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Diet-induced inflammation in the anterior paraventricular thalamus induces compulsive sucrose-seeking

Nature Neuroscience volume 25, pages 1009–1013 (2022)Cite this article

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Abstract

Overconsumption of palatable food may initiate neuroadaptive responses in brain reward circuitry that may contribute to eating disorders. Here we report that high-fat diet (HFD) consumption impedes threat-cue-induced suppression of sucrose-seeking in mice. This compulsive sucrose-seeking was due to enhanced cue-triggered neuronal activity in the anterior paraventricular thalamus (aPVT) resulting from HFD-induced microglia activation. Thus, metabolic inflammation in the aPVT produces an adaptive response to threat cues, leading to compulsive food-seeking.

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Fig. 1: HFD consumption for 1 week induces compulsive sucrose-seeking behavior in adult mice.
Fig. 2: Excitation of aPVT excitatory neurons promotes compulsive sucrose-seeking behavior in mice.
Fig. 3: HFD-induced microglia proliferation in the aPVT promotes compulsive sucrose-seeking in mice.

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Data availability

Source data are available in the source data files for Figs. 1–3, Extended Data Figs. 1–10 and Supplementary Figs. 2 and 3. Source data are provided with this paper.

Code availability

No custom software code was used.

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Acknowledgements

We thank the excellent technical assistance of the Imaging Facility at Zhejiang University School of Medicine. This work was supported by a MOST grant 2019YFA0801900 (Y.-D.Z.), National Natural Science Foundation of China grants 81770839 and 81821091 (Y.-D.Z.), 81971139 (Y.S.) and 81901374 (J.C.) and National Key Research and Development Program grant 2021YFC2701901 (J.F.).

Author information

Author notes

  1. Chunlu Li

    Present address: Department of Psychology, School of Medical Humanitarians, Guizhou Medical University, Guiyang, China

  2. These authors contributed equally: Jingjing Cheng, Xiaolin Ma, Chunlu Li.

Authors and Affiliations

  1. Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou, China

    Jingjing Cheng, Xiaolin Ma, Chunlu Li, Rahim Ullah, Xiaoyu Wang, Jianmei Long, Zhenxin Yuan, Yi Shen & Yu-Dong Zhou

  2. Department of Ophthalmology of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Jingjing Cheng, Xiaolin Ma, Xiaoyu Wang, Jianmei Long, Zhenxin Yuan & Yu-Dong Zhou

  3. Laboratory Medicine Center, Department of Transfusion Medicine, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, China

    Jingjing Cheng

  4. Department of Endocrinology, Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China

    Rahim Ullah & Junfen Fu

  5. Core Facilities, Zhejiang University School of Medicine, Hangzhou, China

    Shuangshuang Liu

  6. Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

    Zhong Chen

  7. Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, China

    Yi Shen & Yu-Dong Zhou

  8. Lingang Laboratory, Shanghai, China

    Yu-Dong Zhou

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Contributions

Y.-D.Z. and Y.S. designed the study. Y.-D.Z. and J.C. wrote the paper. J.C., X.M., C.L., R.U., X.W., Z.Y., J.L., S.L. and Y.S. analyzed the data. J.C., X.M., C.L., Z.Y. and J.L. performed behavioral studies. X.M. performed electrophysiology and fiber photometry experiments. J.C., X.M., C.L., R.U., X.W., J.L. and S.L. performed immunostaining and biochemical studies. Z.C. and J.F. contributed intellectually to the manuscript. All authors commented on the manuscript.

Corresponding authors

Correspondence to Yi Shen or Yu-Dong Zhou.

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The authors declare no competing interests.

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Nature Neuroscience thanks Gavan McNally, Chun-Xia Yi 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 Compulsive eating behavior in HFD mice appears before a greater body weight gain in these mice than in chow mice.

a, Quantification of the numbers of lever presses in the 30-min baseline (BL, solid bars) and 30-min test (open bars) sessions of the sucrose self-administration test in mice fed chow (n = 14 mice) or HFD for 3 days (n = 9 mice), 1 week (1-wk, n = 8 mice), 2 weeks (2-wks, n = 7 mice), 4 weeks (4-wks, n = 10 mice), or 8 weeks (8-wks, n = 11 mice). b, Bar graph showing the ratios of test lever presses to baseline lever presses in animal groups shown in a. BL, baseline. c, Quantification of the body weight of mice fed chow (n = 11 mice), chow + PLX3397 (n = 10 mice), HFD (n = 11 mice), or HFD + PLX3397 (n = 10 mice) in a period of 30 days. d, Bar graphs showing the body weight of mice in c at 7 days (left), 14 days (middle), and 28 days (right) following their respective treatment. e, Quantification of calorie (Kcal) intake of mice fed chow (n = 4 cages, 20 mice), chow + PLX3397 (n = 3 cages, 18 mice), HFD (n = 4 cages, 20 mice), or HFD + PLX3397 (n = 3 cages, 18 mice) for 14 days. * P < 0.05, ** P < 0.01, *** P < 0.001. Data are mean ± SEM. See Supplementary Tables 1 and 2 for further details of statistical data analysis.

