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Hypothalamic dopamine neurons motivate mating through persistent cAMP signalling

Nature volume 597, pages 245–249 (2021)Cite this article

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Abstract

Transient neuromodulation can have long-lasting effects on neural circuits and motivational states1,2,3,4. Here we examine the dopaminergic mechanisms that underlie mating drive and its persistence in male mice. Brief investigation of females primes a male’s interest to mate for tens of minutes, whereas a single successful mating triggers satiety that gradually recovers over days5. We found that both processes are controlled by specialized anteroventral and preoptic periventricular (AVPV/PVpo) dopamine neurons in the hypothalamus. During the investigation of females, dopamine is transiently released in the medial preoptic area (MPOA)—an area that is critical for mating behaviours. Optogenetic stimulation of AVPV/PVpo dopamine axons in the MPOA recapitulates the priming effect of exposure to a female. Using optical and molecular methods for tracking and manipulating intracellular signalling, we show that this priming effect emerges from the accumulation of mating-related dopamine signals in the MPOA through the accrual of cyclic adenosine monophosphate levels and protein kinase A activity. Dopamine transients in the MPOA are abolished after a successful mating, which is likely to ensure abstinence. Consistent with this idea, the inhibition of AVPV/PVpo dopamine neurons selectively demotivates mating, whereas stimulating these neurons restores the motivation to mate after sexual satiety. We therefore conclude that the accumulation or suppression of signals from specialized dopamine neurons regulates mating behaviours across minutes and days.

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Fig. 1: Motivational regulation of male mating behaviours across minutes and days.
Fig. 2: Specialized hypothalamic dopamine neurons control mating drive.
Fig. 3: Dopaminergic input to the MPOA builds up a persistent motivation to mate.
Fig. 4: Increased cAMP levels and PKA activity in the MPOA underlie mating drive persistence.

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Data availability

Plasmids and sequences related to biPAC and PDE4D3-Cat have been deposited to Addgene under accession numbers 169127 for biPAC and 169128 for PDE4D3-Cat. The data that support the findings in this study are available from the corresponding author upon request.

Code availability

The custom analysis code and designs in this paper are publicly available on GitHub (https://github.com/xzhang03/Code-for-Zhang-et-al-2021).

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Acknowledgements

We thank M. Baum, B. Lowell, M. Crickmore, D. Rogulja, Y. Livneh, Y. Chen, O. Yizhar, V. Ruta, R. Froemke, L. Stowers, D. Lin, M. Frank, O. Amsalem, D. Tingley and members of the Andermann laboratory for feedback. H. Lauterwasser, C. McHugh, D. Fleharty, H. Kaul and K. Fernando assisted with animal care, behavioural experiments and histology. J. Madara and B. Lowell assisted with brain-slice imaging and A. Verstegen shared Esr1-Cre mice. B. Lowell and G. Yellen provided the hybrid PMT and time-correlated single photon counting board, respectively. S. Thornquist informed us of the lifetime properties of cADDis. S. Gupta, M. Lehtinen, Boston Children’s Hospital Viral Core, BIDMC Histology Core and HMS Research Instrumentation Core provided technical services. Authors were supported by a Lefler Fellowship (S.X.Z.), an NIH F32 DK112589 and a Davis Family Foundation Award (A.L.), a Bertarelli Fellowship (H.F.), NIH R01 DK109930, DP1 AT010971, DP1 AT010971-02S1, the McKnight Foundation, the Klarman Family Foundation, and the Harvard Brain Science Initiative Bipolar Disorder Seed Grant, supported by Kent and Liz Dauten (M.L.A), and by the Deutsche Forschungsgemeinschaft Projektnummer 374031971 TRR 240/A04 and Projektnummer 417451587 (G.N.).

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Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Stephen X. Zhang, Andrew Lutas, Adriana Diaz, Hugo Fluhr & Mark L. Andermann

  2. Institute of Physiology, Department of Neurophysiology, Biocenter, Julius-Maximilians-University of Würzburg, Würzburg, Germany

    Shang Yang, Georg Nagel & Shiqiang Gao

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Contributions

S.X.Z. and M.L.A. conceived the project and wrote the manuscript. S.X.Z. designed and performed the behavioural experiments, fibre photometry recording, Fos-related experiments, and in vivo two-photon FLIM imaging. A.D. helped to conduct behavioural and photometry experiments. H.F. tracked mice in photometry experiments. A.L. designed and built the FLIM system. S.X.Z. and A.L. performed two-photon imaging experiments of acute brain slices. S.X.Z., A.L., A.D., H.F. and M.L.A. analysed all data except for the biochemical characterizations of biPAC. S.Y., S.G. and G.N. developed biPAC and PDE4D3-Cat, designed and performed all initial biochemical characterizations, and analysed related data.

