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Food craving-like episodes during pregnancy are mediated by accumbal dopaminergic circuits

Nature Metabolism volume 4, pages 424–434 (2022)Cite this article

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Abstract

Preparation for motherhood requires a myriad of physiological and behavioural adjustments throughout gestation to provide an adequate environment for proper embryonic development1. Cravings for highly palatable foods are highly prevalent during pregnancy2 and contribute to the maintenance and development of gestational overweight or obesity3. However, the neurobiology underlying the distinct ingestive behaviours that result from craving specific foods remain unknown. Here we show that mice, similarly to humans, experience gestational food craving-like episodes. These episodes are associated with a brain connectivity reorganization that affects key components of the dopaminergic mesolimbic circuitry, which drives motivated appetitive behaviours and facilitates the perception of rewarding stimuli. Pregnancy engages a dynamic modulation of dopaminergic signalling through neurons expressing dopamine D2 receptors in the nucleus accumbens, which directly modulate food craving-like events. Importantly, persistent maternal food craving-like behaviour has long-lasting effects on the offspring, particularly in males, leading to glucose intolerance, increased body weight and increased susceptibility to develop eating disorders and anxiety-like behaviours during adulthood. Our results reveal the cognitively motivated nature of pregnancy food cravings and advocates for moderating emotional eating during gestation to prevent deterioration of the offspring’s neuropsychological and metabolic health.

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Fig. 1: Sweet taste perception and food craving-like behaviour increase during pregnancy.
Fig. 2: Brain functional networks related to reward and emotions are transiently increased during pregnancy.
Fig. 3: Accumbal D2R neurons underlie pregnancy-specific food craving-like behaviour.
Fig. 4: Recurrent maternal highly palatable food craving-like behaviour deteriorates offspring health.

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Data availability

The data that support the findings of the study are available from the corresponding authors upon reasonable request. Source data are provided with this paper. All other data are available in the main text or the Supplementary Information.

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Acknowledgements

We are grateful to J. M. Marimon (Universitat de Barcelona) for mouse vasectomy procedures; A. Garcia (IDIBAPS) for assistance with mouse breeding; S. Luquet (Université de Paris), A. Quintana (Universitat Autònoma de Barcelona) and M. Schneeberger (Yale University) for valuable comments on the manuscript. This study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 725004) and supported by: ‘la Caixa’ Foundation (ID100010434) under agreement LCF/PR/HR19/52160016 and the CERCA Programme/Generalitat de Catalunya (to M.C.); grant no. PID2019-105136RB-100, Spanish Ministry of Economy and Competitiveness (MINECO) and European Regional Development Fund (ERDF; to A.B.); Marie Skłodowska-Curie Action fellowship (H2020-MSCA-IF) NEUROPREG (grant agreement no. 891247; to R.H-T.); the Spanish Ministry of Science and Innovation, Juan de la Cierva fellowship (IJC2018-037341-I to S.R.); Miguel Servet contract (CP19/00083) from Instituto de Salud Carlos III co-financed by ERDF (to A.O.). This work was carried out in part at the Esther Koplowitz Centre.

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Authors and Affiliations

  1. Neuronal Control of Metabolism (NeuCoMe) Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Roberta Haddad-Tóvolli, Sara Ramírez, Maria Milà-Guasch, Macarena Pozo, Iñigo Chivite, Arnaud Obri, Alicia G. Gómez-Valadés, Miriam Toledo, Elena Eyre & Marc Claret

  2. Experimental 7T MRI Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Emma Muñoz-Moreno & Guadalupe Soria

  3. Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain

    Lluis Miquel-Rio & Analia Bortolozzi

  4. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Lluis Miquel-Rio & Analia Bortolozzi

  5. CIBER de Salud Mental (CIBERSAM), Madrid, Spain

    Lluis Miquel-Rio & Analia Bortolozzi

  6. Laboratory of Metabolism, Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Jordi Altirriba

  7. IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France

    Emmanuel Valjent

  8. Laboratory of Surgical Neuroanatomy, Faculty of Medicine and Health Sciences, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain

    Guadalupe Soria

  9. CIBER de Bioingeniera, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain

    Guadalupe Soria

  10. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain

    Marc Claret

  11. School of Medicine, Universitat de Barcelona, Barcelona, Spain

    Marc Claret

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  1. Roberta Haddad-Tóvolli
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Contributions

R.H.-T. and M.C. conceptualized and supervised the study, and acquired project funding. M.C. administered the project. R.H.-T., S.R., M.M.-G., M.P., I.C., A.O., A.G.G.-V., M.T., E.E., L.M.-R., J.A. and A.B. performed experiments and discussed data. E.M.-M. and G.S. performed fMRI data acquisition and analyses. R.H.-T., S.R., E.M.-M., E.V., G.S., L.M.-R., A.B. and M.C. contributed to method development and data interpretation. R.H.-T., E.M.-M., G.S. and M.C. developed the data visualizations. R.H-T. and M.C. wrote the original draft of the paper with editing and reviewing inputs from all authors.

