Functional circuit architecture underlying parental behaviour



Parenting is essential for the survival and wellbeing of mammalian offspring. However, we lack a circuit-level understanding of how distinct components of this behaviour are coordinated. Here we investigate how galanin-expressing neurons in the medial preoptic area (MPOAGal) of the hypothalamus coordinate motor, motivational, hormonal and social aspects of parenting in mice. These neurons integrate inputs from a large number of brain areas and the activation of these inputs depends on the animal’s sex and reproductive state. Subsets of MPOAGal neurons form discrete pools that are defined by their projection sites. While the MPOAGal population is active during all episodes of parental behaviour, individual pools are tuned to characteristic aspects of parenting. Optogenetic manipulation of MPOAGal projections mirrors this specificity, affecting discrete parenting components. This functional organization, reminiscent of the control of motor sequences by pools of spinal cord neurons, provides a new model for how discrete elements of a social behaviour are generated at the circuit level.

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We thank S. Sullivan for help with behaviour and mouse husbandry. E. Kremer (Montpellier) and R. Neve (MIT) provided viral vectors. E. Soucy and J. Greenwood helped design motivation assay. R. Hellmiss and K. Wilbur helped with illustrations. H. S. Knobloch-Bollmann provided advice on PVN cell types. We thank the members of the Dulac laboratory for comments on the manuscript. This work was supported by a Human Frontier Long-Term Fellowship, an EMBO Long-Term Fellowship and a Sir Henry Wellcome Fellowship to J.K., Fondation pour la Recherche Médicale grant SPE20150331860 to B.M.B., a NIH K99 Award and a NARSAD Young Investigator Award to A.E.A., a Howard Hughes Gilliam Fellowship to B.M.-R., a Harvard Mind Brain and Behavior faculty grant to N.U. and NIH grant 1R01HD082131-01A1 to C.D. C.D. and L.L. are investigators of the Howard Hughes Medical Institute.

Reviewer information

Nature thanks V. Grinevich and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. Howard Hughes Medical Institute, Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, MA, USA

    • Johannes Kohl
    • , Nimrod D. Rubinstein
    • , Anita E. Autry
    • , Brenda Marin-Rodriguez
    •  & Catherine Dulac
  2. Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, MA, USA

    • Benedicte M. Babayan
    • , Vikrant Kapoor
    •  & Naoshige Uchida
  3. Howard Hughes Medical Institute, Department of Biology, Stanford University, Stanford, CA, USA

    • Kazunari Miyamishi
    •  & Liqun Luo
  4. Department of Pharmacology, University of Washington, Seattle, WA, USA

    • Larry S. Zweifel
  5. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA

    • Larry S. Zweifel


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J.K. and C.D. conceived and designed the study. J.K performed and analysed tracing and optogenetics experiments. J.K. and B.M.B. performed and analysed photometry recordings. A.E.A. helped with in situ hybridization experiments, B.M.-R. helped with CTB tracing experiments, N.D.R. helped to analyse tracing data, and V.K. helped with optogenetics experiments. L.S.Z., K.M. and L.L. shared unpublished viral reagents. N.U. provided fibre photometry setup. J.K., B.M.B., N.D.R., A.E.A. and C.D. analysed and interpreted the results. J.K. and C.D. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Catherine Dulac.

Extended data figures and tables

  1. Extended Data Fig. 1 Putative functional roles of brain areas providing monosynaptic inputs into MPOAGal neurons.

    a, Comparison between MPOAGal input fractions in virgin males (n = 3) and virgin females (n = 3) after rabies tracing (see Fig. 1a). Sexually dimorphic inputs are highlighted. Two-tailed t-tests, supraoptic nucleus (SON), **P = 0.0041; posteriomedial amygdalo-hippocampal area (AHPM), ***P = 0.0007; medial septum (MS), *P = 0.0133. b, Comparison between MPOAGal input fractions after rabies tracing was initiated from the right (n = 3) or left (n = 3) hemisphere in virgin females. No significant differences were found (P > 0.05; two-tailed paired t-test). c, Comparison between rabies-injected (ipsilateral (ipsi)) and non-injected (contralateral (contra)) MPOA of a mother after parental behaviour. Activated (Fos+) rabies+ neurons are shown (top, arrowheads). Fos+ neuron numbers are not significantly different between hemispheres (bottom, P = 0.43, 95% confidence interval −4.176–1.843; two-tailed paired t-test; n = 6). d, MPOAGal neurons receive monosynaptic inputs from magnocellular SONAVP neurons (mothers, 72.7 ± 9.3% overlap, n = 3; virgin females, 77.4 ± 4.3%, n = 3; fathers, 83.3 ± 3.3%, n = 3) but rarely from SONOXT neurons (mothers, 4.6 ± 4.2% overlap, n = 2; virgin females, 4.5 ± 1.0%, n = 2; fathers, 2.8 ± 1.8%, n = 2). Data are mean ± s.e.m. Scale bars, 100 μm (c) and 50 μm (d).

