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A distinct hypothalamus–habenula circuit governs risk preference

Nature Neuroscience volume 28, pages 361–373 (2025)Cite this article

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Abstract

Appropriate risk evaluation is essential for survival in complex, uncertain environments. Confronted with choosing between certain (safe) and uncertain (risky) options, animals show strong preference for either option consistently across extended time periods. How such risk preference is encoded in the brain remains elusive. A candidate region is the lateral habenula (LHb), which is prominently involved in value-guided behavior. Here, using a balanced two-alternative choice task and longitudinal two-photon calcium imaging in mice, we identify risk-preference-selective activity in LHb neurons reflecting individual risk preference before action selection. By using whole-brain anatomical tracing, multi-fiber photometry and projection-specific and cell-type-specific optogenetics, we find glutamatergic LHb projections from the medial (MH) but not lateral (LH) hypothalamus providing behavior-relevant synaptic input before action selection. Optogenetic stimulation of MH→LHb axons evoked excitatory and inhibitory postsynaptic responses, whereas LH→LHb projections were excitatory. We thus reveal functionally distinct hypothalamus–habenula circuits for risk preference in habitual economic decision-making.

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Fig. 1: Mice display strong preferential traits for safe or risky options that are stable across time.
Fig. 2: LHb population activity resembles individual risk preference before present action selection.
Fig. 3: Selective LHb cells encode individual risk preference before action selection.
Fig. 4: Retrograde and anterograde AAV labeling of LHb inputs.
Fig. 5: Functional coupling of long-range glutamatergic inputs and LHb is divergent.
Fig. 6: Functionally distinct hypothalamus–LHb circuits are required for risky decision-making.
Fig. 7: LH and MH axonal projections to LHb show distinct functional properties.

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Data availability

Pre-processed raw minimum datasets from multi-fiber photometry, extracellular electrophysiology and two-photon recordings have been made publicly available in Zenodo via https://doi.org/10.5281/zenodo.13834711 (ref. 76). Unprocessed datasets are available from the corresponding authors upon request. Source data are provided with this paper.

Code availability

MATLAB code is provided alongside pre-processed raw data on Zenodo via https://zenodo.org/records/13834711 (ref. 76). All other custom code used for analyses described herein will be available from the corresponding author upon request.

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Acknowledgements

This work was supported by grants to F.H. from the Swiss National Science Foundation (SNSF; project grant nos. 310030-127091 and 310030_192617; Sinergia grant no. CRSII5-18O316) and the European Research Council (ERC Advanced Grant, BRAINCOMPATH, 670757), by SNSF Ambizione grants (PZ00P3_209114 to P.R. and PZ00P3_216312 to S.H.), and by grants to D.G., C.L., P.R. and S.H. from the University of Zurich (Forschungskredit grants, projects K-41220-05-01, K-41220-04, K-41220-06-01 and K-41220-07-01). F.H. and T.K. received funding from the University Research Priority Program (URPP) ‘Adaptive Brain Circuits in Development and Learning’ (AdaBD). We thank P. Bethge for managing transgenic mouse lines, D. Dujmovic-Göckeritz for genotyping, the 3R Hub at the ETH Zurich for their support with the additional behavior experiments and analysis, H. Kasper and S. Giger for technical support, and C. Ruff, P. Tobler and M. Mameli for helpful discussions.

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Author notes

  1. Tevye Stachniak

    Present address: Division of Biomedical Sciences, Memorial University, St. John’s, Newfoundland, Canada

  2. Yaroslav Sych

    Present address: Institute of Cellular and Integrative Neuroscience, Strasbourg, France

  3. These authors contributed equally: Anna Maria Reuss, Peter Rupprecht.

Authors and Affiliations

  1. Brain Research Institute, University of Zurich, Zurich, Switzerland

    Dominik Groos, Peter Rupprecht, Tevye Stachniak, Christopher Lewis, Shuting Han, Adrian Roggenbach, Yaroslav Sych, Martin Wieckhorst, Theofanis Karayannis & Fritjof Helmchen

  2. Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

    Dominik Groos, Anna Maria Reuss, Peter Rupprecht, Shuting Han, Adrian Roggenbach, Oliver Sturman, Johannes Bohacek, Theofanis Karayannis, Adriano Aguzzi & Fritjof Helmchen

