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The medial preoptic area mediates depressive-like behaviors induced by ovarian hormone withdrawal through distinct GABAergic projections

Nature Neuroscience volume 26, pages 1529–1540 (2023)Cite this article

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Abstract

Fluctuations in reproductive hormone levels are associated with mood disruptions in women, such as in postpartum and perimenopausal depression. However, the neural circuit mechanisms remain unclear. Here we report that medial preoptic area (MPOA) GABAergic neurons mediate multifaceted depressive-like behaviors in female mice after ovarian hormone withdrawal (HW), which can be attributed to downregulation of activity in Esr1 (estrogen receptor-1)-expressing GABAergic neurons. Enhancing activity of these neurons ameliorates depressive-like behaviors in HW-treated mice, whereas reducing their activity results in expression of these behaviors. Two separate subpopulations mediate different symptoms: a subpopulation projecting to the ventral tegmental area (VTA) mediates anhedonia and another projecting to the periaqueductal gray mediates immobility. These projections enhance activity of dopaminergic neurons in the VTA and serotonergic neurons in the dorsal raphe, respectively, with increased release of dopamine and serotonin, possibly through disinhibition mechanisms. Thus, the MPOA is a hub that mediates depressive-like behaviors resulting from transitions in reproductive hormone levels.

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Fig. 1: MPOA GABAergic activity is modulated by HW and correlated with depressive-like phenotypes.
Fig. 2: Cellular changes underlying the hypoactivity of MPOA GABAergic neurons.
Fig. 3: Silencing of MPOAGABA → VTA and MPOAGABA → PAG projections induces different effects on depressive-like behaviors.
Fig. 4: Activation of MPOAGABA → PAG and MPOAGABA → VTA projections alleviates different features of depressive-like behaviors.
Fig. 5: MPOA GABAergic activity promotes VTA dopaminergic activity.
Fig. 6: MPOA GABAergic activity promotes DR serotonergic activity.
Fig. 7: The Esr1+ subpopulation of GABAergic neurons mediates HW-induced depressive-like behaviors.

Data availability

All the source data for the results of this study are provided. Source data are provided with this paper.

Code availability

The code used for animal detection is available at https://github.com/GuangWei-Zhang/TraCon-Toolbox. Other code that supports the findings of this study is available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health to L.I.Z. (R01DC008983, R01DC020887 and U01MH116990) and H.W.T. (EY019049 and MH116990).

Author information

Author notes

  1. These authors contributed equally: Can Tao, Guang-Wei Zhang.

Authors and Affiliations

  1. Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Can Tao, Guang-Wei Zhang, Junxiang J. Huang, Zhong Li, Huizhong W. Tao & Li I. Zhang

  2. Graduate Programs in Biological and Biomedical Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Junxiang J. Huang

  3. Center for Neural Circuits and Sensory Processing Disorders, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Huizhong W. Tao & Li I. Zhang

  4. Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Huizhong W. Tao & Li I. Zhang

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Contributions

L.I.Z. and H.W.T guided and supervised the project. C.T. and G.-W.Z. performed the experiments and data analysis. J.J.H. helped with behavioral tests. Z.L. helped with fiber photometry recording. H.W.T., C.T., G.-W.Z. and L.I.Z. wrote the manuscript.

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Correspondence to Huizhong W. Tao or Li I. Zhang.

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Extended data

Extended Data Fig. 1 Ovarian hormone withdrawal induced depressive-like behaviors in female mice and effects of silencing MPOA GABAergic neurons in male mice.

