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Reciprocal cortico-amygdala connections regulate prosocial and selfish choices in mice

Nature Neuroscience volume 25, pages 1505–1518 (2022)Cite this article

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Abstract

Decisions that favor one’s own interest versus the interest of another individual depend on context and the relationships between individuals. The neurobiology underlying selfish choices or choices that benefit others is not understood. We developed a two-choice social decision-making task in which mice can decide whether to share a reward with their conspecifics. Preference for altruistic choices was modulated by familiarity, sex, social contact, hunger, hierarchical status and emotional state matching. Fiber photometry recordings and chemogenetic manipulations demonstrated that basolateral amygdala (BLA) neurons are involved in the establishment of prosocial decisions. In particular, BLA neurons projecting to the prelimbic (PL) region of the prefrontal cortex mediated the development of a preference for altruistic choices, whereas PL projections to the BLA modulated self-interest motives for decision-making. This provides a neurobiological model of altruistic and selfish choices with relevance to pathologies associated with dysfunctions in social decision-making.

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Fig. 1: Mice prefer altruistic over selfish decisions.
Fig. 2: Mice are willing to take altruistic decisions under costly situations.
Fig. 3: Mice display more selfish choices with unfamiliar recipients.
Fig. 4: Social dominance hierarchy modulates preference for altruistic choices.
Fig. 5: BLA neuronal silencing abolishes the preference for altruistic choices.
Fig. 6: The BLA is required for the learning of altruistic choices.
Fig. 7: Chemogenetic silencing of the BLA–PFC reciprocal connection has a different impact on altruistic choices.
Fig. 8: A brain circuit and factors involved in altruistic choices.

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Data availability

All source data used to generate the figures are available at https://doi.org/10.5061/dryad.bnzs7h4dv.

Code availability

Custom-written analysis code is available at https://doi.org/10.5061/dryad.bnzs7h4dv.

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Acknowledgements

We are grateful to G. Contarini, J. Stanic, M. Morini, D. Cantatore and C. Esposto for their excellent technical support. We thank NOLIMITS, an advanced imaging facility established by the Università degli Studi di Milano. This work was supported by funding from Fondazione Istituto Italiano di Tecnologia, Ministero della Salute (project: GR-2016-02362413) and Fondazione Telethon Italia (project: GGP19103) to F.P. and Fondazione Cariplo (2019-1747) to D.S.

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Authors and Affiliations

  1. Genetics of Cognition Laboratory, Neuroscience Area, Istituto Italiano di Tecnologia, Genova, Italy

    Diego Scheggia, Federica Maltese, Giulia Chiacchierini, Cinzia Molent, Fabrizio Bernardi & Francesco Papaleo

  2. Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy

    Diego Scheggia, Filippo La Greca, Maria Italia, Giulia Coccia, Nicolò Carrano, Elisa Zianni, Fabrizio Gardoni & Monica Di Luca

  3. Dipartimento di Medicina Sperimentale (Di.Mes), Università degli Studi di Genova, Genova, Italy

    Cinzia Molent

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  1. Diego Scheggia
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Contributions

D.S. conceptualized and designed the study. D.S., F.L.G., F.M., G.C., C.M. and E.Z. performed chemogenetic and behavioral experiments. F.M. and G.C. performed fiber photometry. G.C., C.M. and F.B. analyzed fiber photometry data. M.I. performed c-Fos experiments. F.G. provided suggestions on the c-Fos experiments and imaging. F.L.G., F.M., G.C., M.I. and N.C. performed histology. D.S., F.L.G., M.D. and F.P. wrote the manuscript. D.S. supervised the study. D.S., F.G., M.D. and F.P. provided resources and acquired funding. All authors revised the manuscript.

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Correspondence to Diego Scheggia.

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Extended data

Extended Data Fig. 1 Characterization of behaviors in the SDM task.

a, Individual decision preference scores in mice tested with (orange) or without (grey) recipient mouse over the five days of SDM task. b, Cumulative number of altruistic choices for each mouse (altruistic, orange; selfish, blue) during each daily session in the SDM task. c, Altruistic responses (in %) in altruistic (n = 11) and selfish (n = 5) mice (two-way RM ANOVA, group (altruistic, selfish) x time (days 1-5), F(4, 56)=21.55, p < 0.0001) and individual scores of altruistic responses across five days of SDM. d, Number of tested mice grouped by percentage of altruistic responses. e, Number of choices (orange, altruistic; maroon, selfish) of altruistic mice on the last session of training in the SDM task (two-way RM ANOVA, choice (altruistic, selfish) x time (minutes), F(7, 70)=5.67, p < 0.0001). f, Number of choices (light blue, altruistic; blue, selfish) of selfish mice on the last session of training in the SDM task (two-way RM ANOVA, choice (altruistic, selfish) x time (minutes), F(7, 35)=2.61, p = 0.0276). g, Number of head entries in the food magazine of recipient mice tested with altruistic (orange, n = 14) or selfish (blue, n = 14) actors (two-way RM ANOVA, group (altruistic, selfish) x time (days 1-5), F(4, 103)=3.04, p = 0.0203). h, Following training in the SDM task actor mice were tested in an additional session with sated (red, n = 6) or food-restricted (orange, n = 6) recipient mice (two-tailed unpaired t-test: t = 2.37, d.f.=10, p = 0.0387). I, Left, decision preference score in mice tested with food-restricted (orange, n = 12) or sated (red, n = 9) recipient mice over the five days of SDM task (two-way RM ANOVA, group (sated, food-restricted) x time (days 1-5), F(4, 76)=2.62, p = 0.0409). Right, individual curves representing decision preference scores. *p < 0.05, ***p < 0.001. Values are expressed as mean ± s.e.m.