Corresponding authors

Correspondence to Roberta Haddad-Tóvolli or Marc Claret.

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The authors declare no competing interests.

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Peer review information

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

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Extended data

Extended Data Fig. 1 Sweet taste perception, food craving-like behaviour and anxiety-like states during pregnancy.

a, Preference for diverse sucralose concentrations (0.05–2.5 mM). Black arrow indicates the selected concentration in which virgin female mice were unable to distinguish sucralose from water (n = 5 mice per group/ average of 5 measurements per week). b, Preference for diverse sucrose concentrations (25–200 mM). Black arrow indicates the selected concentration in which virgin female mice were unable to distinguish sucrose from water (n = 5 mice per group/ average of 5 measurements per week). c, Daily food intake of chow when pregnant females (during the second and third week of pregnancy) were exposed to the two-bottle paradigm. Water (n = 32), Sucrose (n = 29), Sucralose (n = 31). d, Schematic illustration of HPF “limited access” paradigm. e, Total daily caloric intake of virgin (n = 8), pseudopregnant (n = 22) and pregnant (n = 13) mice. f, Serum progesterone levels of virgin (n = 5), pseudopregnant (n = 15) and pregnant (n = 8) mice throughout the study. g, h, Recorded parameters to assess open field performance in virgin (n = 10), pregnant (n = 12) and after pregnancy (n = 10) mice, including percentage of time spent per zone (g), and total distance travelled (h). i, j, Recorded parameters to assess dark-light box performance in virgin (n = 8), pregnant (n = 12) and after pregnancy (n = 9) mice, including the latency to cross to the light compartment (i) and the time spent in the light compartment (j). Dots in all panels represent individual sample data. Data are expressed as mean ± SEM. Exact P values are shown. Statistical analysis was performed by one-way ANOVA with Tukey’s multiple comparisons test for c, g, h, i, j and by two-way ANOVA with Tukey’s multiple comparisons test for e, f. When the factors Group, Time and/or the interaction Group:Time were considered significant, results are shown with significant factor or the interaction effect next to it (f). BP: before pregnancy; W1: first week of pregnancy (or concomitant experimental week); W2: second week of pregnancy (or concomitant experimental week); W3: third week of pregnancy (or concomitant experimental week); AP: after pregnancy.

Source data

Extended Data Fig. 2 The architecture of the female mouse brain resting-state network during pregnancy.

Independent component spatial maps for the 13 cortical and subcortical resting-state networks of the pregnant female mouse brain. Virgins (n = 7), Pregnants (n = 8), After Pregnancy (n = 7). Representative axial, sagittal and coronal slices for each component are shown. a, Cingulate/Retrosplenial Cortex. b, Primary Somatosensory Area 1. c, Prefrontal Cortex. d, Right Thalamus. e, Primary Somatosensory Area 2. f, Left Hippocampus. g, Cortico-striatal network (motor cortex and striatum). h, Thalamus. i, Right Hippocampus. j, Primary Somatosensory Area 4. k, Ventral Striatum. l, Temporal association Area. m, Salience Network (insular cortex and midbrain).

Extended Data Fig. 3 Main dopaminergic markers and Th neuronal activity are not altered in the VTA during pregnancy.

a, Gene expression levels of dopaminergic markers, Th and Slc6a3, in the VTA of virgin (n = 5 for Th/6 for Slca3a), pregnant (n = 6) and after pregnancy (n = 4) mice. b, Representative confocal images of TH (red) and Fos (green) expression in the VTA of virgin, pregnant and after pregnancy mice. Nuclei are stained with DAPI (blue). Scale bar: 50 μm. c, Percentage of Fos positive TH neurons in the VTA of virgin (n = 3), pregnant (n = 4) and after pregnancy (n = 3) mice. d, Number of TH positive neurons throughout the VTA (bregma -3.10 to -3.70) of virgin (n = 3), pregnant (n = 3) and after pregnancy (n = 3) mice. Dots in all panels represent individual sample data. Data are expressed as mean ± SEM. Exact P values are shown. Statistical analysis was performed by one-way ANOVA with Tukey’s multiple comparisons test for a, c, d. VTA: ventral tegmental area; Th: tyrosine hydroxylase; Slc6a3: Solute Carrier Family 6 Member 3 encoding for the dopamine transporter (DAT); Gapdh: Glyceraldehyde 3-phosphate dehydrogenase.