Source data

Extended Data Fig. 2 Mice fed HFD perform normally in the spontaneous sucrose consumption, EPM, and open field tests.

a, Representative tracings of chow and HFD mice performing the spontaneous sucrose consumption test in an open field apparatus. b-e, Quantification of the number of entries (b), the time spent (c), and the total distance (d) and speed (e) of travel per feeding zone during the sucrose consumption test for chow and HFD mice. n = 10 mice for each group. f, Bar graph showing the consumption of 10% and 30% sucrose during the test for chow and HFD mice. n = 10 mice for each group. g, Representative tracings of chow and HFD mice performing the EPM test. Open arms are horizontal in the panel. h, Quantification of the number of entries into the open arms (left) and the time spent in the open arms (right) for chow and HFD mice. n = 12 mice for each group. i, Representative tracings of control and HFD mice performing the open field test. j, Quantification of the number of central entries (left), the time spent in the central area (middle), and the total distance travelled (right) for control and HFD mice. n = 12 mice for each group. Data are mean ± SEM. See Supplementary Table 2 for further details of statistical data analysis.

Source data

Extended Data Fig. 3 The aPVT shows increased neuronal activities following the compulsive sucrose seeking test but not the spontaneous sucrose consumption and fear conditioning tests in HFD mice compared to chow mice.

a, Representative images of c-fos+ cells (green) in the aPVT and pPVT areas in mice fed chow or HFD for 1 week. b, Quantification of the densities of c-fos+ cells in the aPVT (n = 10 sections/3 mice for Chow group and 8 sections/3 mice for HFD group) and pPVT (n = 6 sections/3 mice for Chow group and 9 sections/3 mice for HFD group) in chow and HFD mice. c, Representative images of c-fos+ cells in various brain regions of chow and HFD mice. d, Quantification of the densities of c-fos+ cells in various brain areas of chow (Cg2_PrL: n = 4 sections/3 mice; M2: n = 8 sections/3 mice; AcbSh: n = 8 sections/3 mice; LSD + LSV: n = 11 sections/3 mice; BLA: n = 4 sections/3 mice; VMH: n = 4 sections/3 mice; DMH: n = 3 sections/3 mice; MePV_Aco: n = 4 sections/3 mice) and HFD (Cg2_PrL: n = 10 sections/3 mice; M2: n = 6 sections/3 mice; AcbSh: n = 8 sections/3 mice; LSD + LSV: n = 7 sections/3 mice; BLA: n = 3 sections/3 mice; VMH: n = 4 sections/3 mice; DMH: n = 3 sections/3 mice; MePV_Aco: n = 3 sections/3 mice) mice. e, Representative images (left) and quantification of the number (right) of c-fos+ cells in the aPVT in chow (n = 22 sections/4 mice) and HFD (n = 19 sections/5 mice) mice after the spontaneous sucrose consumption test. f, Representative images (left) and quantification of the number (right) of c-fos+ cells in the aPVT in chow (n = 10 sections/3 mice) and HFD (n = 14 sections/4 mice) mice the fear conditioning test. Scale bars, 100 μm. * P < 0.05, ** P < 0.01. Data are mean ± SEM. See Supplementary Table 2 for further details of statistical data analysis.

Source data

Extended Data Fig. 4 The CaMKIIα neurons in the aPVT do not respond to visual cues and foot-shocks in chow and HFD mice before and after fear conditioning.

a, b, Average GCaMP6f responses to visual cues followed by foot-shocks, visual cues only, and foot-shocks only from CaMKIIɑ+ neurons in the aPVT in chow and HFD mice before (a) and after (b) fear conditioning. n = 9 mice for Chow group and 8 mice for HFD group. c, d, Heatmap of ΔF/F for all individual trials from chow and HFD mice before (c) and after (d) fear conditioning. e, f, Quantification of the area under the curve (AUC) of GCaMP6f responses in the period of 6 s in chow and HFD mice before (e) and after (f) fear conditioning. n = 9 mice for Chow group and 8 mice for HFD group. Data are mean ± SEM. See Supplementary Table 2 for further details of statistical data analysis.