a, Top, schematic behavioral assay of sucrose preference test (SPT). Bottom, percentage sucrose water consumption. Sham vs HW, ***P = 0.0004, NHW vs HW, **P = 0.0048, Sham vs NHW, N.S., P = 0.6103, two-tailed one-way ANOVA with postdoc hoc test, n = 9 mice in each group. b, Immobility time in tail suspension test (TST). Sham vs HW, **P = 0.003, NHW vs HW, **P = 0.0028, Sham vs NHW, N.S., P = 0.9997, two-tailed one-way ANOVA with postdoc hoc test, n = 9 mice in each group. c, Immobility time in forced swimming test (FST). Sham vs HW, **P = 0.0012, NHW vs HW, **P = 0.0048, N.S., P = 0.8448, two-tailed one-way ANOVA with postdoc hoc test, n = 9 mice in each group. d, Percentage time spent in opened arms in the elevated plus maze (EPM). ****P < 0.0001, N.S., P = 0.8923, two-tailed one-way ANOVA with postdoc hoc test, n = 9 mice in each group. e, Percentage time spent in the center in the open field test (OFT). ***P = 0.0001, ****P < 0.0001, N.S., P = 0.9562, two-tailed one-way ANOVA with postdoc hoc test, n = 9 mice in each group. f, Time of pup grooming. Sham vs HW, **P = 0.0036, NHW vs HW, **P = 0.0016, N.S., P = 0.9434, two-tailed one-way ANOVA with postdoc hoc test, n = 9 mice in each group. g, Social preference index in the three-chamber sociability test. ***P = 0.0006, ****P < 0.0001, N.S., P = 0.6586, one-way ANOVA with postdoc hoc test, n = 9 mice in each group. Data are presented as mean values ± s.d. h, Chemogenetic suppression of MPOA Vgat+ neurons by injecting AAV-DIO-hM4Di (or DIO-mCherry as control) in normal Vgat-Cre male animals. i-o, Various behavioral tests. Statistics: **P = 0.0024 (i), ****P < 0.0001 (j), **P = 0.0015 (k), **P = 0.0002 (l), ****P < 0.0001 (m), N.S., P = 0.8111 (n), **P = 0.0085 (o), two-tailed Mann-Whitney test, n = 9 mice in each group, mean ± s.d.

Source data

Extended Data Fig. 2 Post hoc verification of recording position, viral expression and cannula implantation.

a, Schematic of optrode recording in MPOA. b, Left, an example image showing the electrode track marked by DiI. Scale bar, 200 µm. Right, registration of the electrode track with the mouse brain atlas. c, Superimposed optrode tracks in different experiments. d, Schematic of stereotactic injection of AAV-DIO-ChR2-EYFP into MPOA. e, Expression of ChR2-EYFP in MPOA. Each red dot represents an individual neuron. Scale bar, 200 µm. Position of each cell is registered to the mouse brain atlas. f, Superimposed ChR2-expressing cells in different experiments. Opacity of pink color is proportional to the number of mice expressing the desired channel in that location. g, An example image showing the track of implanted drug cannula, highlighted by white arrows. Blue, Nissl staining. Scale bar, 500 µm. h, Registration of the cannula implantation with the brain atlas. i, Superimposed cannula implantation tracks in different experiments.

Extended Data Fig. 3 Functional verification of chemogenetics and optogenetics approaches, slice whole-cell recording and spike features.

a, Membrane hyperpolarization in response to perfusion of CNO in an example cell. Whole-cell recording was performed in a DREADD receptor expressing Vgat+ neuron in MPOA (labeled by mCherry). b, Spontaneous firing rates before and after perfusion of CNO. **P = 0.0079, Two-tailed Mann-Whitney test. n = 5 Vgat+ cells from 2 animals. c, Images showing the morphology of recorded MPOA neurons after biocytin staining. Scale bar, 100 µm. d, An example image showing the expression of ChR2 in MPOA, Scale bar, 400 µm. e, Slice whole-cell recording from a ChR2-expressing neuron showing action potentials evoked by 470 nm LED light pulses (marked by blue bars). f, Average resting membrane potentials of MPOA Vgat+ neurons in NHW and HW slices. N.S., P = 0.5689, Two-tailed Mann-Whitney test. g, Action potential threshold of MPOA Vgat+ neurons in NHW and HW slices. N.S., P = 0.1309, two-tailed Mann-Whitney test. f-g, n = 17 and 17 cells for NHW and HW respectively, from 4 animals in each group. Error bar, s.d. h, Example traces of membrane potential response to 60 pA current injection in MPOA Vgat+ neurons. Red dot marks the onset of action potential. i, Example spike shapes (2nd evoked spikes) and their superimposition. Scale bar, 20 mV, 2 ms. The horizontal dotted line indicates the half-peak width of the spike and the arrow marks the trough voltage. j, Average half-peak spike width of MPOA Vgat+ neurons in NHW and HW slices. n = 14 cells from 4 animals in each group. ****P < 0.0001, two-tailed Mann-Whitney test. k, Average trough voltage at different injection current amplitudes. n = 14 cells from 4 animals in each group. **P < 0.01; ****P < 0.0001, two-way repeated measures ANOVA, for exact P values see Extended Data Table 1. l, Example traces of spontaneous spikes of MPOA Vgat+ neurons in NHW and HW slices. m, Average spike shapes (solid color) of MPOA Vgat+ neurons. Light colors label individual spikes. n, Average half-peak spike width of spontaneous spikes of MPOA Vgat+ neurons in NHW and HW slices. n = 8 cells from 4 animals in each group. ***P = 0.0002, two-tailed Mann-Whitney test. o, Average trough voltage of spontaneous spikes. n = 11 cells from 4 animals. **P = 0.0015, two-tailed Mann-Whitney test. For boxplot, centerline, mean, upper and lower end, 90 and 10 percentile.