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Correspondence to Mark L. Andermann.

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Extended data figures and tables

Extended Data Fig. 1 Males suppress non-mating behaviours and gradually increase their sexual arousal during mating epochs.

a, In the pre-mating epoch (after female entry and before the first mount), males engaged in feeding, digging, or trying to escape during ~25% of the “available” time (defined as the time not spent in sniffing the female, mounting the female, or lower-body grooming). In trials where males gained intromission at least once, they became hyper-engaged in mating. In the subsequent mating epoch (i.e. in the time between the first mount and the transfer of reproductive fluids), males spent almost no available time feeding, digging, or trying to escape. After transferring fluids, these males re-engaged in these non-mating behaviours. In trials where males never gained intromission (defined as the male’s thrusting movements becoming deeper and slower), they did not demonstrate a similarly hyper-engaged mode restricted to mating-related behaviours (n = 7, 6, 5, 6 males). b, We defined the appetitive sniffing metric as the fraction of pre-mounting time (i.e. the time from introduction of the female to up to 5 min later or to the first mount, whichever came first) spent in sniffing females. This metric was not significantly correlated with mounting latency (n = 47 first mounts from 20 males). c, About 80% of the first mounts were immediately preceded by a bout of sniffing (black arrows). This fraction gradually dropped across subsequent mounts, to about 5% for the fourth and fifth mounts (1st mounts: n = 48; 2nd and 3rd mounts: n = 52; 4th and 5th mounts: n = 49 mounts; 20 males). ***p<0.001. See Supplementary Table 1 for statistics.

Extended Data Fig. 2 Specialized dopamine release in the MPOA during appetitive mating behaviours.

a–d, Optogenetically stimulating all dopaminergic inputs to the MPOA (in TH-Cre males, a) increased appetitive sniffing behaviour (b: n = 6 males) and decreased mounting latency (c: n = 5 males). The same stimulation did not further increase the fraction of males that mount in the first 15 min after introduction of the female (d), as this fraction was already near ceiling in the absence of stimulation (n = 6 trials from 6 males, mean ± 95% c.i.). e, dLight1.1 expression and fibre location in the MPOA (scale bar: 200 μm). f, The average dLight1.1 signal remained largely flat when a male mouse approached another male (n = 7 males). g–i, Normalizing the durations of different bouts of approach to the female to a fixed “stretched" time across bouts (g) still results in a ramp-and-drop profile in the dLight1.1 signal (h). This suggests that ramps are not the result of averaging of square-shaped signals of varying durations. For illustration purposes, we set this fixed stretched time to 10 s, the approximate median length of a sniffing bout. Normalizing the bout lengths of sniffs in a similar manner did not reveal any increase in dopamine release either during or after the sniffs (i) (n = 6 males). dLight1.1 signal is calculated as the difference between the signal at 465-nm excitation and the signal at the isosbestic excitation wavelength of 405 nm, after the 405-nm trace has been linearly scaled to fit the 465-nm trace. See also Fig. 2b. j–n, Quantification of the magnitude of the ramp and of the drop in the dLight1.1 signal (j) shows greatly diminished dopamine ramps (k) and drops (l) after satiety. The differences between baseline and post-satiety magnitudes of the ramp and of the drop persisted even after we sub-selected all pairs of sniffs (one per condition) with matching latencies to sniff onset (i.e. with latencies that differed by <2 s; 81% of the sniffs were matched) (m,n). Latency to sniff onset was defined as the number of minutes since female entry (n = 8 baseline and 6 satiated males). o, Overlay of changes in MPOA dLight1.1 signal and male speed surrounding each sniff. p, q, Scatter plots of dLight1.1 signal and male speed (both in 1-s bins) in the 5-s window surrounding the sniffs in two example males (Pearson correlation; p: n = 80 trials; q = 50 trials). r, Moment-to-moment dLight1.1 signal in the MPOA is more correlated with male speed than with male-female distance, which also depends on female movements (n = 6 males). Correlation coefficients are calculated as in p and q. s–u, Same as o–q but for correlation between dLight1.1 signal and male-female distance (Pearson correlation; t: n = 80 trials; u = 50 trials). Mean ± s.e.m. unless otherwise specified. ***p<0.001. See Supplementary Table 1 for statistics.

