Abstract
Our own experience of emotional events influences how we approach and react to others’ emotions. Here we observe that mice exhibit divergent interindividual responses to others in stress (that is, preference or avoidance) only if they have previously experienced the same aversive event. These responses are estrus dependent in females and dominance dependent in males. Notably, silencing the expression of the corticotropin-releasing factor (CRF) within the medial prefrontal cortex (mPFC) attenuates the impact of stress self-experience on the reaction to others’ stress. In vivo microendoscopic calcium imaging revealed that mPFC CRF neurons are activated more toward others’ stress only following the same negative self-experience. Optogenetic manipulations confirmed that higher activation of mPFC CRF neurons is responsible for the switch from preference to avoidance of others in stress, but only following stress self-experience. These results provide a neurobiological substrate underlying how an individual’s emotional experience influences their approach toward others in a negative emotional state.
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Data availability
Individual data can be accessed from the open repository of the Istituto Italiano di Tecnologia (https://doi.org/10.48557/9BICTS). All raw images, calcium imaging recordings and videos can be shared upon request to the corresponding author because of their large sizes. Source data are provided with this paper.
Code availability
All custom analysis codes generated in MATLAB can be accessed from the open repository of the Istituto Italiano di Tecnologia (https://doi.org/10.48557/9BICTS).
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Acknowledgements
We are grateful to M. Morini, D. Cantatore, G. Pruzzo, C. Diana, A. Monteforte and C. Chiabrera for technical support. We thank A. Chen and Y. Shemesh from the Weizmann Institute of Science for input and material. This work was supported by funding from the Istituto Italiano di Tecnologia, Fondazione Telethon Italia (project GGP19103), and Italian Ministry of University and Research (National Recovery and Resilience Plan, project MNESYS PE0000006) to F.P. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Conceptualization, F. Maltese and F.P. Methodology and investigation, F. Maltese, G.P., A.M.C., F. Manago, N.d.L., A.M., M.N., R.W., F.L. and F.P. Resources, F.P. Writing, F. Maltese and F.P. Visualization and analysis, F. Maltese, F.B. and F.P. Supervision, F.P. All authors revised and approved the paper.
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Extended data
Extended Data Fig. 1 Emotion recognition in naive and restraint stress self-experienced male and female mice.
(a, f) Experimental design of the EDT with one restraint stress (purple) and one neutral (gray) demonstrator in (a) naive and (f) negative self-experience condition. (b, d, g, i) Percentage of time spent sniffing demonstrators in restraint stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by (b, g) male and (d, i) female (b, d) naïve and (g, i) self-experience observers (two-tailed multiple t-test, Bonferroni correction. N = 38 Naïve Males and 35 Naïve Females. mice. N = 38 Self-experience Males and 44 Self-experience Females). (c, e, h, j) Time spent sniffing demonstrators in restraint stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by (c, h) male and (e, j) female (c, e) naïve and (h, j) self-experienced observers (two-tailed multiple t-test, Bonferroni correction. N = 38 Naïve Males and 35 Naïve Females. N = 38 Self-experience males and 44 Self-experience Females). (k) Time spent grooming during the first 2 min of the test displayed by neutral (gray bars) or restraint stress (purple bars) demonstrators in naïve and restraint stress self-experience condition (two-way ANOVA, Bonferroni correction. N = 32 neutral and N = 32 restraint stress demonstrators). (l, n) No significant correlation was found between observers’ discrimination index (in y axis) and restraint stress demonstrators’ grooming (in x axis) during the first 2 min of the test in (l) naive and (n) self-experience condition (two-tailed Pearson correlation; N = 25 observers/condition and N = 25 restraint stress demonstrators/condition). (m, o) No correlation was found between observers’ grooming behavior (in y axis) and restraint stress demonstrators’ grooming (in x axis) during the first 2 min of the test in (m) naïve and (o) restraint stress self-experience condition (two-tailed Pearson correlation; N = 89 observers/condition and N = 89 stress demonstrators/condition). Bar and line graphs show mean ± s.e.m. ***P < 0.0005.
Extended Data Fig. 2 Effects of different stressful experiences on emotion recognition.