  2. Extended Data Fig. 2 MPOAGal projections in males and downstream connectivity.

    a, Synaptophysin–GFP (Syn–GFP) labelling of presynaptic sites in MPOAGal projections. b, Representative MPOAGal projections from a virgin male, identified by tdTomato fluorescence. c, Representative MPOAGal projections, identified by tdTomato fluorescence, after viral injection into the left MPOA. d, Fos+ fractions of virally labelled MPOAGal projections in fathers (n = 6, 3, 4, 3, 3, respectively, from top to bottom). Red line depicts the population average3. Data are mean ± s.e.m. e, Trans-synaptic retrograde rabies tracing from AVPeTH neurons. f, MPOAGal neurons presynaptic to AVPeTH neurons in females (left, indicated by arrowheads, 21.4% Gal+ neurons, 47 out of 220 neurons, n = 3) and males (right, 16.7% Gal+, 4 out of 24 neurons, n = 2). g, Direct and indirect MPOAGal to PVNOXT connectivity. Asterisk, AVPeTH neurons form excitatory synapses with PVNOXT neurons in females11. h, Conditional monosynaptic retrograde tracing initiated from PAG. i, j, Injection sites with mCherry+ starter neurons in PAG of Vgat-IRES-Cre (i, left) or Vglut2-IRES-Cre (j, left) mice. Presynaptic, rabies+Gal+ neurons are detected in MPOA when tracing is initiated from PAGVgat (i, right, indicated by arrowheads), but not PAGVglut2 (j, right), neurons. Scale bars, 50 μm (a, f and i, inset), 200 μm (i and j, left) 250 μm (b, c, inset and i and j, right) and 500 μm (c, left).

  3. Extended Data Fig. 3 MPOAGal projections correspond to mostly non-overlapping neuronal subpopulations.

    a, Control injection of a 1:1 mixture of CTB-488 and CTB-647 into PAG results in highly overlapping neuron populations in the MPOA (quantification in c). b, Strategy to determine collaterals between pairwise injected MPOAGal projections in Gal::cre+/−loxP-Stop-loxP-tdTomato+/− mice. An example with two double-labelled MPOAGal neurons is shown after injection of CTB-488 into PAG and CTB-647 into VTA (right, indicated by arrowheads). c, Quantification of data in a, b. Data are mean ± s.e.m. (n = 6, 6, 3, 3, 3, 3, 3, respectively, from top to bottom). d, Representative image from MPOA of Gal::cre+/−loxP-Stop-loxP-tdTomato+/− mouse after injection of CTB-647 into PAG. Note high overlap between Gal+ and CTB+ neurons. e, Frequency of Gal+ neurons in individual, CTB-labelled MPOA projections (n = 4, 6, 4, 3, 3, 3, respectively, from top to bottom). Red line depicts expected labelling frequency, based on proportion of Gal+ MPOA neurons3 (around 20%). c, e, Data are mean ± s.e.m. f, Distribution of cell bodies corresponding to specific MPOAGal projections. Individual MPOAGal projection areas in Gal::Cre virgin females were injected with Cre-dependent CAV2-FLEx-ZsGreen (see Fig. 2h). Only labelling patterns on the ipsilateral, injected side are shown and only two projection-specific subpopulations per side are displayed for clarity. Mouse brain images in this figure have been reproduced with permission from Elsevier37. g, Zones occupied by MPOAGal cell bodies projecting to MeA, PAG, VTA and PVN in anterior (left), central (middle) and posterior (right) MPOA. f, g, Distance from bregma is shown in mm. Scale bars, 50 μm (a, b and d, inset) and 250 μm (d).

  4. Extended Data Fig. 4 MPOAGal projections barely collateralize.

    a, Strategy to detect brain-wide axon collaterals of specific MPOAGal projections. b, Dense labelling of MPOAGal neurons after injection of retrograde tracer CAV into PAG and reporter AAV into MPOA. c, Absence of MPOAGal labelling in negative control without injection of CAV. df, Only minor axon collaterals are detectable from MPOAGal neurons projecting to PAG (d; n = 2 virgin males), VTA (e; n = 3 virgin males) or MeA (f; n = 2 virgin males). Note the MPOA to MeA fibre tract in BNST in f. Signal was enhanced using anti-GFP immunostaining (Methods). Scale bars, b, c, 400 μm (b, c), 100 μm (insets) and 150 μm (df).

  5. Extended Data Fig. 5 Negative controls for monosynaptic retrograde tracing.

    a, Absence of rabies+ background labelling in the MPOA of AAV- and rabies-injected C57BL/6 control mice (n = 2). b, Labelling of MPOAGal neurons after injection of CAV into PAG and starter AAVs into MPOA of Gal::cre mice (261 ± 19 neurons, n = 4). c, Near-absence of labelling in AAV-only negative control (11 ± 2 neurons, n = 2). d, Background rabies+ neurons were present in the following brain areas of CAV-, AAV- and rabies-injected C57BL/6 control mice (n = 3): MPOA, BNST, anterior hypothalamus (AH), PVN and SON. These areas were therefore excluded from analysis (see Fig. 2k, l and Methods). Scale bars, 400 μm (main images) and 150 μm (insets).