Extended Data Fig. 2 Male mice make more altruistic responses than females.

a, Altruistic responses in males (n = 8) and females (n = 8) across five days of testing in the SDM (two-way RM ANOVA, gender, F(1, 14)=5.90, p = 0.0292; time (days 1-5), F(4, 56)=4.59, p = 0.0028). b, Number of tested mice grouped by gender and by percentage of altruistic responses. c, Number of nose pokes responses in male mice tested in the conditions with recipient (n = 8) and no recipient (n = 6) on day five of the SDM (two-way ANOVA, group (with recipient, no recipient) x response (nose-poke 1, nose-poke 2), F(1, 24)=6.2, p = 0.0199). d, Number of nose pokes responses in female mice tested in the conditions with recipient (n = 8) and no recipient (n = 6) (two-way ANOVA, group (with recipient, no recipient), F(1, 12)=4.1, p = 0.0630). *p < 0.05, **p < 0.01, n.s., not significant. Values are expressed as mean ± s.e.m.

Extended Data Fig. 3 Mice change their responses to share food rewards with their conspecifics.

a, Experimental design of the SDM. Actor mice were trained on a two-choice decision paradigm where nose pokes resulted in food rewards. In the condition i. ‘with recipient’ (orange) one nose poke resulted in food reward to actor (selfish choice) and the other nose poke in food reward both to the actor and to the recipient, in the adjacent compartment (altruistic choice). After an inter-trial interval of 5 seconds (ITI), a new trial started, and actor could make their choice. The location of the two responses were counterbalanced between left and right nose-pokes. In the condition ii. ‘no recipient’ (grey) the structure of the task was identical, but the adjacent compartment was empty. iii. In the condition ‘with toy’, the recipient was replaced. b, Nose poke responses (in percentage) during baseline training in the right and left nose poke holes were not different at the group level (two-tailed paired t-test: t = 0.47, d.f.=24, p = 0.6423, n = 13 mice). c, Change of preference (in percentage) to altruistic responses during the SDM with recipient compared to the baseline (one-sample t-test, t = 2.36, d.f.=64, p = 0.0211, n = 13 mice). d, Number of tested mice grouped by preference. e, Change of preference (in percentage) to altruistic responses during the last session of SDM in males (n = 7) compared to females (n = 6) mice (two-tailed paired t-test: t = 1.94, d.f.=11, p = 0.0773). f, Change of preference when animals were tested one additional day with their recipient (R→R, n = 7) or with an inanimate object (toy, R→T, n = 6) (two-tailed unpaired t-test, t = 2.49, d.f.=11, p = 0.0296). *p < 0.05. Values are expressed as mean ± s.e.m.

Extended Data Fig. 4 Mice are willing to take altruistic decisions under costly situations.

Altruistic responses (orange) reinforced on FR2, FR4 and FR6 and selfish responses (blue) reinforced on FR1 expressed as percentage of the total in males (light blue, (n = 7) and females (red, n = 4) mice and responses on the preferred nose poke (NP1, dark grey) reinforced on FR2, FR4 and FR6 and responses on the non-preferred nose poke (NP2, light grey) reinforced on FR1 in mice tested without recipient (n = 6) (FR2: two-way RM ANOVA, group (with recipient males, with recipient females, no recipient) x response (FR1, FR2), F(2, 13)=3.5, p = 0.05. FR4: two-way RM ANOVA, group (with recipient males, with recipient females, no recipient) x response (FR1, FR2), F(2, 13)=5.1, p = 0.0192; FR6. two-way RM ANOVA, group (with recipient males, with recipient females, no recipient) x response (FR1, FR2), F(2, 13)=6.6, p = 0.0103. FR8: two-tailed unpaired t-test, t = 8.32, d.f.=6, p = 0.0002). *p < 0.05, **p < 0.01, ***p < 0.005 n.s., not significant. Values are expressed as mean ± s.e.m.