(a, c) Experimental design of the EDT with one footshock (green) vs one neutral (gray) demonstrator in (a) naïve and (c) footshock self-experienced observers. (b, d) Time (in seconds) spent sniffing demonstrators in footshock stress (green bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by (b) naïve and (d) footshock self-experienced observer mice (two-tailed multiple t-test, Bonferroni correction. N = 8 naïve and 16 footshock self-experience observers). (e) Mice in naïve (white) and footshock self-experience (blue) condition do not differ based on the amount of time spent grooming across the 6 min test (two-tailed unpaired t-test; N = 8 naïve and N = 16 footshock self-experienced mice). (f) No significant correlation was found between discrimination index (in y axis) and grooming (in x axis) of footshock self-experienced observer (two-tailed Pearson correlation; N = 16 mice). (g, i) Experimental design of the EDT with one restraint stress (purple) vs one neutral (gray) demonstrator in (g) naïve and (i) footshock-experienced mice. (h, j) Time spent sniffing demonstrators in restraint stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by (h) naïve and (j) footshock-experienced observer mice (two-tailed multiple t-test, Bonferroni correction. N = 14 naïve and 11 footshock-experience observers). (k) Naïve (white) and footshock-experienced (green) observers did not differ based on the amount of time spent grooming across the 6 min test (two-tailed unpaired t-test; N = 25 naïve and N = 11 footshock-experienced mice). (l) No significant correlation was found between discrimination index (in y axis) and grooming (in x axis) of footshock-experienced observer (two-tailed Pearson correlation; N = 11 mice). (m, o) Experimental design of the EDT with one fear vs one neutral demonstrator in (m) naïve and (o) restraint-experienced mice. (n, p) Time spent sniffing demonstrators in fear (red bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by (n) naïve and (p) restraint-experienced observer mice (two-tailed multiple t-test, Bonferroni correction. N = 10 naïve and 12 restraint-experience observers). (q) Naïve (white) and restraint-experienced observers (purple) did not differ based on the amount of time spent grooming across the 6 min test (two-tailed unpaired t-test; N = 10 naïve and N = 12 restraint-experienced mice). (r) No significant correlation was found between discrimination index (in y axis) and grooming (in x axis) of footshock-experienced observer (two-tailed Pearson correlation; N = 12 mice). Bar and line graphs show mean ± s.e.m. *P < 0.05, ***P < 0.0005.
Extended Data Fig. 3 Social hierarchy and estrus cycle in negative self-experience modulation of emotion recognition.
(a, d) Experimental design of the EDT in (a) naïve and (d) self-experience condition. (b, e) Time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by (left) dominant or (right) subordinate (b) naïve and (e) self-experience males (two-tailed multiple t-test, Bonferroni correction. N = 8 dominant and 13 subordinate observers). (c, f) Time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by (left) estral or (right) diestral (c) naïve and (f) self-experienced females (two-tailed multiple t-test, Bonferroni correction. (N = 7 naïve estral and 7 diestral observers; N = 15 self-experience estral and 13 diestral observers). (g) Both dominant and subordinate self-experienced observers differ from naïve mice in the total social exploration towards stress, but not neutral (Three-way RM ANOVA, Bonferroni correction; N = 7 naïve and 7 self-experienced dominants, N = 11 naïve and 13 self-experienced subordinates). (h) Time spent grooming (two-tailed unpaired t-test; N = 7 dominant and N = 13 subordinate mice) and (i) corticosterone levels (two-tailed unpaired t-test; N = 5 dominant and N = 4 subordinate mice) by self-experience dominant (orange) and subordinate (dark green) observers. (j) Both estral and diestral negative self-experienced observers significantly differ from naïve mice in the total social exploration towards stress, but not neutral, demonstrators (Three-way RM ANOVA, Bonferroni correction; N = 5 naïve and 15 self-experienced estral, N = 7 naïve and 13 negative self-experienced diestral). (k) Estral (light purple) and diestral (purple) self-experienced female mice do not differ in the time spent grooming across the 6 min test (two-tailed unpaired t-test; N = 15 estral and N = 13 diestral observers). (l, m) Time in (l) seconds or (m) percentage of time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test displayed by (left) rank 2 or (right) rank 3 self-experienced subordinate mice (two-tailed multiple t-test, Bonferroni correction. N = 7 rank 2 and 6 rank 3 observers). (n) Time in seconds and (o) percentage of time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test, which occurred 24 hr after self-experience, displayed by observer mice that were in (left) estrus or (right) diestrus when self-experience of stress occurred (two-tailed multiple t-test, Bonferroni correction. (N = 16 in estrus and 6 in diestrus). Bar and line graphs show mean ± s.e.m. *P < 0.05. **P < 0.005. ***P < 0.0005.
Extended Data Fig. 4 Silencing of CRF in mPFC modulates negative self-experience effect on stress emotion recognition.
