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A hypothalamic circuit that modulates feeding and parenting behaviours

Nature volume 645, pages 981–990 (2025)Cite this article

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Abstract

Across mammalian species, new mothers undergo behavioural changes to nurture their offspring and meet the caloric demands of milk production1,2,3,4,5. Although many neural circuits underlying feeding and parenting behaviours are well characterized6,7,8,9, it is unclear how these different circuits interact and adapt during lactation. Here we performed transcriptomic profiling of the arcuate nucleus (ARC) and the medial preoptic area (MPOA) of the mouse hypothalamus in response to lactation and hunger. Furthermore, we showed that heightened appetite in lactating mice was accompanied by increased activity of hunger-promoting agouti-related peptide (AgRP) neurons in the ARC (ARCAgRP neurons). To assess the strength of hunger versus maternal drives, we designed a conflict assay in which female mice chose between a food source or pups and nesting material. Although food-deprived lactating mothers prioritized parenting over feeding, hunger reduced the duration and disrupted the sequences of parenting behaviours in both lactating and virgin females. We found that ARCAgRP neurons inhibit bombesin receptor subtype 3 (BRS3) neurons in the MPOA (MPOABRS3 neurons), which become more active postpartum and govern parenting and satiety. Activation of this ARCAgRP-to-MPOABRS3 circuit shifted behaviours from parenting to food-seeking. Thus, hypothalamic networks are modulated by physiological states and work antagonistically during the prioritization of competing motivated behaviours.

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Fig. 1: Lactating mice exhibit increased appetite and ARCAgRP neuronal activity.
Fig. 2: Hunger delays and reduces parenting behaviours in virgin females and lactating mothers.
Fig. 3: ARCAgRP→MPOA activation or MPOA Parent-TRAP inhibition shifts behaviours from parenting to feeding.
Fig. 4: MPOABRS3 neurons regulate parenting and feeding behaviours.
Fig. 5: ARCAgRP neurons inhibit MPOABRS3 neurons, which show postpartum plasticity and projections to various brain regions.

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Data availability

Data are provided in all main and extended figures and accompanying Source Data. Our raw sequencing data are deposited in the Gene Expression Omnibus (GEO) with the accession number GSE295610. Other public sequencing data analysed in our study are from GEO with the accession numbers GSE93374 and GSE113576. Our processed sequencing data are available at Zenodo (https://doi.org/10.5281/zenodo.15319501)68. Source data are provided with this paper.

Code availability

Code used to analyse scRNA-seq data was derived from https://satijalab.org/seurat/. Code used to analyse FED3 data was from https://github.com/earnestt1234/FED3_Viz. Custom code for our study is available at Zenodo (https://doi.org/10.5281/zenodo.15319501)68.

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Acknowledgements

The authors thank A. Fleischmann, W. Li, W. S. Young, and members of the M.J.K. and A. Lutas laboratories for discussions and support; G. Parham for assisting with coding and data analysis; and A. Franks for assisting with mouse husbandry. This research was funded by the Intramural Research Program of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases (ZIA-DK075087, ZIA-DK075088) and the National Institute of Environmental Health Sciences (ZIC-ES102545).

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Authors and Affiliations

  1. Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Ivan C. Alcantara, Chia Li, Claire Gao, Shakira Rodriguez González, Laura E. Mickelsen, Abigail I. Goldschmidt, Isabel M. Cohen, Isabel de Araujo Salgado, Ramón A. Piñol, Cuiying Xiao, Eva O. Karolczak, Marc L. Reitman & Michael J. Krashes

  2. Department of Neuroscience, Brown University, Providence, RI, USA

    Ivan C. Alcantara

  3. Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA

    Brian N. Papas & Jian-Liang Li

  4. National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA

    Christopher M. Mazzone & Guohong Cui

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  1. Ivan C. Alcantara
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Contributions

I.C.A. and M.J.K. conceived the project and designed the experiments. I.C.A. and C.L. performed stereotaxic surgeries. I.C.A., S.R.G., A.I.G. and E.O.K. performed behavioural experiments and fibre photometry recordings. R.A.P. performed cold exposure experiments paired fibre photometry recordings. C.L. performed slice electrophysiological recordings. I.C.A. analysed behavioural data. I.C.A., C.L. and R.A.P. analysed neuronal activity data. I.C.A., L.E.M., C.M.M. and G.C. collected samples for scRNA-seq. I.C.A., C.G., B.N.P. and J.-L.L. analysed the scRNA-seq data. I.C.A., C.G. and I.M.C. performed RNAscope and analysed the data. I.C.A., A.I.G. and M.J.K. performed histology and antibody staining. A.I.G. performed cell counting and axonal projection density analysis. C.X. and M.L.R. generated the Brs3-T2A-FlpO mouse line. I.C.A., C.L., B.N.P., A.I.G. and I.d.A.S. prepared the figures. I.C.A. wrote the manuscript, which all authors reviewed and edited.

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Correspondence to Michael J. Krashes.