Source data

Extended Data Fig. 4 Dopamine receptors expression in dStri and NAc of female mice.

a, Representative confocal images of Drd1 (white), Drd2 (green) and Fos (red) mRNA expression in the dStri of virgin, pregnant and after pregnancy mice. Nuclei are stained with DAPI (blue). Scale bar: 7.5 μm. b, DStri Drd1 mRNA particles per neuron of virgin (n = 3), pregnant (n = 3) and after pregnancy (n = 3) mice. c, Percentage of Fos positive Drd1 neurons in the dStri of virgin (n = 3), pregnant (n = 3) and after pregnancy (n = 3) mice. d, DStri Drd2 mRNA particles per neuron of virgin (n = 3), pregnant (n = 3) and after pregnancy (n = 3) mice. e, Percentage of Fos positive Drd2 neurons in the dStri of virgin (n = 3), pregnant (n = 3) and after pregnancy (n = 3) mice. f, Representative confocal images of Drd1 (white), Drd2 (green) and Fos (red) mRNA expression in the NAc of virgin, pregnant and after pregnancy mice. Nuclei are stained with DAPI (blue). Scale bar: 7.5 μm. Dots in all panels represent individual sample data. Data are expressed as mean ± SEM. Statistical analysis was performed by one-way ANOVA with Tukey’s multiple comparisons test for b, c, d, e. dStri: dorsal striatum; NAc: nucleus accumbens; Drd1: dopamine receptor 1; Drd2: dopamine receptor 2.

Source data

Extended Data Fig. 5 Dopaminergic signalling is not altered in the dStri of pregnant mice.

a, Immunoblot assessing TH phosphorylation levels at residues Ser31 (p-THS31) and Ser40 (p-THS40) in dStri extract from virgin (n = 5), pregnant (n = 5) and after pregnancy (n = 5) mice. b, Immunoblot assessing G protein-dependent and non-canonical β−arrestin-dependent signalling pathways showing its downstream targets, DARPP-32 phosphorylation levels (at residue pThr34; p-D-32T34) and GSK3β phosphorylation levels (at residue pSer9; p-GSK3βS9), respectively, in dStri extract from virgin (n = 5), pregnant (n = 5) and after pregnancy (n = 5) mice. c, Complete immunoblot assessing TH phosphorylation levels at residues Ser31 (p-THS31) and Ser40 (p-THS40) in NAc extract from virgin (n = 5), pregnant (n = 5) and after pregnancy (n = 5) mice. d, Complete immunoblot assessing G protein-dependent and non-canonical β−arrestin-dependent signalling pathways showing its downstream targets, DARPP-32 phosphorylation levels (at residue pThr34; p-D-32T34) and GSK3β phosphorylation levels (at residue pSer9; p-GSK3βS9), respectively, in NAc extract from virgin (n = 5), pregnant (n = 5) and after pregnancy (n = 5) mice. e-f, Neurotransmitter (DA, DOPAC and HVA) levels (e), dopamine turnover (DOPAC to DA ratio) and dopamine storage (HVA to DA ratio) (f) in the dorsal striatum (dStri) of virgins (n = 9) and pregnant (n = 8) females. Dots in all panels represent individual sample data. Data are expressed as mean ± SEM. Exact P values are shown. Statistical analysis was performed by one-way ANOVA with Tukey’s multiple comparisons test for a, b and by two-way ANOVA with Sidak’s multiple comparisons test for e, f. dStri: dorsal striatum; Th: tyrosine hydroxylase; DA: dopamine; PKA: protein kinase A; DARPP-32: dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa; Gsk3β: glycogen synthase kinase 3 beta; NAc: nucleus accumbens; DOPAC: 3,4-Dihydroxyphenylacetic acid; HVA: homovanillic acid.