(a, d) Experimental design of the EDT in (a) naïve and (d) negative self-experience condition. (b, c) Time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by naïve (b) scrambled and (c) anti-CRF shRNA naïve observers (two-tailed multiple t-test, Bonferroni correction. (b) SCRAMBLED. 2 min: P = 0.0002, 4 min: P = 0.01, 6 min: P = 0.01, N = 14 observers. (c) anti-CRF shRNA. 2 min: P = 0.0006; 4 min: P = 0.03; 6 min: P = 0.01; N = 15 observers). (e, f) Time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by negative self-experienced (e) scrambled and (f) anti-CRF shRNA observers (two-tailed multiple t-test, Bonferroni correction. (e) SCRAMBLED: no significant differences; N = 14 observers. (f) anti-CRF shRNA. 6 min: P = 0.01; N = 16 observers). (g, h) Time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by anti-CRF shRNA negative self-experienced (g) dominants and (h) subordinates (two-tailed multiple t-test, Bonferroni correction. (g) DOMINANTS. 6 min: P = 0.02; N = 7 mice. (h) SUBORDINATES. 6 min: P = 0.052; N = 9 mice). Bar and line graphs show mean ± s.e.m. *P < 0.05; ***P < 0.0005.
Extended Data Fig. 5 mPFC-CRF neurons activity during EDT and falcon restraint.
(a) CRF-Cre mice were injected into the mPFC with Syn.Flex.GCaMP6f.eYFP and implanted with a GRIN lens (n = 4/5mice). (b) Representative images of viral infection and GRIN lens placement of the five mice tested. (c, e) Experimental design of the EDT in (c) naïve and (e) negative self-experience condition. (d) Averaged percentage of time spent in the zone around a stress (purple bars) or a neutral (gray bars) demonstrator, displayed by naïve observers (two-tailed paired t-test; N = 4 observers). (f) Averaged percentage of time spent in the zone around a stress (purple bars) or a neutral (gray bars) demonstrator, displayed by negative self-experienced observers (left) with or (right) without preference towards stress demonstrators (two-tailed paired t-test. (left) Preference for stress: N = 3 mice. (right) No preference for stress: N = 2 mice. (g-j) Heatmaps of entrances in stress (g, i) or neutral (h, j) zone associated with neuronal inactivation in (g, h) naïve and (i, j) negative self-experience condition. (k) Experimental design: mice were placed for 10 min inside an empty cage (before restraint stress), and subsequently moved inside a 50 ml falcon for 30 min. (l, m) Average peaks’ (l) frequency and (m) amplitude before (yellow) and after (purple) restrain stress (two-tailed Wilcoxon matched-pairs signed ranks test. (l) Number of pairs: 62, p < 0.0001. (m) Number of pairs: 62, p = 0.84). Bar and line graphs show mean ± s.e.m. ***P < 0.0005.
Extended Data Fig. 6 Optogenetic inhibition of mPFC-CRF neurons during Emotion Recognition, Object Discrimination and Tube Test.
(a) Experimental design of the EDT with one stress and one neutral demonstrator in naïve condition. Photoinhibition (λ = 532 nm) was paired to exploration of neutral demonstrator. (b) Time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by naive observers tested in (left) light OFF and (right) light ON condition (two-tailed multiple t-test, Bonferroni correction. N = 5 observers/condition). (c) Total social exploration during the 6-min test, displayed by naive observers tested in light OFF and light ON condition (two-tailed paired t-test; N = 5 observers/condition). (d) Experimental design of the EDT with two neutral demonstrators in naïve condition. Photoinhibition (λ = 532 nm) was paired to the exploration of one demonstrator. (e, f) Time spent sniffing two neutral demonstrators in (e) percentage or (f) seconds, during the 6-min test divided into three consecutive 2-min epochs, displayed by naïve observers tested in (left) light OFF or (right) light ON condition (two-tailed multiple t-test, Bonferroni correction. N = 11 observers/condition). (g) Left: Cumulative time spent sniffing two neutral demonstrators in light OFF and light ON conditions (three-way RM ANOVA; N = 11 observers). Right: representative tracking plot for light OFF (top) and light ON (bottom) conditions. (h) Total social exploration during the 6-min test, displayed by naïve observers tested in light OFF and light ON condition (two-tailed paired t-test; N = 11 observers/condition). (i) Experimental design of the EDT with one stress and one neutral demonstrator in self-experience condition. Photoinhibition (λ = 532 nm) was paired to exploration of stress demonstrator. (j) Time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by self-experience observers tested in (left) light OFF and (right) light ON condition (two-tailed multiple t-test, Bonferroni correction. N = 9 observers/condition). (k) Total social exploration during the 6-min test, displayed by negative self-experienced observers tested in light OFF and light ON condition (two-tailed paired t-test; N = 9 observers/condition). (l, m) Time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by self-experience (left) dominant or (right) subordinate mice tested in (l) light OFF and (m) light ON condition (two-tailed multiple t-test, Bonferroni correction. N = 4 dominant and 5 subordinate observers). (n) Experimental design of the EDT with two inanimate objects in naïve condition. Photoinhibition (λ = 532 nm) was paired to exploration of one of the two objects. (o, p) Time spent sniffing two objects in (o) percentage or (p) seconds, during the 6-min test divided into three consecutive 2-min epochs, displayed by naïve observers. (two-tailed multiple t-test, Bonferroni correction. N = 10 observers). (q) Experimental design of photoinhibition (λ = 532 nm) during tube test performed on cages of two or three mice. (r) Summary of mPFC-CRF neurons photoinhibition–induced rank change. Each line represents one animal. (s) Mean rank change induced by mPFC-CRF neurons photoinhibition. N = 11 mice. Bar and line graphs show mean ± s.e.m. *P < 0.05. **P < 0.005.
