse Metabolic and Phenotyping Core of CWRU (IACUC no. 2019-0029) is acknowledged for the use of metabolic caging.

Author information

Authors and Affiliations

Authors

Contributions

I.M. and B.F. performed water intake studies. B.F. performed immunohistochemistry. J.C.B. carried out the alkaline phosphatase tag staining. B.F. performed fiber photometry recording experiments. I.M., B.B., M.A.R., A.M., A.H., S.B., A. Sharp, C.P., B.K. and A.L. performed motor function and learning assays. A.M.B., L.H.K. and T.L. performed in vivo electrophysiology and MATLAB analysis. I.M., B.B. and B.F. maintained mouse colonies and conducted genotyping of mice. I.M., Y.H. and A.R.C. defined the methodology. I.M., B.F. and A. Sathyanesan conducted the analysis. I.M. and A.R.C. conceptualized the idea. I.M. wrote the original draft. A. Sathyanesan, R.V.S., Y.H. and A.R.C. supervised, provided funding and reviewed and edited the manuscript.

Corresponding authors

Correspondence to Yanlin He or Atul R. Chopra.

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Competing interests

A.R.C. has been awarded asprosin-related patents and is a co-founder and equity holder of Aceragen and Recall Therapeutics. The other authors declare no competing interests.

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Nature Neuroscience thanks Albert Chen 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 AgRP neuron-specific Ptprd deletion does not affect water intake.

(a) Body weight of 5-week-old male and female Ptprdf/f and AgRP-cre;Ptprdf/f mice maintained on ad libitum fed normal chow diet (n = 8 males and 9 females/group). (b-c) 24h food and water intake of 14-week-old male and 8-week-old female Ptprdf/f and AgRP-cre;Ptprdf/f mice maintained on ad libitum normal chow diet (n = 4/group). (d) Body weight of female Ptprdf/f and AgRP-cre;Ptprdf/f mice on normal chow (week 5, n = 10/group), and after 5 weeks of high fat diet (Week 10; n = 8/ group). (e-g) Daily Food intake (E), cumulative water intake (F) and average daily water intake (G) of 14-week-old Ptprdf/f and AgRP-cre;Ptprdf/f mice, measured over 4 days using the Promethion metabolic system (n = 6 /group). Error bars represent mean ± s.e.m. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001; by Two-way ANOVA followed by Sidak’s multiple comparison in A-E, 2-Way ANOVA (effect of genotype) in F and two tailed unpaired Student’s t-test in G. Raw data values, P values and details of statistical tests in Extended source data 1.

Source data

Extended Data Fig. 2 Cerebellar Purkinje neurons, but not granule neurons, are responsive to asprosin.

(a) Data analysis of cerebellar granule neurons resting membrane potential in response to puff (2s) treatment of 30 nM recombinant asprosin (n = 19 neurons from 3 male mice). (b) Data analysis of cerebellar granule neurons resting membrane potential in response to puff (2s) treatment of 30 nM recombinant asprosin, in the presence of cocktail synaptic blockers including 1 μM tetrodotoxin (TTX, 30 μM AP-5, 30 μM CNQX and 50 μM bicuculline; n = 17 neurons from 3 male mice). (c) Schematic of coronal brain section showing Purkinje neurons recorded in different places. (d-e) Data analysis of cerebellar Purkinje neurons firing frequency and resting membrane potential in response to puff (2s) treatment of 30 nM recombinant asprosin (n = 21 neurons with baseline firing from 3 male mice in the range of 1–6 Hz, n = 14 neurons from 3 male mice with baseline firing in the range of 10–30, n = 38 neurons from 3 male mice with baseline firing in the range of 46–64 Hz). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001; by Two-tailed paired Student’s t-test. Raw data values, P values and details of statistical tests in Extended source data 2.

Source data

Extended Data Fig. 3 Chemogenetic activation of Purkinje neurons enhances water intake without affecting food intake or body weight.

(a-i) Mean ± s.e.m. 24h water intake (A,D,G) food intake (B,E,H) and body weight (C,F,I) post intraperitoneal injection of CNO (3 mg/kg, twice/day) or saline in Pcp2cre male mice stereotaxically injected with Cre-dependent AAV expressing hSyn-DIO-hM3Dq-mCherry in lobe IV-V, VII-VIII and VIII-IX of cerebellum (n = 6 mice/treatment/brain site). (j-l) CNO treatment does not cause hyperdipsia in absence of hSyn-DIO-hM3Dq-mCherry. Mean ± s.e.m. 24h food and water intake (number of drinking bouts, time spent drinking and water intake) post intraperitoneal injection of CNO (3 mg/kg, twice/day) or saline in Pcp2cre male mice stereotaxically injected with Cre-dependent AAV expressing hSyn-DIO-mCherry in lobe VII-VIII of cerebellum (n = 6 mice/treatment). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001; by unpaired two-tailed Student’s t-test. Raw data values, P values and details of statistical tests in Extended source data 3.

Source data

Extended Data Fig. 4 Purkinje neuron-specific Ptprd deletion affects water, isotonic and hypertonic saline intake.