Source data

Extended Data Fig. 6 Pharmacological blockage of pan-DR receptors reverts pregnancy-specific increase in HPF consumption.

a, Schematic illustration of experimental strategy (left) and percentage of daily caloric intake (right) consumed, during the 2-hours of HPF access, by female mice treated with saline or pan-DR antagonist flupenthixol before and during the second week of pregnancy (n = 11 mice/group). b, Total daily caloric intake (chow + HPF) of female mice treated with saline or pan-DR antagonist flupenthixol before and during the second week of pregnancy (n = 11 mice/group). c-e, Recorded parameters to assess open field performance in female mice treated with saline and pan-DR antagonist flupenthixol, including global activity (c), time spent immobile (d), and total distance travelled (e) (n = 3 mice/group). Schematic of the open field test highlights center (purple) and corner (cream) zones is shown. Dots in all panels represent individual sample data. Data are expressed as mean ± SEM. Exact P values are shown. Statistical analysis was performed by two-way ANOVA with Sidak’s multiple comparisons test for a, b, and by unpaired t-test for c, d, e. BP: before pregnancy; W2: second week of pregnancy.

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Extended Data Fig. 7 Chemogenetic inhibition of accumbal, but not dorsal striatal, D2R-neurons reverts pregnancy-specific food craving-like behavior.

a, Schematic illustration of the DREADD strategy used. b-c, Representative images of mCherry reporter in Drd2Cre/+ female mice injected in the dStri (b) or in the NAc (c) with the AAV-hSyn-DIO-hM4Di-mCherry. Scale bar: 25 μm. d-e, Representative images of mCherry (red) and Fos (green) immunostaining of Drd2+/+ and Drd2Cre/+ mice bilaterally injected in the dStri (d) and in the NAc (e) with the AAV-hSyn-DIO-hM4Di-mCherry. Nuclei are stained with DAPI (blue). Scale bar: 25 μm. f, Number of Fos positive cells per section after CNO injection in the NAc and dStri of Drd2+/+ (n = 3) and Drd2Cre/+ (n = 6 for NAc/5 for dStri) mice. g-h, Representative images of mCherry (red), DARPP-32 (green) and Fos (grey) immunostaining of Drd2Cre/+ mice bilaterally injected in the dStri (g) and in the NAc (h) with the AAV-hSyn-DIO-hM4Di-mCherry. Nuclei are stained with DAPI (blue). Scale bar: 25μm. i, Percentage of Fos positive cells after CNO injection in the NAc (n = 3) and dStri (n = 3) of Drd2Cre/+ mice categorized as D2R (mCherry+ and DARPP-32+) or as D1R (only DARPP-32+). j, Schematic of experimental strategy (left) and total daily caloric intake (chow + HPF) of Drd2+/+ (n = 7) and Drd2Cre/+ (n = 5) female mice after chemogenetic inhibition of D2R neuronal activity in the NAc. k-n, Recorded parameters of open field performance in Drd2+/+ (n = 3) and Drd2Cre/+ (n = 5) female mice after NAc D2R chemogenetic inhibition, including global activity (k), total distance travelled (l), percentage of time spent per zone (m), and representative traces (n). o, Schematic illustration of the experimental strategy (left) and total daily caloric intake (chow + HPF) of Drd2+/+ (n = 4) and Drd2Cre/+ (n = 3) female mice after chemogenetic inhibition of D2R neuronal activity in the dStri. p-s, Recorded parameters to assess open field performance in Drd2+/+ (n = 11) and Drd2Cre/+ (n = 14) female mice after dStri D2R chemogenetic inhibition, including global activity (p), total distance travelled during the test (q), percentage of time spent per zone (r), and representative traces (s). Dots in all panels represent individual sample data. Data are expressed as mean ± SEM. Exact P values are shown. Statistical analysis was performed by unpaired t-test for k, l, p, q, by two-way ANOVA with Sidak’s multiple comparisons test for f, i, j, m, o, r. dStri: dorsal striatum; NAc: nucleus accumbens; CNO: clozapine-n-oxide; BP: before pregnancy; W2: second week of pregnancy.

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Extended Data Fig. 8 Pharmacological treatment with D2R biased ligand UNC9994 reverts pregnancy-specific increase in HPF consumption.

a, Schematic illustration of experimental strategy (left) and percentage of daily caloric intake consumed (right), during the 2-hours of HPF access, by female mice treated with either vehicle or D2R biased ligand UNC9994 before pregnancy (BP) and during the second week of pregnancy (W2) (n = 6 mice/group). b, Total daily caloric intake (chow + HPF) of female mice treated with either vehicle or D2R biased ligand UNC9994 before pregnancy and during the second week of pregnancy (n = 6 mice/group). c-f, Recorded parameters to assess open field performance in female mice treated with either vehicle or D2R biased ligand UNC9994, including global activity (c) (n = 4 for vehicle and 5 for UNC9994) time spent immobile (d) (n = 7 mice/group) total distance travelled (e) (n = 7 mice/group) and percentage of time spent in each compartment (f) (n = 7 mice/group). Schematic of the open field test highlights center (purple) and corner (cream) zones. Dots in all panels represent individual sample data. Data are expressed as mean ± SEM. Exact P values are shown. Statistical analysis was performed by two-way ANOVA with Sidak’s multiple comparisons test for a, b, and by unpaired t-test for c, d, e and by two-way ANOVA with Sidak’s multiple comparisons test for f. BP: before pregnancy; W2: second week of pregnancy; VEH: vehicle.