Source data

Extended Data Fig. 4 Changes in sEPSC frequency and effects of changes in synaptic event amplitude on spike rate.

a, Example sEPSC events within a 10-sec window, red dot indicates the peak. b, Distribution of sEPSC amplitudes shown in (a), red dashed line represents the median value. c, Cumulative distribution of sEPSC amplitudes shown in (a). P < 0.0001, two-tailed K-S test. d, Simulated conductances of spontaneous excitatory and inhibitory events. e, Spikes generated from integrating spontaneous excitatory and inhibitory events using the leaky integrate-and-fire neuron model (see Methods). f, Raster plots of spontaneous spikes with increasing excitatory (and inhibitory) synaptic strength, with a constant overall E/I ratio. g, Simulated spike rate versus the mean amplitude of sEPSCs. Note that the E/I ratio was kept the same. n = 10 trials, error bar represents s.d.

Source data

Extended Data Fig. 5 Dual color retrograde labeling of VTA- or PAG-projecting MPOA Vgat+ neurons.

a, Schematic of injections of CTb in Vgat-Cre::Ai14 mice. b, Images showing CTb647-labeled (PAG-targeting), CTb488-labeled (VTA-targeting), and Vgat + (tdTomato expressing) neurons in MPOA. Scale bar, 100 µm. c, Percentage of MPOA Vgat+ neurons showing single and double CTb labeling (mean ± s.d., n = 3 animals).

Source data

Extended Data Fig. 6 Control experiments for the dual optical stimulation.

a, Experimental strategy: expressing EYFP in MPOA Vgat+ neurons and ChrimsonR in VTA Dat+ neurons, while delivering 470 nm LED light stimulation in MPOA. b, Raster plot (upper) and PSTH (lower) for an example VTA Dat+ neuron in response to 470 nm light stimulation. c, Firing rates before and after the onset of light stimulation. n = 13 cells from 2 animals. N.S., P = 0.3421, two-tailed paired t test. Error bar, s.d. d-f, Similar to a-c but for expressing ChR2 in MPOA Vgat+ neurons and ChrimsonR in VTA Dat+ neurons, while delivering 625 nm light stimulation in MPOA. n = 19 cells from 2 animals. N.S., P = 0.7076, two-tailed paired t test. Error bar, s.d. g-i, Similar to a-c but for expressing EYFP in MPOA Vgat+ neurons and ChrimsonR in DR Sert+ neurons, while delivering 470 nm light stimulation in MPOA. n = 14 cells from 2 animals. N.S., P = 0.2668, two-tailed paired t test. Error bar, s.d. j-l, Similar to d-f but for expressing ChR2 in MPOA Vgat+ neurons and ChrimsonR in DR Sert+ neurons, while delivering 625 nm LED light stimulation in MPOA. n = 16 cells from 2 animals. N.S., P = 0.5587, two-tailed paired t test. Error bar, s.d.

Source data

Extended Data Fig. 7 Verification of monosynaptic connections between MPOA and VTA/PAG.

a, Whole-cell patch clamp recording from Vgat+ neurons in VTA of Vgat-Cre::Ai14 mice. AAV-syn-ChR2 was injected into MPOA. b, Average trace (black, n = 5 trials) of light-evoked inhibitory synaptic responses (recorded at 0 mV) in the control condition, after application of TTX and after co-application of TTX and 4AP. Blue shade represents raw traces. c, Mean IPSC amplitudes in the three conditions. Pre-TTX vs TTX, **P = 0.0013. Pre-TTX vs TTX + 4AP, N.S. P = 0.1518, TTX vs TTX + 4AP, **P = 0.0017, repeated measures one-way ANOVA with multiple comparisons, n = 5 cells in each group, from 2 animals. Error bar, s.d. d, Whole-cell recording from Vgat+ neurons in vlPAG of Vgat-Cre::Ai14 mice. AAV-syn-ChR2 was injected into MPOA. e, Average trace (black, n = 5 trials) of light-evoked inhibitory synaptic responses (recorded at 0 mV) in the control condition, after application of TTX and after co-application of TTX and 4AP. Blue shade represents raw traces. f, Mean IPSC amplitudes in the three conditions. Pre-TTX vs TTX, *P = 0.0401. Pre-TTX vs TTX + 4AP, P = 0.1151, TTX vs TTX + 4AP, n = 6 cells from 3 animals in each group. Error bar, s.d, **P = 0.0468. Repeated measures one-way ANOVA with multiple comparisons.