(a-b) Water intake of 8-week-old Pcp2cre;Ptprd+/+ and Pcp2cre;Ptprdflox/flox female mice maintained on normal chow diet, measured using the Promethion metabolic system (n = 5/group). (c) Body weight of 8-week-old Pcp2cre;Ptprd+/+ and Pcp2-cre;Ptprdflox/flox female mice maintained on normal chow diet (n = 5/group). (d-f) Cumulative food intake (D), hourly energy expenditure (E) and respiratory exchange ratio (F) of 8-week-old Pcp2-cre;Ptprd+/+ and Pcp2cre;Ptprdflox/flox female mice maintained on normal chow diet, measured using the Promethion metabolic system (n = 5/ group). (g-h) Lick frequency (counts per first minute, and cumulative counts per first 5 minutes of water access) of Pcp2cre;Ptprd+/+ (n=5 per group) and Pcp2cre;Ptprdflox/flox male (n = 4 per group) mice given re-access to water after overnight water deprivation. (i-j) 48h isotonic and hypertonic (500mM) saline intake of Pcp2-cre;Ptprd+/+ and Pcp2cre;Ptprdflox/flox male mice (n = 4 per group). Error bars represent mean ± s.e.m. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001; by Student’s t-test (B, C,G-J) and two-way ANOVA (effect of genotype) in A,D,E and F. Raw data values, P values and details of statistical tests in Extended source data 4.

Source data

Extended Data Fig. 5 Purkinje neuron-specific Ptprd deletion does not protect from diet induced obesity.

Weekly body weight change of Pcp2cre;Ptprd+/+ (male: n=8; female: n=5) and Pcp2cre;Ptprdflox/flox (male: n=7; female: n=5) mice maintained on high-fat diet (HFD) from 5-weeks-of-age. NS: not significant; by two-way ANOVA (effect of genotype). Raw data values, P values and details of statistical tests in Extended source data 5.

Source data

Extended Data Fig. 6 Purkinje neuron-specific Ptprd loss results in increased regularity of Purkinje neuron complex spikes.

(a) Schematic representation of an in vivo awake single-unit recording. (b-c, top) Raw electrophysiological trace of Purkinje cell activity in awake Pcp2-cre;Ptprd+/+ (B) and Pcp2cre;Ptprdflox/flox (C) mice (scale: 1 s). (B-C, bottom) Cumulative overlay of multiple simple spike (left) and complex spike (right) waveforms demonstrating the consistency in the action potential shapes from the above representative traces. (d-f) Comparison of simple spike features including firing rate (D), CV (E), and CV2 (F) in Pcp2-cre;Ptprd+/+ (N = 7, n = 18) and Pcp2cre;Ptprdflox/flox (N = 7, n = 17) mice. (g-j) Comparison of complex spike features including firing rate (G), CV (H), and CV2 (I) in Pcp2-cre;Ptprd+/+ (N = 7, n = 18) and Pcp2cre;Ptprdflox/flox (N = 7, n = 17) mice. Mean of firing rate, CV and CV2 plotted in (D-I). Number of animals is represented as ‘N’ while number of cells is represented as ‘n’. *p < 0.05 as determined by unpaired t-tests with Welch’s correction and adjusted for multiple comparisons using the Bonferroni method. Raw data values, P values and details of statistical tests in Extended source data 6.

Source data

Extended Data Fig. 7 Purkinje neurons are unresponsive to traditional dipsogenic stimuli.

(a-c) GCaMP7 fluorescent response of Pcp2cre neurons in response to hypertonic stress (3M NaCl and 2M mannitol) and hypovolemic stress (30% polyethylene glycol; PEG; n = 5 wild type mice in each treatment). (d-f) 2h water intake (D,E) and 48 h water intake (F) of control (Pcp2-cre;Ptprd+/+) and knockout (Pcp2-cre;Ptprdflox/flox) mice injected with 3M NaCl (D), 2M mannitol (E) and 30% PEG (F). n = 6 Pcp2-cre;Ptprd+/+ and 11 Pcp2-cre;Ptprdflox/flox mice in (D) or 5 Pcp2-cre;Ptprd+/+ and 11 Pcp2-cre;Ptprdflox/flox mice in (E) and n = 12 Pcp2-cre;Ptprd+/+ and n = 11 Pcp2-cre;Ptprdflox/flox mice in (F). Error bars represent mean ± s.e.m. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001; by two-tailed unpaired Student’s t-test. Raw data values, P values and details of statistical tests in Extended source data 7.

Source data

Extended Data Fig. 8 Purkinje Neurons modulate thirst.

Asprosin activates the cerebellar Purkinje neurons via the Ptprd receptor, leading to rapid manifestation of water drinking behavior.

Supplementary information

Supplementary Information

Supplementary Figs. 1–7

Reporting Summary

Supplementary Video 1

Video analysis of mice subjected to photostimulation. Representative video of water drinking behavior in Pcp2-ChR2-EYFP mice post yellow light (598 nm, 5 Hz, 3 s on and 3 s off) stimulation. See analysis in Fig. 3p,q.

Supplementary Video 2

Video analysis of mice subjected to photostimulation. Representative video of water drinking behavior in Pcp2-ChR2-EYFP mice post blue light (473 nm, 5 Hz, 3 s on and 3 s off) stimulation. See analysis in Fig. 3p,q.

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Mishra, I., Feng, B., Basu, B. et al. The cerebellum modulates thirst. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01700-9

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