  3. Institute of Neuropathology, University of Zurich, Zurich, Switzerland

    Anna Maria Reuss & Adriano Aguzzi

  4. Institute for Neuroscience, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland

    Oliver Sturman & Johannes Bohacek

  5. University Research Priority Program (URPP), Adaptive Brain Circuits in Development and Learning, University of Zurich, Zurich, Switzerland

    Theofanis Karayannis & Fritjof Helmchen

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Contributions

D.G. conceived the project; D.G. and F.H. designed the study; D.G. carried out all surgeries, behavioral training and in vivo experiments with the help of Y.S. (fiber photometry), C.L. (extracellular electrophysiology) and P.R. (two-photon imaging); D.G., A.R., O.S., P.R. and C.L. analyzed behavioral, optical and in vivo electrophysiological data; A.M.R. performed tissue clearing and light-sheet imaging together with D.G.; S.H. and D.G. analyzed light-sheet data; T.S. performed and analyzed ex vivo brain slice recordings; D.G. and M.W. designed and M.W. wrote the custom behavior control software; J.B., T.K., A.A. and F.H. provided supervision; D.G. and F.H. wrote the paper with comments from all authors.

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Correspondence to Dominik Groos or Fritjof Helmchen.

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Extended data

Extended Data Fig. 1 Mice performing two alternative choice task adapt their choices depending on preferred spout orientation and expected values.

Fraction of preferred (a), decisive (b), and non-preferred (c) choices aligned to spout inversion (solid vertical line). Gray lines indicate individual inversion sessions (2-4 spout inversions per mouse), colored lines indicate mean across sessions for individual animals, dashed line indicates preference threshold. d, Every plot represents data from an individual mouse in response to decreasing value of the safe option. Every black dot represents the mean risky choices across four stable sessions with 200 trials each. Data are represented as mean ± s.e.m. Dotted lines indicate indifference point for each individual. Sigmoid fit.

Source data

Extended Data Fig. 2 Risk preference is independent of motivation, decisiveness, anxiety or sex.

a, Fraction of engaged trials for all risk averse (cyan, n = 32) and risk prone (magenta, n = 15) mice. Open circles indicate fractions of engaged trials (decisive and indecisive) from all trials an animal could engaged in (200 or 300 per session in 14 sessions, 2800 or 4200 trials for each mouse; p = 0.1076). b, Fraction of decisive trials measured as the fraction of all trials an animal could engage in subtracted by the number of indecisive trials (p = 0.2178). Results from plus maze test of animals after completion of two-alternative choice task. Comparison of risk averse (cyan, n = 21) and risk prone (magenta, n = 4) mice in open field (c-f; p = 0.9188, p = 0.7596, p = 0.3948, p = 0.9729), light-dark (g-j; p = 0.9729, p = 0.3958, p = 0.3591, p = 0.5633), and elevated plus maze test (k-o; p = 0.4756, p = 0.9188, p = 1.0, p = 0.5187, p = 0.7084). Fraction risky (p, p = 0.6207), engaged (q, p = 0.1564), and decisive (r, p = 0.8421) trials for male (blue, n = 10) and female (red, n = 9) mice (based on 600 trials across 3 sessions). Comparison of the same animals in open field (s-v; p = 0.0338, p = 0.1063, p = 0.8872, p = 0.4117), light-dark (w-z; p = 0.1834, p = 0.0253, p = 0.0219, p = 0.8650), and elevated plus maze test (aa-ee; p = 0.4791, p = 1.0, p = 0.3802, p = 0.3502, p = 0.1484).*p < 0.05, two-sided Wilcoxon rank sum test. For box plots, the median is indicated by the central line; 25th and 75th percentiles are indicated by the box and maximum/minimum values excluding outliers are indicated by the whiskers.

Source data

Extended Data Fig. 3 LHb fiber photometric signal in reward and post-reward period.

a, Illustration of reward period used for analysis. b, LHb photometry example traces from one animal aligned to reward valve opening. Data are plotted as mean ± s.e.m. c-e, Correlation of reward signal ratios and riskiness across animals. f, Illustration of post-reward period used for analysis. g, LHb photometry example traces for post-reward period (same animal as b). Data are plotted as mean ± s.e.m. h-j, Correlation of post-reward signal ratios and riskiness across animals.