Extended Data Fig. 3 Anatomically and functionally separable sources of dopamine in MPOA and NAc.

a, b, VTA and SNc dopamine neurons (which can be labeled by either DAT-Cre or VMAT2-Cre following injection of a Cre-dependent reporter virus) send few or no axons to the MPOA. The right panels of a and b only show the GFP (green) channel. Scale bar: 200 μm. Data from Allen Institute15. c, Cre-dependent expression of AAV8-EF1a-DIO-synaptophysin-mCherry in VTA of a DAT-Cre (Slc6a3-Cre) mouse shows dopamine terminals in the dorsal striatum (dSTR), the ventral striatum (vSTR, NAc), and the olfactory tubercle (OT). Some axons terminate in lateral preoptic area (LPOA). Almost no axons terminate in the MPOA. Scale bar: 200 μm. d, In the NAc, dLight1.1 photometry shows dopamine release after sniff onsets (n = 7 males). e–g, When males sniffed a novel, inanimate object (d), photometry recordings of dLight1.1 showed dopamine transients in the NAc (e) but not in the MPOA (f) (e: n = 7 males; f: n = 6). Mean ± s.e.m. for this figure.

Extended Data Fig. 4 Dopamine neurons in the AVPV and PVpo nuclei of the hypothalamus.

a, b, Data acquisition and analysis steps for quantifying TH and Fos co-localization. Brief description (see Supplementary Methods for details): high-redundancy volumes of 60-μm thick brain slices (50 volumes of 15-30 steps, 2-4 μm/step) that have been stained for TH and Fos were collected using a two-photon microscope. To segment dopaminergic somas, we first identified independent components of the TH volume along the z-axis through standard PCA/ICA analysis60. We then applied a morphological filter to the independent components, each usually containing a few closely located cells, to separate the individual somas. The preliminary segmentation results (see b for a sample; scale bar: 200 μm) were then manually corrected and validated before the regions-of-interest (ROIs) were applied to the Fos channel. An ROI was considered positive for both TH and Fos only if the two intensity profiles (along the z-axis) contained co-localized peaks. c, Representative images of co-localization of TH and Fos in AVPV, PVpo, and ADP. Cells positive for both TH and Fos are highlighted with dashed circles (Scale bars: 200 μm).d, Brain regions that did not show differences in fos expression in dopamine neurons (n = 8 males for ADP; 4-5 for all other brain regions; mean ± s.e.m). ADP, anterior dorsal preoptic area; PVa, anterior periventricular nucleus; PVi, intermediate periventricular nucleus; Arc, arcuate nucleus; ZI, zona incerta; SNc, substantia nigra pars compacta; VTA, ventral tegmental area. e–i, Projections of AVPV/PVpo dopamine neurons (identified by injecting Cre-dependent axon-GCaMP6s in unilateral AVPV/PVpo of a TH-Cre male). Note that no axons were observed in the basolateral amygdala, which receives strong mesolimbic dopamine inputs. 3V, third ventricle; ac, anterior commissure; Arc, arcuate hypothalamic nucleus; BLA, basolateral amygdala nucleus; BMA, basomedial amygdala nucleus; BNST, bed nucleus of stria terminalis; BNSTa, anterior bed nucleus of the stria terminalis; CEA, central amygdala nucleus; COA, cortical amygdala area; DMH, dorsomedial nucleus of the hypothalamus; fx, column of fornix; LPOA, lateral preoptic area; LSc, caudal lateral septum; LSr, rostral lateral septum; MEAad, anterodorsal medial amygdala nucleus; MEAav, anteroventral medial amygdala; PIR, piriform area; PVH, paraventricular nucleus of the hypothalamus; PVT, paraventricular nucleus of the thalamus; sm, stria medullaris; Tu, tuberal nucleus; VMH, ventromedial nucleus of the hypothalamus. Scale bars: 200 μm.