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Extended Data Fig. 9 Characterization of maternal physiology under diverse nutritional paradigms.

a, Body weight of females exposed to either ad libitum chow (n = 4), “limited access” paradigm (n = 5) and ad libitum Western diet (n = 6). Females were crossed with Chow-fed males at 12 weeks of age. b, Glucose tolerance test at E14.5-E16.5 pregnant females exposed to either ad libitum chow (n = 4), “limited access” paradigm (n = 5) and ad libitum Western diet (n = 6). c-e, Blood glucose levels (c), plasma insulin (d), and plasma leptin (e) of E14.5-E16.5 females exposed to either ad libitum Chow (n = 4), “limited access” paradigm (n = 5) and ad libitum Western diet (n = 6) after 6 hours of fasting. Dots in all panels represent individual sample data. Data are expressed as mean ± SEM. Exact P values are shown. Statistical analysis was performed by two-way ANOVA with Tukey’s multiple comparisons test for a and b. Green P values refer to the comparison between limited access group and Western diet-fed group. Yellow P values refer to the comparison between chow-fed group and Western diet-fed group. Statistical analysis was performed by one-way ANOVA with Tukey’s multiple comparisons test for c, d, e. When the factors Diet, Age/Time and/or the interaction Age/Time:Diet were considered significant, results are shown with significant factor or the interaction effect next to it.

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Extended Data Fig. 10 Predisposition to eating disorders and expression of dopaminergic markers in HPF craving-like offspring.

a-b, Total distance travelled during an open field (a) and a NORT (b) paradigm in 12-week-old male (n = 8 mice/group) and female (n = 7 Chow-O and 8 HPF-O) Chow-O (n = 5) and HPF-O (n = 5) mice. c, Schematic illustration of compulsive eating-like (CE) paradigm used to assess eating disorders predisposition in the offspring. d, Total daily caloric intake of Chow-O and HPF-O male (left panel) and female (right panel) mice exposed to a compulsive eating paradigm during adolescence (n = 5 mice per group/average of 3 measurements per week). e-j, Transcript expression of Th (n = 8 Chow-O and 7 HPF-O males/n = 5 Chow-O and 7 HPF-O females) (e) and Slc6a3 (n = 7 Chow-O and HPF-O males/n = 5 Chow-O and 7 HPF-O females) (f) in the ventral tegmental area (VTA); Drd1 (g) Drd2 (h) in the nucleus accumbens (NAc) (n = 7 Chow-O and HPF-O males/n = 5 Chow-O and 8 HPF-O females); Drd1 (n = 8 Chow-O and HPF-O males/n = 6 Chow-O and HPF-O females) (i) Drd2 (n = 8 Chow-O and HPF-O males/n = 5 Chow-O and 6 HPF-O females) (j) in the dorsal striatum (dStri) of 16-week-old male and female offspring from Chow-O (n = 5) and HPF-O (n = 5) mice. Dots in all panels represent individual sample data. Data are expressed as mean ± SEM. Exact P values are shown. Statistical analysis was performed by ANODE for a, b, e, f, g, h, i, j or ANODE followed by Benjamini–Yekutieli adjustment for d. When the factors Sex, Diet, Time and/or the interaction Sex:Diet, Sex:Time, Diet:Time, Sex:Diet:Time were considered significant, results were shown with significant factor or the interaction effect with Tukey’s post-hoc analysis within the same sex group. VTA: ventral tegmental area; NAc: nucleus accumbens; dStri: dorsal striatum; Th: tyrosine hydroxylase; Slc6a3: Solute Carrier Family 6 Member 3 encoding for the dopamine transporter (DAT); Drd1: dopamine receptor 1; Drd2: dopamine receptor 2.

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Haddad-Tóvolli, R., Ramírez, S., Muñoz-Moreno, E. et al. Food craving-like episodes during pregnancy are mediated by accumbal dopaminergic circuits. Nat Metab 4, 424–434 (2022). https://doi.org/10.1038/s42255-022-00557-1

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