Extended Data Fig. 5 Characterization of the role of social dominance and emotional state matching in social decision-making.

a, Number of altruistic and selfish choices in subordinate (two-way RM ANOVA, choice (altruistic, selfish) x time (days), F(4, 152)=4.92, p = 0.0009, n = 19), and dominant actor mice (F(4, 144)=3.26, p = 0.0122, n = 20). b, Dominant actor mice grouped by altruistic (two-way RM ANOVA, choice (altruistic, selfish) x time (days), F(4, 96)=8.83, p < 0.0001, n = 13) and selfish preference (two-way RM ANOVA, choice (altruistic, selfish) x time (days), F(4, 48)=10.45, p < 0.0001, n = 7) on the SDM task. c, Subordinate actor mice grouped by altruistic (two-way RM ANOVA, choice (altruistic, selfish) x time (days), F(4, 48)=3.09, p < 0.0001, n = 7) and selfish preference (two-way RM ANOVA, choice (altruistic, selfish) x time (days), F(4, 88)=12.52, p < 0.0001, n = 12) on the SDM task. d-e, Social dominance (normalized David’s Score) quantified based on the number and directionality of interactions in the tube test in actor and recipient mice grouped by selfish (d, two-tailed paired t-test: t = 3.17, d.f.=34, p = 0.0032; n = 18) and altruistic (e, two-tailed paired t-test: t = 0.79, d.f.=38, p = 0.4324; n = 20) actors and respective recipient conspecific. f,g, Normalized David’s Score in actor mice grouped by altruistic (f) or selfish (g) preference and by their social rank in relation to the normalized David’s Score of their respective recipient. h, Decision preference score in actor mice grouped by social rank (α: n = 8, β: n = 9, γ: n = 12, δ: n = 8; one-way ANOVA, F(3, 33)=3.90, p = 0.0172; two-tailed unpaired t-test, α vs. β: t = 2.12, d.f.=15, p = 0.050; α vs. γ: t = 2.87, d.f.=18, p = 0.0100; α vs. δ: t = 2.26, d.f.=14, p = 0.7982; δ vs. γ: t = 2.42, d.f.=18, p = 0.0261). i, Top, Schematic representation of the observational fear learning and freezing behavior in actor mice, grouped by altruistic (n = 6) or selfish (n = 7) preference during baseline (two-tailed unpaired t-test: t = 15.31, d.f.=13, p = 0.1497). Bottom, freezing behavior (conditioning-baseline) in altruistic and selfish actors (two-tailed unpaired t-test: t = 3.30, d.f.=13, p = 0.0057) and total time spent in the proximity of the divider between the actor and recipient compartment (two-tailed paired t-test: t = 0.39, d.f.=13, p = 0.7021). j, Social dominance (normalized David’s Score) predicts affective sensitivity (freezing behavior during observational fear learning) (linear regression, n = 27 mice, y = 8.971x + 15.61, F(1, 25)=4.47, p = 0.0446). *p < 0.05, **p < 0.01, ***p < 0.001. n.s., not significant. Values are expressed as mean ± s.e.m.

Extended Data Fig. 6 Behavioral effects of BLA neuronal silencing.

a, Representative images of viral expression in the BLA after injection with AAV-CamKIIa-hM4D-mCherry (data from 3 independent experiments). b, Reconstruction of viral expression. Red areas represent viral expression (higher expression = darker color). c, Left, schematic illustration of the actor-recipient testing chambers with graphical representation of the amount of time mice spent in different parts of the chambers (with blue as the shortest and red as the longest time). Right, social exploration, was measured in the area highlighted in red, in control (n = 10) and hM4D (n = 7) mice towards their recipients during the SDM task (two-way ANOVA, group (control, hM4D), F(4, 60)=5.0, p = 0.0013). d, Number of nose pokes in control (n = 9) and hM4D (n = 10) mice (two-way ANOVA, group (control, hM4D), F(1, 13)=0.54, p = 0.4721), e, Latency to respond in control (n = 8) and hM4D (n = 9) mice (two-way ANOVA, group (control, hM4D), F(1, 11)=0.02, p = 0.877), and f, Locomotor activity (two-way ANOVA, group (control, hM4D), F(1, 11)=0.10, p = 0.7566), during the five days of testing in the SDM task in control (n = 6) and hM4D (n = 7) mice. g, Observers mice received intraperitoneal (i.p.) injection of CNO (3 mg/kg) and after 30 minutes were tested with their respective demonstrators on the observational fear learning paradigm. h-i, Freezing behavior displayed by actor mice, control (n = 8) and hM4D (n = 7), during baseline (h, two-tailed unpaired t-test: t = 0.83, d.f.=13, p = 0.4170) and conditioning phases of the test (i, two-tailed unpaired t-test: t = 2.22, d.f.=13, p = 0.0447). *p < 0.05. Values are expressed as mean ± s.e.m.