Extended Data Fig. 5 AVPV/PVpo TH-Cre+ neurons release dopamine in the MPOA and promote mating behaviours.

a, Co-localization of TH-Cre+ cells (i.e., expressing EYFP) in the AVPV/PVpo with TH staining. Both EYFP and TH proteins were visualized with antibody staining. Scale bar: 200 μm. b, c, Optogenetic stimulation of TH-Cre+ AVPV/PVpo axonal projections to the MPOA in awake, head-fixed males triggers robust local dopamine release that can be measured with the dopamine sensor dLight1.1 (n = 5 males). Note that the mean amplitude of the optogenetically evoked dLight1.1 transient is similar to the magnitude of transients evoked by female approach behaviours in Fig. 2b, c. d–h, Unilateral chemogenetic inhibition of AVPV/PVpo dopamine (d) neurons largely suppressed the ramp and drop of dopamine (surrounding sniffs) in the MPOA after injecting the agonist C21 (f) but not saline (e). Quantifications are shown in panels g and h, which use the same definitions of ramping and dropping as Extended Data Fig. 2j (n = 5 males). i, j, Bilateral chemogenetic inhibition of male AVPV/PVpo dopamine neurons did not suppress ingestive behaviours (n = 10 males). k, l, Optogenetic stimulation of AVPV/PVpo dopamine neuron cell bodies (‘Soma’) or axons in the MPOA reinvigorates both appetitive sniffing (k: n = 7, 9, 9 males) and consummatory mounting behaviours (l: n = 7, 9, 9, mean ± 95% c.i.) in sexually sated mice. m, Optogenetic pre-stimulation of all dopamine axons in the MPOA (in TH-Cre males) did not further increase the fraction of males that mount in the first 15 min after introduction of the female, as this fraction was already near ceiling in the absence of stimulation (n = 10, 8, 10, 9, 12, 12 trials from 7 males, mean ± 95% c.i.). n–p, Optogenetic pre-stimulation of all dopamine axons in the MPOA led to a sustained increase in male appetitive sniffing behaviour towards dioestrus females (n: n = 6 males) and a decrease in the latency to onset of the consummatory mounting behaviour (o: n = 6 males) at 10 min and 30 min after the stimulation. This stimulation did not further increase the fraction of males that mount in the first 15 min after introduction of the female, as this fraction was already near ceiling in the absence of stimulation (p: n = 13, 14, 14, 14, 14, 14 trials from 6 males, mean ± 95% c.i.). q–s, Brief optogenetic pre-stimulation of dopaminergic somas in the AVPV/PVpo led to a sustained increase in male appetitive sniffing behaviour (q: n = 6 males) and a decrease in the latency to onset of the consummatory mounting behaviour (r: n = 6 males). This stimulation did not further increase the fraction of males that mount in the first 15 min after introduction of the female, as this fraction was already near ceiling in the absence of stimulation (s: n = 9, 8, 7, 8 trials from 6 males, mean ± 95% c.i.). t, Brief optogenetic pre-stimulation of AVPV/PVpo dopamine axons in the MPOA did not further increase the fraction of males that mount in the first 15 min after introduction of the female, as this fraction was already near ceiling in the absence of stimulation (n = 22, 12, 18, 18, 18, 18 trials from 6 males, mean ± 95% c.i.). u, Female priming followed by pre-stimulation of all dopamine axons in the MPOA did not further increase the fraction of males that mount in the first 15 min after introduction of the female, as this fraction was already near ceiling in the absence of stimulation (n = 10, 7, 7, 8 trials from 5 males, mean ± 95% c.i.). Mean ± s.e.m. unless otherwise specified. *p<0.05, **p<0.01, ***p<0.001. See Supplementary Table 1 for statistics.