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Extended data figures and tables

Extended Data Fig. 1 Lactating mice exhibit increased appetite during dark and light cycles.

a, mean daily food intake of control (n = 8) and lactating (n = 14) mice during baseline, pregnancy, lactation, and post-weaning. b-c, daily food intake of representative lactating mouse with 9 pups (b) or 3 pups (c). d-i, daily food intake measurement using FED3 in the dark cycle (d-e) and light cycle (f-g) of control (n = 6) and lactating (n = 5) mice during baseline, pregnancy, lactation, and post-weaning. h-i, same data as e and g but replotted to compare light vs. dark cycle food intake in control (h) and lactating (i) mice. Plots show mean ± s.e.m. Data analyzed using two-way RM-ANOVA with Šidák’s multiple comparisons test (a, e, g, h, i). Statistical details in Source Data.

Source data

Extended Data Fig. 2 Agrp+ neuronal cluster in the ARC exhibits the most changes in gene expression upon fasting.

a, heat map of relative expression of marker genes in each ARC neuronal cluster with dendrogram (top) showing similarities between clusters. b, comparison of our ARC clusters (columns) with ARC clusters from a previous scRNA-seq publication (rows). c, comparison of fasted virgin vs. fed virgin groups showing the contribution of each cluster to the first 8 principal components (PCs), highlighting the top contributor, cluster 0. Dashed red line shows contribution if all cluster contributed equally. d, FeaturePlot showing ARC neurons and clusters in UMAP space with Agrp and Npy expression.

Source data

Extended Data Fig. 3 Hunger delays and reduces parenting behaviors in virgin females and lactating mothers in the dark cycle.

a, schematic of the timing of fasting, refeeding, and conflict assay for fasted and refed groups. b, percent of animals that either performed pup retrieval or feeding as their first behavior (nvirgin = 7 mice, nlactating = 6 mice). c-f, probability density of pup retrieval and feeding events throughout the conflict assay (all trials). 1 total pellet consumed by 1 virgin female (refed) at time = 32.65 min is not shown to avoid skewing the visualization. g, transition probabilities between pup retrieval and feeding events in fasted virgin females and fasted lactating mothers. Only the feeding events prior to the completion of pup retrieval were used for the calculation. h, food intake. i, number of pups retrieved. j, latency to retrieve the first pup. k, nest score. l, preference index. m, food intake (# pellets) vs. % time in parenting chamber of virgin and lactating females in the fasted condition. Bar graphs show mean ± s.e.m. Box plots show median, upper/lower quartiles, and upper/lower extremes. Data analyzed using two-way RM-ANOVA with Šidák’s multiple comparisons test (h-l) or simple linear regression (m). Statistical details in Source Data.

Source data

Extended Data Fig. 4 Photostimulation of ARCAgRP projections to MPOA expressing ChR2 or eYFP.

a-i, ARCAgRP-ChR2. a, schematic of stimulation paradigms in fed mice. Created in BioRender. Alcantara, I. (2025) https://BioRender.com/09eqaav. b, 30 min food intake across different stimulation paradigms at 10 and 1 mW light intensity; “no stim” data are identical for 10 and 1 mW comparisons (n = 10 virgin females). c-d conflict assay without food (n = 8 virgin females). c, number of pups retrieved. d, number of pups attacked. e, nest score. f-i, conflict assay in Npy-KO background (n = 6 virgin females). f, food intake. g, number of pups retrieved. h, number of pups attacked. i, nest score. j-o, ARCAgRP-eYFP. j, histology. k, food intake. l-o, conflict assay. l, food intake. m, nest score. n, number of pups retrieved. o, preference index. Scale bars = 200 μm. Bar graphs show mean ± s.e.m. Box plots show median, upper/lower quartiles, and upper/lower extremes. Data analyzed using one-way RM-ANOVA with Šidák’s multiple comparisons test (b), one-sided paired t-test (c-e, g-h), two-sided paired t-tests (f, i, k) or one-way RM-ANOVA with Tukey’s multiple comparisons test (l-o). Statistical details in Source Data.

Source data

Extended Data Fig. 5 Inhibition of parenting neurons in MPOA reduces parenting in fed lactating mothers.

a, number of pups retrieved. b, nest score. c-d, food intake over time in Parent-TRAP (c) and Negative-TRAP (d) animals. e, total food intake at 40 min time point. f-g, preference index over time in Parent-TRAP (f) and Negative-TRAP (g) animals (n = 7 Parent-TRAP lactating mothers, n = 6 Negative TRAP lactating mothers). Bar and line graphs show mean ± s.e.m. Box plots show median, upper/lower quartiles, and upper/lower extremes. Data analyzed using two-way RM-ANOVA with Šidák’s multiple comparisons test. P-values in c-d, f-g indicate the treatment effect of CNO. Statistical details in Source Data.