Source data

Extended Data Fig. 4 Divergence in LHb fiber photometric signal cannot be explained by body movement.

a, Cross-correlation of body movement with bulk LHb signal. Data were obtained from the same animals as in Fig. 2 f-k (n = 9 mice), and are presented as mean ± s.e.m. b, Quantification of cross correlation latency to peak and maximum amplitude across animals. c, Correlation of body movement and riskiness of the respective animal. d, Correlation of body movement and LHb photometry signal in the DP. For box plots, the median is indicated by the central line; 25th and 75th percentiles are indicated by the box and maximum/minimum values excluding outliers are indicated by the whiskers.

Source data

Extended Data Fig. 5 Inter-individual and bulk LHb two-photon data.

a, Mean calcium transients (smoothed) for individual mice for all decisive trials sorted for mean activity in the DP. b, Quantification of two-photon bulk activity during the DP for present preferred (violet) and non-preferred (gray) choice trials (n = 12 mice). Line colors indicate individual risk preference (risk averse (cyan), risk neutral (black), risk prone (magenta), p = 0.0425). Two-photon bulk data were achieved from drawing a single region of interest (ROI) containing all recorded cells across the entire field of view (FOV). c, Ratio of LHb ΔF/F integrals during the DP for present risky and safe choice bulk activity correlated with individual risk preference across sessions (n = 12 mice; data are represented as mean ± s.e.m.). d and e, Same as b and c but trials were sorted for choice in the preceding trial (p = 0.0049).Two-sided Wilcoxon-signed rank test.

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Extended Data Fig. 6 LHb DP activity attenuates over trials but not sessions and independent of trial choice.

a, Single trial DP activity of LHb example cell (decisive trials only) across one example session. b, Quantification of mean single cell correlation with trial number (520 cells pooled across 12 mice; original (bue), shuffled (gray) data; p = 5.0193e-17). c, Activity of the same cell plotted across sessions. d, Quantification of across sessions (p = 0.1549). e-h Same as a-d but for multi-unit silicon probe recordings (90 recording sites across 5 mice (across trials (f): p = 3.1374e-14; across sessions (h): p = 0.27). i-l Same as a-d and e-h but for fiber photometric recordings of LHb bulk activity (n = 5 mice; across trials (j): p = 0.0849; across sessions (l): p = 0.0543). Mean trial ID for safe (cyan) and risky (magenta) choices for two-photon (m; n = 12 mice; p = 0.9697), silicon probe (n; n = 5 mice; p = 0.6250), and fiber photometry (o; n = 5 mice; p = 0.8125).Line colors indicate individual risk preference (risk averse (cyan), risk neutral (black), risk prone (magenta)). Two-sided Wilcoxon signed rank test (paired). *** p < 0.001. For box plots, the median is indicated by the central line; 25th and 75th percentiles are indicated by the box and maximum/minimum values excluding outliers are indicated by the whiskers.

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Extended Data Fig. 7 Positive and negative risk-preference selective cells (RPSCs) show divergent activity upon reward delivery.

a, Illustration of reward period used for analysis. b, Example traces of three positive (top row) and three negative RPSCs (bottom row) aligned to reward delivery from three different animals (one positive and one negative cell for each mouse; from left to right: mouse #8, #2, and #13). Data are plotted as mean ± s.e.m. Quantification of mean activity integrals (c; p = 4.29E-07)) and fraction of cells with positive values (d; p = 1.67E -06) for medium safe reward for positive (blue) and negative (red) RPSCs. Same as c and d but for small risky lose (e, p = 5.26E -03 (activity);f, p = 1.18E -05 (fractions)) and for large risky win reward (g, p = 2.08E -04 (activity); h, p = 1.02E -11 (fractions). Reward signal ratios for safe/lose (i; p = 2.87E -04), safe/win (j; p = 7.42E -19), and win/lose (k; p = 9.86E -04).*** p < 0.001, two-sided Wilcoxon rank sum test (activity), χ2-test (cell fractions), or two-sampled Kolmogorov Smirnov test (activity ratios). For box plots, the median is indicated by the central line; 25th and 75th percentiles are indicated by the box and maximum/minimum values excluding outliers are indicated by the whiskers.