Extended Data Fig. 6 Measuring cAMP production with the sensor cADDis in brain slices and in vivo.

a, b, Application of forskolin (an activator of adenylyl cyclase) to brain slices of NAc (a) and MPOA (b) induces cAMP production, as measured using the cAMP sensor cADDis. cAMP production can be measured from changes either in fluorescence intensity or in fluorescence lifetime of cADDis (a: n = 6 slices from 3 mice; b: n = 2 slices from 2 mice). Photobleaching is only observed in the intensity traces (e.g., prior to application of forskolin). The y-axes are flipped to make the plots more intuitive, as cADDis fluorescence intensity and fluorescence lifetime both decrease with increasing cAMP. c, Experimental design for cADDis photometry in the MPOA with Chrimson stimulation of AVPV/PVpo dopamine neurons. d, Histology of cADDis expression, dopamine axons, and fibre location in the MPOA (scale bar: 200 μm). e, Raw photometry measurements of cADDis fluorescence intensity in the MPOA of awake, head-fixed males (during two example trials) show a persistent, downward deflection (increase in cAMP) after stimulating dopamine axons in the MPOA (red). Grey traces are mono-exponential fits of the pre-stimulation photometry data (fitted using the first 5 min of the traces), in order to estimate and account for the effects of photobleaching. A.U., arbitrary units. f, Experimental design for GRABDA2m61 (a D2-based dopamine sensor) photometry in the MPOA, together with Chrimson stimulation of AVPV/PVpo dopamine neurons. g, Blocking D1/D5 transmission with SCH23390 (0.6 mg/kg, i.p.) did not affect optogenetically evoked dopamine release (n = 5 males). h–j, Repeated optogenetic stimulation of AVPV/PVpo dopamine axons in the MPOA (from data collected from the same experiments as in c-e) increased male appetitive sniffing behaviour (h: n = 7 males) and decreased mounting latency (i: n = 7 males). But this stimulation did not further increase the fraction of males that mount in the first 15 min after introduction of the female, as this fraction was already at ceiling in the absence of stimulation (j: n = 14 trials from 7 males each, mean ± 95% c.i.). Mean ± s.e.m. unless otherwise specified. See Supplementary Table 1 for statistics.

Extended Data Fig. 7 Persistent PKA activity in the MPOA.

a, b, Application of forskolin to brain slices containing the NAc (a) or the MPOA (b) induces PKA activity, which can be measured with the PKA sensor FLIM-AKAR. PKA activity can be measured from changes either in fluorescence intensity or in fluorescence lifetime of FLIM-AKAR (a: n = 3 slices from 2 mice; b: n = 4 slices from 2 mice). Photobleaching is only seen in the fluorescence intensity traces. The y-axes are flipped to make the plots more intuitive, as FLIM-AKAR fluorescence intensity and fluorescence lifetime decrease with increasing PKA activity. c–e, cell body ROIs and corresponding neuropil rings for two representative cells (c, d), segmented from the intensity frames (top) and applied to the lifetime frames (bottom) during in vivo two-photon FLIM imaging via a GRIN lens inserted in the MPOA. The ROIs and corresponding rings are shaded red in left and right panels, respectively, and also displayed in insets at higher magnification. The purpose of calculating lifetime changes in both ROIs and in surrounding neuropil rings was to subtract lifetime changes in the neuropil rings from those in the ROIs, thereby isolating changes in cell body PKA activity above and beyond contributions from nearby neuropil. Samples traces of the ROI, neuropil ring, and ROI after neuropil ring subtraction are shown in e (same plotting format as in Fig. 4c; red horizontal bar: Chrimson stimulation). The cell highlighted in c (Cell 1) showed increased PKA activity following stimulation in the ROI but not in the surrounding neuropil. See Methods for detailed descriptions of ROI segmentation and neuropil ring calculation. Scalebar: 200 μm. f–h, Average lifetime traces per mouse (f: n = 3 mice), per field-of-view (g: n = 8-9 fields of view, with fields of view from the same mouse spaced a minimum of 80 μm apart along the Z-axis), and per cell (h: n = 121, 86 cells) show persistent increases in PKA activity in the MPOA after optogenetically stimulating AVPV/PVpo dopamine axons in the MPOA. Thin lines: individual traces. Thick lines: means across traces. No change in PKA activity is seen in the no-stimulation controls. Neuropil changes were subtracted for all traces. Individual traces in f and g were obtained by averaging changes in fluorescence lifetime across all cells in each mouse (f) or in each field of view (g). i, j, K-means clustering (i, k = 2) reveals a sub-population of 36% of the MPOA neurons that show strong responses to dopamine stimulation (j, left). The other cluster includes cells that did not respond to the stimulation and cells in the no-stimulation control experiments (j, right; n = 43, 164 cells). We used this clustering method to identify responsive cells because each field of view was only imaged once per experimental condition. Neuropil changes were subtracted for all traces. k, Mean traces of cells analyzed in j (n = 43 responsive and 78 unresponsive cells from 3 males). l, Across responsive cells, the magnitude of change in FLIM-AKAR lifetime with dopamine stimulation was positively correlated with baseline lifetime, indicating that cells that show the strongest stimulation-evoked increases in PKA activity also exhibited lower initial PKA activity (Pearson correlation; n = 43 cells from 3 males). Mean ± s.e.m. unless otherwise specified. *p<0.05, ***p<0.001. See Supplementary Table 1 for statistics.