Extended Data Fig. 7 Optogenetic activation of mPFC-CRF neurons during Emotion Recognition, Object Discrimination and Tube Test.
(a) Experimental design of the EDT with one neutral and one stress demonstrator in naive condition. Photostimulation (λ = 473 nm) was paired with one stress demonstrator. (b) Time spent sniffing demonstrators in stress (purple bars) or neutral (gray bars) state during the 6-min test, divided into three consecutive 2-min epochs, displayed by naïve observers tested in (left) light OFF and (right) light ON condition (two-tailed multiple t-test, Bonferroni correction. N = 6 observers/condition). (c) Total social exploration during the 6-min test, displayed by self-experience observers tested in light OFF and light ON condition (two-tailed paired t-test; N = 6 observers/condition). (d) Experimental design of the EDT with two neutral demonstrators in naive condition. Photostimulation (λ = 473 nm) was paired to exploration of one of the two neutral demonstrators. (e, f) Time spent sniffing two neutral demonstrators in (e) percentage or (f) seconds, during the 6-min test divided into three consecutive 2-min epochs, displayed by naïve observers tested in (left) light OFF and (right) light ON condition (two-tailed multiple t-test, Bonferroni correction. N = 7 observers/condition). (g) Left: Cumulative time spent sniffing two neutral demonstrators in light OFF and light ON conditions (three-way RM ANOVA). Right: representative tracking plot for light OFF (top) and light ON (bottom) conditions. N = 7 observers/condition. (h) Total social exploration during the 6-min test, displayed by naïve observers tested in light OFF and light ON condition (two-tailed paired t-test; N = 7 observers/condition). (i) Experimental design of the EDT with two neutral demonstrators in self-experience condition. Photostimulation (λ = 473 nm) was paired to exploration of one of two neutral demonstrators. (j) Time spent sniffing two neutral demonstrators during the 6-min test, divided into three consecutive 2-min epochs, displayed by self-experienced observers tested in (left) light OFF and (right) light ON condition (two-tailed multiple t-test, Bonferroni correction. N = 5 observers/condition). (k) Total social exploration during the 6-min test, displayed by naive observers tested in light OFF and light ON condition (two-tailed paired t-test; N = 6 observers/condition). (l, m) Time spent sniffing two neutral demonstrators during the 6-min test, divided into three consecutive 2-min epochs, displayed by negative self-experienced (left) dominant and (right) subordinate mice tested in (l) light OFF and (m) light ON condition (two-tailed multiple t-test, Bonferroni correction. N = 3 observers/condition). (n, q) Experimental design of the EDT with two inanimate objects in (n) naïve or (q) self-experience condition. Photostimulation (λ = 473 nm) was paired to exploration of one of the two object. (o, r) Percentage of time spent sniffing two objects during the 6-min test, divided into three consecutive 2-min epochs, displayed by (o) naïve or (r) self-experienced observers (two-tailed multiple t-test, Bonferroni correction. N = 8 naïve and 7 self-experience observers). (p, s) Time spent sniffing two objects during the 6-min test, divided into three consecutive 2-min epochs, displayed by (p) naïve or (s) self-experienced observers (two-tailed multiple t-test, Bonferroni correction. N = 8 naïve and 7 self-experience observers). (t) Experimental design of photostimulation (λ = 473 nm) during tube test performed on cages of two mice. (u) Summary of mPFC-CRF neurons photostimulation–induced rank change. Each line represents one animal. (v) Mean rank change induced by mPFC CRF neurons photostimulation. Bar and line graphs show mean ± s.e.m. *P < 0.05.
Supplementary information
Supplementary Information
Supplementary Figs. 1–7 and Tables 1–3.
Supplementary Video 1
Miniscope recording of CRF mPFC neurons during EDT in naive condition.
Supplementary Video 2
Miniscope recording of CRF mPFC neurons during EDT in self-experience condition.
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Maltese, F., Pacinelli, G., Monai, A. et al. Self-experience of a negative event alters responses to others in similar states through prefrontal cortex CRF mechanisms. Nat Neurosci 28, 122–136 (2025). https://doi.org/10.1038/s41593-024-01816-y
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DOI: https://doi.org/10.1038/s41593-024-01816-y
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