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Extended Data Fig. 8 Anticipatory licking and preparatory mouth movement do not explain two-photon LHb single cell activity during the DP.

a, Mean number of anticipatory licks during the DP for preferred (violet) and non-preferred choice trials. Line colors indicate individual risk preference (risk averse (cyan), risk neutral (black), risk prone (magenta); p = 4.88E -04; two-sided Wilcoxon signed rank test). b, Correlation of mean DP activity with number of anticipatory licks for three example cells across three different mice. c, Mean correlation coefficient across all cells from individual mice for original (circle) and shuffled (triangle) data. d, Quantification of original and shuffled correlation coefficients (n = 12 mice; p = 0.8501; two-sided Wilcoxon signed rank test). Cell fractions (e, p = 6.055E -06; χ2-test), RPSC selectivity (f, p = 0.0182; two-sided Wilcoxon signed rank test) and correlation of RPSC DP activity difference between risky and safe choice with individual riskiness for present choices (g) calculated from trials without anticipatory licks. Positive RPSCs in blue negative RPSCs in red. h, Correlation of mean single cell activity with mouth movement during 1-s baseline period (BL), DP, and 1-s post-deliberation period (PDP; 483 cells from n = 12 mice; Friedman-test; ***p < 0.001; ns p > 0,05). i, Correlation of preparatory mouth movement ratios (mean across trials) with mean activity of LHb neurons during DP (520 cells from n = 12 mice). Cross-correlation lags of mean neuronal activity with mean preparatory mouth movement (j) and fraction of cells (k) based on 0.5 s-threshold (475 cells from n = 12 mice). l, Correlation of individual riskiness with preparatory mouth movement ratios (n = 12 mice). For box plots, the median is indicated by the central line; 25th and 75th percentiles are indicated by the box and maximum/minimum values excluding outliers are indicated by the whiskers.

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Extended Data Fig. 9 LHb RPSCs adapt their selectivity DP with changing preference.

a, Fraction of non-preferred option choices with changing expected value ratio (n = 4 mice). Every dark circle represents 3-5 sessions with 200 free choice trials each. Sigmoid fit. b, Fractions of LHb RPSCs tracked across sessions depending on their adaptation to preference change (baseline sessions compared to last highest ratio sessions). Positive (blue) and negative (red) LHb RPSCs (selectivity and fraction of cells) depending on their responses: Cells either increased (c,d), inverted (e, f), or lost (g, h) their selectivity. All data are represented as mean ± s.e.m. *** p < 0.001, two-sided Wilcoxon rank sum test (activity) or χ2-test (cell fractions).

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Extended Data Fig. 10 LH and MH fiber photometric signal in reward and post-reward period.

a, Illustration of reward period used for analysis. b, MH photometry example traces from one animal aligned to reward delivery. c, Quantification of MH population activity integrals aligned to reward delivery for medium safe (cyan), small risky lose (red), and large risky win (green) reward outcomes (p = 0.2199; n = 9 mice). Correlation of reward signal ratios and riskiness for safe/lose (d), safe/win (e), and win/lose (f). Same as a-f but for post-reward period (1-5 s post reward period; g-l; p = 0.4305). Same as a-l but for LH population activity (n = 9 mice; m-x; reward period p = 0.3228; post-reward period p = 0.4959).All data are plotted as mean ± s.e.m. ns: p > 0.05; repeated measure ANOVA with two-sided Bonferroni’s multiple comparison test. For box plots, the median is indicated by the central line; 25th and 75th percentiles are indicated by the box and maximum/minimum values excluding outliers are indicated by the whiskers.

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Supplementary information

Supplementary Information

Supplementary Fig. 1: On-target and off-target labeling of anterograde tracing. Supplementary Fig. 2: On-target and off-target labeling of multi-fiber recordings. Supplementary Fig. 3: Off-target effect on decisiveness and choice preference of retrograde optogenetic perturbation. Supplementary Fig. 4: Optogenetic stimulation of hypothalamic terminals in acute LHb-containing brain slices. Supplementary Fig. 5: Fiber placement of individual mice across experimental approaches. Supplementary Data Table 1: Statistical tests and exact P values. Supplementary Data Table 2: Abbreviations of retrogradely labeled LHb input regions.

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Groos, D., Reuss, A.M., Rupprecht, P. et al. A distinct hypothalamus–habenula circuit governs risk preference. Nat Neurosci 28, 361–373 (2025). https://doi.org/10.1038/s41593-024-01856-4

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