Extended Data Fig. 8 Persistent cAMP elevation in the MPOA.

a, Setup and protocol for optogenetic Chrimson stimulation of dopamine axons in the MPOA in awake, head-fixed males while measuring PKA activity using two-photon fluorescence lifetime imaging (FLIM) of the cAMP sensor, cADDis, via a GRIN lens. Stimulation protocol: 10-ms pulses at 10 Hz for 5 s, repeated every 30 s. FLIM frames were collected 10 min before stimulation as well as 30, 60, and 120 min after stimulation. b, Left: mean cADDis fluorescence intensity image. Brighter regions: cell bodies. Scale bar: 200 μm. Right: dopamine stimulation (red dashed line) induced a persistent decrease in cADDis lifetime (increase in cAMP concentration) that gradually returned to baseline over tens of minutes. Scale bar: 200 μm. c, d, Average lifetime changes across fields-of-view (c: n = 8, 6 fields of view) and across mice (d: n = 4 mice) demonstrated a persistent decrease in lifetime following stimulation (segmentation and neuropil ring subtraction were performed as in FLIM-AKAR imaging, cf. Extended Data Fig. 7c, d). e, Left: experimental design. Right: head-fixed two-photon FLIM imaging sessions prior to priming (‘A’) and after priming (‘B’) show increased baseline cAMP concentration in the MPOA following priming (n = 6 fields of view from 3 mice, each value is the average of all cells in a field of view). Mean ± s.e.m. ***p<0.001. See Supplementary Table 1 for statistics.

Extended Data Fig. 9 AVPV/PVpo dopamine neurons signal to ESR1 neurons in the MPOA through D1/D5 transmission.