Source data

Extended Data Fig. 8 Activation of VTA Dat+ neurons and DR Sert+ neurons in HW-treated mice.

a, Schematic injection of AAV-DIO-ChR2 in VTA of Dat-Cre female HW animals. b, Percentage sucrose water consumption in SPT. **P = 0.0029, two-tailed Mann-Whitney test. c, Immobility time in TST. **P = 0.0041, two-tailed Mann-Whitney test. d, Immobility time in FST. **P = 0.0035, two-tailed Mann-Whitney test. e, Percentage time spent in open arms in EPM. P = 0.6737, two-tailed Mann-Whitney test. f, Percentage time spent in the center in OFT. P = 0.8945, two-tailed Mann-Whitney test. g, Pup grooming time. **P = 0.0082, two-tailed Mann-Whitney test. h, Social preference index in the three-chamber sociability test. **P = 0.0012, two-tailed Mann-Whitney test. b-h, n = 7 mice in each group, mean ± s.d. i-p, Similar to a-h but for photo-activation of DR Sert+ neurons. n = 7 mice in each group, mean ± s.d. Statistics: P = 0.40214 (j), ***P = 0.0006 (k), **P = 0.0012 (l), *P = 0.0437 (m), ***P = 0.0006 (n), ***P = 0.0006 (o), ***P = 0.0006 (p), two-tailed Mann-Whitney test.

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Extended Data Fig. 9 Esr1+ neurons in MPOA and their target specificity and spike features.

a, RNAscope staining of Esr1, Vglut2 and Vgat in MPOA. Scale bar, 50 µm. b, Percentage of neurons in different specific categories. 80% of Esr1+ neurons were Vgat + . c, Dual-color CTb retrograde tracing of MPOA neurons projecting to VTA and PAG in Esr1-Cre::Ai14 mice. d, Images in MPOA. Arrows indicate Esr1+ (tdTomato + ) neurons co-labelled with CTb647 (blue, from PAG) or CTb488 (green, from VTA). Scale bar, 100 µm. e, Percentage of neurons in specific categories. 60% of Esr1+ neurons were labeled by either CTB647 or CTb488. Mean ± s.d., n = 3 animals. f, Average half-peak spike width of MPOA Vgat+ neurons for spikes evoked by current injections in NHW and HW slices. n = 14 cells for NHW group and 12 cells for HW group, from 3 animals in each group. ****P < 0.0001, two-tailed Mann-Whitney test. g, Average trough voltage at different injection current amplitudes. n = 6, 6 cells for NHW and HW, from 3 animals in each group. *P < 0.05, **P < 0.01, ***P < 0.001, two-way repeated measures ANOVA. h, Average half-peak spike width of spontaneous spikes of MPOA Esr1+ neurons in NHW (n = 10 cells from 3 animals) and HW (n = 10 cells from 3 animals) slices. ***P = 0.0002, two-tailed Mann-Whitney test. i, Average trough voltage of spontaneous spikes. n = 10,10 cells for NHW and HW, from 3 animals for each group. ***P = 0.0002, two-tailed Mann-Whitney test. For boxplot, centerline, mean, upper and lower end, 90 and 10 percentiles.

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Extended Data Fig. 10 Suppressing MPOA Vgat neurons in male mice, local administration of estrogen in MPOA and local administration of an estrogen receptor antagonist in MPOA.

a-h, Local administration of estradiol (E2) (or vehicle) in MPOA following the HW procedure in female mice. N = 8 animals for each group. Mean ± s.d. Statistics: ***P = 0.0002 (b), ****P < 0.0001 (c), ****P < 0.0001 (d), **P = 0.0011 (e), ***P = 0.0004 (f), ***P = 0.0005 (g), ****P < 0.0001 (h), two-tailed Mann-Whitney test, n = 9 mice in each group. i-p, I.p. administration of estradiol (E2) and local administration of estrogen receptor antagonist (ICI 182,780) (or vehicle) in MPOA following the HW procedure in female mice. n = 9 mice in each group, mean ± s.d. Statistics: **P = 0.0097 (j), *P = 0.0379 (k), *P = 0.0362 (l), ***P = 0.0009 (m), *P = 0.0101 (n), **P = 0.0068 (o), ***P = 0.0002 (p), two-tailed Mann-Whitney test.

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Tao, C., Zhang, GW., Huang, J.J. et al. The medial preoptic area mediates depressive-like behaviors induced by ovarian hormone withdrawal through distinct GABAergic projections. Nat Neurosci 26, 1529–1540 (2023). https://doi.org/10.1038/s41593-023-01397-2

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