  6. Extended Data Fig. 6 Histology of photometry recording experiments and tuning of MPOAGal neurons in other behavioural contexts.

    a, Specific GCaMP6m expression in MPOAGal neurons (90.9 ± 4.3% overlap, n = 3, mothers). bd, Implantation sites of optical fibres in the MPOA of Gal::cre+/−loxP-Stop-loxP-tdTomato+/− mother (b), virgin female (c) and father (d). e, Quantification of GCaMP+ neuron numbers in MPOA after AAV injection (‘Total’, n = 4) and after injection of HSV into individual projections (n = 5 each). Data for mothers are shown. Data are mean ± s.e.m. Two-tailed t-tests; Total versus PAG, VTA, MeA, ***P < 0.001, PAG versus MeA, **P = 0.0033. fh, Expression of GCaMP6m in MPOAGal neurons after bilateral infection of axon terminals in PAG (f), VTA (g) or MeA (h) with Cre-dependent, GCaMP6m-expressing HSV. Insets show fibre implantation sites. i, j, Averaged recording traces from MPOAGal neuron activity during sniffing of accessible pups (i) or inaccessible pups enclosed in a wire mesh tea ball (j) in mothers (n = 4), virgin females (n = 3) and fathers (n = 5). k, l, Averaged recording traces from MPOAGal neuron activity during sniffing of female (k) or male (l) intruder in mothers (n = 4), virgin females (n = 3) and fathers (n = 5). Two-tailed t-tests; i, ***P < 0.0001, ***P < 0.0001, ***P = 0.0001 (left to right); j, *P = 0.0380; k, *P = 0.0219; l, *P = 0.0272. mq, Averaged recording traces from MPOAGal neurons projecting to PAG (left, n = 10), VTA (middle, n = 12) or MeA (right, n = 8) during episodes of maternal behaviour. All traces and bar graphs are mean ± s.e.m. Scale bars, 50 μm (a), 400 μm (bd), 1 mm (fh) and 500 μm (fh, insets).

  7. Extended Data Fig. 7 Distribution of parental behaviours in mothers and virgin females.

    Distribution of parental behaviours during 10-min pup interaction assays in mothers (a; n = 23) and virgin females (bn = 20). In a, individuals exhibiting high pup sniffing are indicated in blue across plots, and individuals exhibiting high pup grooming are indicated in orange. In b, individuals exhibiting high pup sniffing are indicated in green. Note that y axis ranges are identical between a and b. Lines depict mean.

  8. Extended Data Fig. 8 Behavioural specificity of MPOAGal projection stimulation.

    a, Channelrhodopsin-2 (ChR2) expression in MPOAGal neurons (97.7 ± 0.2% overlap, virgin females, n = 2). Scale bar, 50 μm. bg, Effect of activating PAG (b, c), VTA (d, e) or MeA (f, g) projections on time spent in nest in virgin females and virgin males (b, n = 13 females and n = 10 males; d, n = 9 females and n = 10 males; f, n = 10 females and n = 10 males) and number of pup-directed sniffing bouts (c, n = 13 females and n = 10 males; e, n = 9 females and n = 10 males; g, n = 10 females and n = 10 males). hm, Effect of activating PAG (h, i), VTA (jk) or MeA (l, m) projections on locomotion velocity (h, n = 13 females and n = 10 males; j, n = 8 females and n = 10 males; l, n = 10 females and n = 10 males) and moved distance (i, k, m). n, q, s, Effect of inhibiting PAG (n, n = 10 females), VTA (q, n = 10 females) or MeA (s, n = 11 females) projections on pup interactions. o, t, Effect of inhibiting PAG (o, n = 10 females) or MeA (t, n = 11 females) projections on number of barrier crosses. p, r, Effect of inhibiting PAG (p, n = 10 females) or MeA (r, n = 11 females) projections on chemoinvestigation of a male intruder. uw, Effect of inhibiting PAG (u), VTA (v) or MeA (w) projections on locomotion velocity and moved distance (n = 10, 10, 11, respectively). Two-tailed paired t-tests; c, *P = 0.0135; f, *P = 0.03; n, *P = 0.0413, q: *P = 0.0264.

  9. Extended Data Table 1 List of brain areas and coordinates
  10. Extended Data Table 2 Summary of manipulations that affect parenting in MPOAGal target areas

Supplementary information

  1. Reporting Summary

  2. Video 1

    MPOAGal population activity during parentingPan-MPOAGal fibre photometry recording in a mother. While (1) no change in signal is visible during interactions with a food object (sniffing, retrieving of cracker), (2) sniffing pups in a wire mesh cage results in modest, and (3) sniffing and grooming of pups in the nest in strong increase in MPOAGal population activity

  3. Video 2

    Barrier crossing evoked by MPOAGal➝VTA activationOptogenetic activation of MPOAGal➝VTA projections in a virgin Gal::Cre female evokes barrier crossing in a task assessing motivation to interact with pups. Photostimulation period indicated by white dot


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