a, b, Fluorescence in situ hybridization (using the RNAscope kit) demonstrates high co-localization of DRD1 and ESR1 expression in the MPOA (a), with an average of ~2 DRD1 puncta per ESR1 cell (n = 3 mice). The masks were selected based on ESR1 puncta. A cropped subregion of these images is shown in Fig. 4f. Scale bars: 100 μm. c, In the LPOA, 39% of the ESR1 neurons also express DRD1 (average ~2 DRD1 puncta per ESR1 cell), and 68% of the DRD1 puncta are found in the ESR1 cells. d, Sample field of view of cADDis expression in the ESR1 neurons in the MPOA (defined as the subregion of the preoptic area within 600 μm from the midline) and the LPOA (defined as the subregion beyond 600 μm from the midline). The definition of the boundary at 600 μm is derived from a standard mouse atlas62. Experimental designs are replotted here. In Experiment 1, we first used a concentric bipolar electrode to locally stimulate the AVPV/PVpo area for 20 rounds (20 Hz trains, 75 μA pulses for 1 s every 20 s) and then washed on the D1/D5 agonist SKF81297 (2 μM; diluted from 100 mM stock solution in dimethyl sulfoxide). In Experiment 2, we first used a minimal stimulation protocol to identify the MPOA ESR1 neurons that responded to AVPV/PVpo stimulations, washed on the D1/D5 antagonist SCH23390 (300 nM; diluted from 50 mM stock solution in saline), and then performed 20 more rounds of AVPV/PVpo stimulation in the presence of the antagonist. e, Heatmaps showing the cell-by-cell cADDis response in the MPOA to both AVPV/PVpo stimulation (left) and D1/D5 agonist wash-on (right). Stimulation responses are averages of 20 trials, following baseline subtraction of the pre-stimulation means, while the agonist response is a single-trial response following baseline subtraction of the pre-agonist value. ESR1 neurons are divided into those that responded to the agonist (above the horizontal blue line) and those that did not (below the horizontal blue line) using a classifier (see Methods). Cells are sorted based on their agonist response and the same order is used for both panels. Grey lines on the top denote the windows that are used for quantification and classification. The colour of the ‘Slide ID’ indicates the identity of the slice (n = 983 neurons from 4 slices, 3 mice) from which the cell was recorded. f, g, In the agonist-responsive group (orange), neurons show persistent cAMP elevations (decreases in cADDis intensity) that accumulate after each AVPV/PVpo stimulation (f). The cAMP elevations are not seen in the agonist-unresponsive group (grey in f; n = 4 slices from 3 males). Panel g summarizes agonist responses (n = 4 slices from 3 males). h, Heatmaps showing the cell-by-cell cADDis response of MPOA ESR1 neurons to AVPV/PVpo stimulation both before (left) and after washing on the D1/D5 antagonist (right). Stimulation responses are averages of 3 and 20 trials, following baseline subtraction of the pre-stimulation means. MPOA ESR1 neurons are divided into those that responded to the pre-antagonist stimulation (above the horizontal blue line) and those that did not (below the horizontal blue line) using a classifier (see Methods). Cells are sorted based on their stimulation response, and the same order is used for both panels. Grey lines on the top denote the windows that are used for quantification and classification. The colour of the ‘Slide ID’ indicates the identity of the slice (n = 947 cells from 4 slices, 3 mice) from which the cell was recorded. i, j, In the stimulation-responsive group (red), neurons show persistent cAMP elevations that are accumulated after each AVPV/PVpo stimulation (i: n = 4 slices from 3 males). The cAMP elevations are not seen after the antagonist wash-on (j: n = 4 slices from 3 males). k, Same as e but for LPOA ESR1 neurons (n = 192 cells from 4 slices, 3 mice). l, m, Same as f, g but for LPOA neurons. Note that LPOA ESR1 neurons (including those in the agonist-responsive group) did not respond to AVPV/PVpo stimulation (n = 4 slices from 3 males). n, o, Same as l–m but for fluorescence lifetime measurements (a bleaching-insensitive way of analyzing fluorescence data; see Methods). Note that LPOA ESR1 neurons did not respond to AVPV/PVpo stimulation, including those in the agonist-responsive group (n = 4 slices from 3 males). p–r, In Experiment 2, we again observed only very few AVPV/PVpo stimulation-responsive neurons in the LPOA, before or after antagonist application (n = 198 cells from 4 slices, 3 mice). Plotting conventions are the same as above. Note that we did not plot average responses of the stimulation-responsive group due to its small size. s, t, In combined data from Experiments 1 and 2, the fraction of cells that responded to AVPV/PVpo stimulation gradually dropped off over distance from the midline (t; n = 2320 cells from 8 slices, 6 mice). Axon fields of AVPV/PVpo dopamine neurons shown here for comparison (s). Scale bars: 200 μm. u, In the agonist-responsive group (orange), MPOA ESR1 neurons show persistent elevations in PKA activity (decreases in FLIM-AKAR lifetime) that accumulate across repeated trials of AVPV/PVpo stimulation. The cAMP elevations are not seen in the agonist-unresponsive group (grey; n = 4 slices from 3 males). The right panel summarizes agonist responses (n = 4 slices from 3 males). v, In the stimulation-responsive group (red), MPOA ESR1 neurons show persistent elevations in PKA activity that accumulate after each AVPV/PVpo stimulation (left: n = 4 slices from 3 males). The elevations in PKA activity are not seen after antagonist wash-on (right: n = 4 slices from 3 males). w, Same as u but for LPOA ESR1 neurons. Note that LPOA ESR1 neurons did not respond to AVPV/PVpo stimulation, including those in the agonist-responsive group (n = 4 slices from 3 males). x, In Experiment 2, we again only recorded very few numbers of AVPV/PVpo stimulation-responsive ESR1 neurons in the LPOA, before or after antagonist. See above for plotting conventions. Note that we did not plot average responses of the stimulation-responsive group due to its small size. Mean ± s.e.m. *p<0.05, **p<0.01, ***p<0.001. See Supplementary Table 1 for statistics.