Source data

Extended Data Fig. 5 Activating the excitatory neurons in the aPVT does not alter Pavlovian fear, nor does it change the pain sensitivities in mice.

a, Bar graph showing the time spent freezing during a 10-s period before (precue) and after (postcue) presentation of a cue light in fear-conditioned control and ChR2 mice under the conditions of laser on/off. n = 7 mice for each group. b, Bar graph showing the foot-shock currents required to elicit flinching, jumping, and vocalizing in control and ChR2 mice under conditions of laser on/off. n = 4 mice for Ctrl group and 7 mice for ChR2 group. Data are mean ± SEM. See Supplementary Table 1 for further details of statistical data analysis.

Source data

Extended Data Fig. 6 Time course of microglia activation following HFD feeding and the interaction between activated neurons and microglia in the aPVT in HFD mice.

a, Representative images of the Iba-1+ cells (green) in the aPVT in mice fed chow, HFD for 3 days (3-day HFD), HFD for 1 week (1-wk HFD), and HFD for 4 weeks (4-wks HFD). Scale bar, 100 μm. b, Quantification of the number of the Iba-1+ microglia in the aPVT from chow (n = 8 sections/3 mice), 3-day HFD (n = 9 sections/3 mice), 1-wk HFD (n = 9 sections/3 mice), and 4-wks HFD (n = 9 sections/3 mice) groups. c, Representative images of the Iba-1+ cells (blue) and the c-fos+ (green) CaMKIIα (red) neurons in the aPVT in chow and HFD mice infused with ACSF or an anti-CSF-1 antibody. Scale bar, 50 μm. d, Quantification of the contact area between the c-fos+ CaMKIIα neurons and the Iba-1+ microglia in chow and HFD mice infused with ACSF or the anti-CSF-1 antibody. e, Quantification of the numbers of the c-fos+ CaMKIIα neurons that are located in three continuous concentric shells (0-2, 2-5, 5-10 μm) centered on individual Iba-1+ microglia in the aPVT of chow and HFD mice infused with ACSF or the anti-CSF-1 antibody. In d and e, n = 7 sections/2 mice, 15 sections/3 mice, 16 sections/3 mice, and 11 sections/3 mice for Chow + ACSF, Chow + anti-CSF-1, HFD + ACSF, and HFD + anti-CSF-1 groups, respectively. * P < 0.05, ** P < 0.01, *** P < 0.001. Data are mean ± SEM. See Supplementary Tables 1 and 2 for further details of statistical analysis.

Source data

Extended Data Fig. 7 Intraventricular administration of PA into the D3V induces microglia proliferation in the aPVT but not in the hypothalamus and promotes compulsive sucrose seeking in chow mice without changing their body weight.

a, Schematic of the experimental approaches of intraventricular (i.c.v.) delivery of PA-BSA complexes and behavioral training and testing sessions. b, c, Representative images of Iba-1+ microglia (b) and quantification of the density of Iba-1+ microglia (c) in the aPVT of chow mice after i.c.v administration of BSA (n = 10 sections/4 mice), 500 μM PA in BSA (n = 8 sections/4 mice), or 800 μM PA in BSA (n = 8 sections/4 mice). Bar, 100 μm. d, e, Quantification of the numbers of lever presses in the baseline (BL, solid bars) and test (open bars) sessions (d) and the ratio of test lever presses to baseline lever presses (e) in the cued sucrose self-administration test in chow mice treated with BSA (n = 9 mice), 500 μM PA in BSA (n = 9 mice), or 800 μM PA in BSA (n = 8 mice). f, Representative images showing the Iba-1+ microglia in the ARC and VMH after i.c.v administration of BSA, 500 μM PA in BSA, or 800 μM PA in BSA. Scale bar, 100 μm. g, h, Bar graphs showing the numbers of Iba-1+ microglia in the ARC (g) and VHM (h) after i.c.v. administration of BSA (n = 17 sections/5 mice), 500 μM PA in BSA (n = 14 sections/3 mice), or 800 μM PA in BSA (n = 15 sections/4 mice). i, Bar graphs showing the body weight of mice after i.c.v. administration of BSA (n = 6 mice), 500 μM PA in BSA (n = 5 mice), or 800 μM PA in BSA (n = 5 mice) for 1 day (left), 7 days (middle), and 14 days (right). * P < 0.05, *** P < 0.001. Data are mean ± SEM. See Supplementary Tables 1 and 2 for further details of statistical data analysis.