Extended Data Fig. 7 BLA neuronal silencing reduces dominance and altruistic choices.

a, Left, average rank change after CNO or vehicle injection in mice that received hM4D in the BLA (two-sided Wilcoxon matched-pairs signed-rank test, p = 0.0002; vehicle n = 10, CNO n = 13). Right, rank changes in each hM4D-expressing mice after i.p. injection of CNO. b, Number of hM4D-expressing mice, grouped by social rank, that showed rank change following CNO injection. c, Left, control and mice that received hM4D for BLA silencing were injected with CNO (3 mg/kg) 30 minutes before the SDM task. At least 1 hour after daily session, mice were tested in the tube test for assessment of social ranking within cage mates. Right, cage composition. Each cage hosted 2 actor-recipient pairs. Actor mice received hM4D or control virus in the BLA. All the recipients received the control virus. d, Number of dominant or subordinate actor mice compared to their recipient conspecific (n = 19; two-sided Fisher’s exact test p = 0.1789). e, Social dominance (normalized David’s Score) quantified based on the number and directionality of interactions in the tube test in actor grouped by control (n = 9) and hM4D (n = 9) mice (two-tailed paired t-test: t = 2.15, d.f.=14, p = 0.0493). f,g, Social dominance (normalized David’s Score) quantified based on the number and directionality of interactions in the tube test in (f) control (two-tailed paired t-test: t = 1.30, d.f.=16, p = 0.2120) and (g) hM4D actor mice (two-tailed paired t-test: t = 1.331, d.f.=14, p = 0.2045). h,i, Rank positions of (h) control and (i) hM4D mice in each cage over testing days. j, Number of altruistic and selfish choices in subordinate (grey, n = 6) and dominant (red, n = 4) mice that received hM4D in the BLA and CNO at the end of training and during the five days of SDM task (two-way ANOVA, group (dominant, subordinate), F(3, 80)=3.9, p = 0.0107). k, Decision preference scores in the SDM task of hM4D-injected animal, grouped by dominant and subordinate. *p < 0.05. Values are expressed as mean ± s.e.m.

Extended Data Fig. 8 Fiber photometry and c-fos expression in the BLA.

a, Targeting maps of GCaMP6f expression and location of optic fibers in the BLA for fiber photometry recordings. b, Top, representative images of c-fos (green) and GAD67 (red) expression. Scale bar (applicable to all micrographs), 50 μm. Bottom, bar graph quantification of c-fos GAD67 double positive cells in altruistic and selfish mice (n = 21 sections from 5 animals; two-tailed unpaired t-test: t = 3.33, d.f.=22, p = 0.0030) and bar graph quantification of cells that were c-fos positive and GAD67 negative in altruistic and selfish mice and mice without recipient (n = 37 sections from 7 animals; one-way ANOVA, F(2, 34)=3.97, p = 0.0282). *p < 0.05, ***p < 0.001. Values are expressed as mean ± s.e.m.

Extended Data Fig. 9 BLA is required to develop altruistic preference.

a, Latency to respond (in sec) grouped by altruistic and selfish choices in control (light and dark orange, n = 7) and hM4D mice (light and dark fuchsia, n = 7) during the five days of SDM task (two-way ANOVA, group (control, hM4D, altruistic, selfish), x time (days 1-5), F(12, 96)=2.39, p = 0.0093). b, Number of altruistic choices over 40 minutes of testing during the five days of the SDM in control and hM4D mice (mixed model analysis for each day of testing, day1: (control, hM4D) x time (min), F(16, 132)=0.48, p = 0.9915; day 2: group F(42, 267)=0.42, p = 0.9994; day 3: F(73, 685)=2.85, p < 0.0001; day 4: F(80, 716)=2.13, p < 0.0001; day 5: F(77, 696)=0.85, p = 0.8057). c, Decision preference score in the five days of SDM and following one additional week of testing (day 13) in control (n = 7) and hM4D (n = 7) mice (two-way RM ANOVA, group (control, hM4D) x time (days), F(5, 60)=2.875, p = 0.0416). d, Number of altruistic and selfish choices on test day 13 of the SDM in control (n = 7) and hM4D (n = 7) mice (two-way RM ANOVA, group (control, hM4D) x choice (altruistic, selfish), F(1, 12)=9.661, p = 0.0091). *p < 0.05, **p < 0.01, ***p < 0.001. Values are expressed as mean ± s.e.m.

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Scheggia, D., La Greca, F., Maltese, F. et al. Reciprocal cortico-amygdala connections regulate prosocial and selfish choices in mice. Nat Neurosci 25, 1505–1518 (2022). https://doi.org/10.1038/s41593-022-01179-2

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