Source data

Extended Data Fig. 6 MPOA neuronal clusters co-express several genetic markers for parenting-promoting neurons.

a, heat map of relative expression of marker genes in each MPOA neuronal cluster with dendrogram (top) showing similarities between clusters. b, comparison of our MPOA clusters (columns) with MPOA clusters from a previous scRNA-seq publication (rows). c, comparison of fed lactating vs. fed virgin groups showing the contribution of each cluster to the first 9 PCs. d, comparison of fasted virgin vs. fed virgin groups showing the contribution of each cluster to the first 10 PCs. e, DotPlot of clusters 3, 5, and 14 showing expression of Slc17a6 (Vglut2), Slc32a1 (Vgat), top 5 enriched genes in cluster 3 (Pde1c, Ptprk, Esr1, Dgkb, Grm8), parenting markers (Gal, Calcr, Prlr, Pgr, Brs3), and NPY receptors (Npy1r, Npy2r). f, fractions of neurons that are Brs3+, i.e. contains at least 1 unique molecular identifier (UMI), per MPOA cluster. g, left: co-expression matrix showing fraction of Gene A+ MPOA neurons that are also Gene B+, highlighting co-expression with Brs3 (e.g., 0.38 of Brs3+ neurons are Slc17a6+); right: fractions of MPOA neurons that are positive for select genes.

Source data

Extended Data Fig. 7 Inhibition of Esr1, Calcr, Crh, or MC4R neurons in MPOA with hM4Di.

a-d, conflict assay: histology (scale bars = 200 μm) (1), food intake (2), number of pups retrieved (3), nest score (4), and preference index (5) of animals expressing hM4Di in MPOAEsr1 (a, n = 8 virgin females), MPOACalcr (b, n = 10 virgin females), MPOACrh (c, n = 6 virgin females), or MPOAMC4R (d, n = 6 lactating mothers). Bar graphs show mean ± s.e.m. Box plots show median, upper/lower quartiles, and upper/lower extremes. Data analyzed using two-way RM-ANOVA with Fisher’s LSD test. Statistical details in Source Data.

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Extended Data Fig. 8 Photometry MPOABRS3 expressing eYFP or GCaMP6s during parenting, feeding, and cold exposure.

a-e, MPOABRS3-eYFP fiber photometry of virgin females (n = 5). a, histology (scale bar = 200 μm). b-d, signal in response to pup (b), object (c), or food (d). e, mean response to all 3 stimuli. f-n, MPOABRS3-GCaMP6s fiber photometry in lactating mothers (n = 6). f, signal in response to pup or object in the fed condition. g, mean response to pup or object. h, signal aligned to pup presentation. i, mean response to pup in the fasted state. j, signal aligned to food presentation. k, mean response to food. l-m, representative traces in the fed (l) and fasted (m) states aligned to behaviors. n, mean signal during behaviors. o-q, MPOABRS3-GCaMP6s neurons in virgin females (n = 7) during cold exposure. o, experimental setup. Created in BioRender. Alcantara, I. (2025) https://BioRender.com/09eqaav. p, GCaMP6s signal (bottom) aligned to changes in ambient temperature (top). q, mean signal at 30 °C or 15 °C at time = 5 to 30 min. Bar and line graphs show mean ± s.e.m. Box plots show median, upper/lower quartiles, and upper/lower extremes. Data analyzed using two-way RM-ANOVA with Šidák’s multiple comparisons test (e, n) or two-tailed paired t-tests (g, i, k, q). P-values in n indicate the effect of hunger states and behavior types to the variance by two-way RM-ANOVA. Statistical details in Source Data.

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Extended Data Fig. 9 Generation of the Brs3-T2A-FlpO line.

a, schematic of the Brs3-T2A-FlpO locus with genotyping strategy by PCR (n = 3 FlpO/+ mice); x475 = wild-type forward primer, x803 = FlpO forward primer, x564 = reverse primer. b, sequences of guide RNAs and long single-stranded DNA template. c, schematic of Flp-dependent GCaMP6s virus injection in MPOA of Brs3-T2A-FlpO line (n = 3 mice). d, representative confocal images from RNAscope experiment showing expression of Flp-dependent GCaMP mRNA and colocalization with Brs3 mRNA in MPOA (scale bar = 50 μm). e, representative images from n = 3 mice showing expression pattern of tdTomato in Brs3-T2A-FlpO mouse line crossed with RC::FLTG reporter along anterior/posterior axis relative to Bregma (scale bars = 200 μm).

Extended Data Fig. 10 Intrinsic properties of MPOABRS3 neurons in virgin females and lactating mothers measured by whole-cell patch clamp.

a, proportion of cells in depolarization block (DB) in virgin and lactating mice (nvirgin = 46 cells, nlactating = 40 cells, n = 6 mice each group). b, current required to hold cells at −70 mV. c, rheobase at −70 mV. d, capacitance. e, resistance. f, inter-spike membrane potential. Data analyzed using two-way RM-ANOVA with Šidák’s multiple comparisons test (b-f). Statistical details in Source Data.

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Alcantara, I.C., Li, C., Gao, C. et al. A hypothalamic circuit that modulates feeding and parenting behaviours. Nature 645, 981–990 (2025). https://doi.org/10.1038/s41586-025-09268-5

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