Source data

Extended Data Fig. 8 Enhanced neuronal activation in the aPVT and DMH is suppressed by PLX3397 treatment in mice fed HFD.

a-d, Representative images (left) and quantification of the number (right) of c-fos+ cells (green) in the aPVT (a), pPVT (b), DMH (c), and VMH (d) in mice from chow (aPVT: n = 12 sections/4 mice; pPVT: n = 12 sections/4 mice; DMH: n = 9 sections/3 mice; VMH: n = 9 sections/3 mice), chow + PLX3397 (aPVT: n = 19 sections/5 mice; pPVT: n = 16 sections/5 mice; DMH: n = 15 sections/5 mice; VMH: n = 11 sections/3 mice), HFD (aPVT: n = 15 sections/4 mice; pPVT: n = 18 sections/5 mice; DMH: n = 15 sections/4 mice; VMH: n = 14 sections/4 mice), and HFD + PLX3397 (aPVT: n = 18 sections/5 mice; pPVT: n = 20 sections/5 mice; DMH: n = 15 sections/4 mice; VMH: n = 12 sections/4 mice) groups. Scale bars, 100 μm. * P < 0.05, *** P < 0.001. Data are mean ± SEM. See Supplementary Table 2 for further details of statistical data analysis.

Source data

Extended Data Fig. 9 Neither the cannula implantation nor the repetitive injections affect microglial activation and neuronal number and morphology in the aPVT in mice fed chow.

a, Representative images of the aPVT Iba-1+ cells (green) in mice from the no cannula implantation (no cannula), cannula implantation without infusion (no injection), cannula implantation with one injection of ACSF (ACSF 1x), cannula implantation with one injection of an anti-CSF-1 antibody (anti-CSF-1 1x), and cannula implantation with 5 injections of the anti-CSF-1 antibody (anti-CSF-1 5x) groups. Scale bar, 100 μm. b, Quantification of the number of the Iba-1+ microglia in the aPVT in mice from the groups in a. n = 8, 9, 8, 9, and 8 sections/3 mice for No cannula, No injection, ACSF 1x, anti-CSF-1 1x, and anti-CSF-1 5x groups, respectively. c, Representative images of the Nissl-stained sections of the aPVT in mice from the no cannula, no injection, ACSF 1x, anti-CSF-1 1x, and anti-CSF-1 5x groups. Scale bars, 1 mm and 200 μm. d, Quantification of the number of the Nissl-stained neurons in the aPVT in mice from the groups in c. n = 9 sections/3 mice for each group. e, Representative images of the CaMKIIα neurons in the aPVT in mice from the no cannula, no injection, ACSF 1x, anti-CSF-1 1x, and anti-CSF-1 5x groups. Scale bar, 50 μm. f, Quantification of the number of the neurite intersections of the CaMKIIα neurons at different distance from the soma in the aPVT in mice from the groups in e. n = 10, 9, 8, 10, and 8 sections/3 mice for no cannula, no injection, ACSF 1x, anti-CSF-1 1x, and anti-CSF-1 5x groups, respectively. Data are mean ± SEM. See Supplementary Tables 1 and 2 for further details of statistical data analysis.

Source data

Extended Data Fig. 10 Partial depletion of microglia in the aPVT does not alter the Pavlovian fear, nor does it change the pain sensitivity in HFD mice.

a, Bar graph showing the time spent freezing during a 10-s period before (precue) and after (postcue) presentation of a cue light in fear-conditioned HFD mice infused with ACSF (n = 5 mice) or anti-CSF-1 antibody (n = 6 mice) in the aPVT. b, Bar graph showing the foot-shock currents required to elicit flinching, jumping, and vocalizing in HFD mice infused with ACSF (n = 6 mice) or anti-CSF-1 antibody (n = 7 mice). * P < 0.05, *** P < 0.001. Data are mean ± SEM. See Supplementary Tables 1 and 2 for further details of statistical data analysis.

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Cheng, J., Ma, X., Li, C. et al. Diet-induced inflammation in the anterior paraventricular thalamus induces compulsive sucrose-seeking. Nat Neurosci 25, 1009–1013 (2022). https://doi.org/10.1038/s41593-022-01129-y

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