Extended Data Fig. 10 Novel optogenetic and molecular tools to manipulate intracellular cAMP in vivo.

a, Peptide sequences of bPAC63 and an improved variant, biPAC. b, cAMP production by bPAC and biPAC in Xenopus laevis oocytes. Measurement was performed 3 days after injection of 30 ng cRNA of Venus-bPAC or Venus-biPAC in the dark (‘Dark’, non-shaded bars) or after 1 min illumination with 473 nm, 0.3 mW/mm2 light (’Light’, shaded bars). The control bar shows uninjected oocytes (n = 3 groups of 5 oocytes). For comparison, the mean value of the uninjected oocytes is also noted with a horizontal dashed line. The Y-axis is on the log scale. Note that, in contrast to bPAC, biPAC does not exhibit increased enzymatic activity in darkness, above levels observed in baseline control conditions. c, Enzymatic activity of Venus-biPAC in dark and light conditions (n = 4, mean ± s.d.). d, Light intensity-dependent cAMP production of Venus-biPAC at 473 nm. After fitting with the Michaelis-Menten function, the Km value was determined to be 32 μW/mm2 (n = 4, mean ± s.d.). Venus tag was used here for protein-quantification purpose (same below). e, cAMP concentrations at different time points in the dark after 500 ms of light stimulation. Fitting a mono-exponential function yielded an off time constant τoff = 8.9 ± 2.2 s (n = 4, mean ± s.d.). f, g, Brief optogenetic stimulation of biPAC expressed in Esr1-Cre cells in the MPOA did not further increase the fraction of males that mount in the first 15 min after subsequent introduction of the female, as this fraction was already near ceiling in the absence of stimulation (ns, non-significant; Fisher’s exact test, n = 35, 36 trials from 12 males, mean ± 95% c.i.). h–j, In mice that did not express biPAC, the same stimulation protocol failed to increase appetitive sniffing (h: n = 6 males), failed to decrease the latency to consummatory mounting behaviours (i: n = 6 males), and failed to increase the fraction of males that mounted (j: n = 18 trial from 6 males, mean ± 95% c.i.). k, l, Design (k) and sequence (l) of PDE4D3-Cat. Upstream conserved regions (UCRs) are inhibitory, regulatory domains in the endogenous hPDE4D364. Replacement of these UCRs with mKate2 substantially increased the enzymatic activity of PDE4D3-Cat over hPDE4D3. m, Enzymatic activity of Venus-PDE4D3-Cat (n = 3, mean ± s.d.). After fitting with the Michaelis-Menten function, the Km value was determined to be 3.1 ± 0.4 μM and the Vmax value was 35.3 ± 2.9 s−1. This enzyme is much faster than the endogenous protein (Vmax = 5-9 s−1)64. ***p<0.001. See Supplementary Table 1 for statistics.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, a Supplementary Discussion and Supplementary References.

Reporting Summary

Supplementary Table 1

Statistical details for Fig. 1-4 and Extended Data Figs. 1-10.

Peer Review File

Supplementary Video 1

Sniffing of female mice by males. After a female mouse enters the home cage of a male mouse, the male starts to investigate the new animal by following and sniffing her.

Supplementary Video 2

Male mounting and lower-body grooming. After investigating a female mouse, a male mouse decides to mount the female. Initially, the male’s lower body thrusting is rapid and shallow. After the female intromits the male, the male’s thrusting movements become deeper and slower. When the mounting bout ends, the male starts to clean his lower body.

Supplementary Video 3

Transfer of reproductive fluids. In the beginning of this video, a male mouse mounts a female and gains intromission a few seconds after. The repeated thrusting ends with the male transferring reproductive fluids, during which he shakes, falls on his side, and becomes temporarily immobilized. After the female moves away, the male stands up and cleans himself.

Supplementary Video 4

Priming of male mating drive by female interaction and dopamine stimulation. In this video, the male mouse’s mating drive has been primed by 1) interacting with a female and then 2) stimulating dopamine axons in the MPOA. The priming steps were done 15 minutes before the start of this video, and the male has been alone in his cage since then. After a new female (i.e., different from the female that the male was primed with) enters the cage, the male only briefly investigates her (~7 seconds) before initiating mounting behavior.

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Zhang, S.X., Lutas, A., Yang, S. et al. Hypothalamic dopamine neurons motivate mating through persistent cAMP signalling. Nature 597, 245–249 (2021). https://doi.org/10.1038/s41586-021-03845-0

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