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Cortico-cortical transfer of socially derived information gates emotion recognition

Nature Neuroscience (2024)Cite this article

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Abstract

Emotion recognition and the resulting responses are important for survival and social functioning. However, how socially derived information is processed for reliable emotion recognition is incompletely understood. Here, we reveal an evolutionarily conserved long-range inhibitory/excitatory brain network mediating these socio-cognitive processes. Anatomical tracing in mice revealed the existence of a subpopulation of somatostatin (SOM) GABAergic neurons projecting from the medial prefrontal cortex (mPFC) to the retrosplenial cortex (RSC). Through optogenetic manipulations and Ca2+ imaging fiber photometry in mice and functional imaging in humans, we demonstrate the specific participation of these long-range SOM projections from the mPFC to the RSC, and an excitatory feedback loop from the RSC to the mPFC, in emotion recognition. Notably, we show that mPFC-to-RSC SOM projections are dysfunctional in mouse models relevant to psychiatric vulnerability and can be targeted to rescue emotion recognition deficits in these mice. Our findings demonstrate a cortico-cortical circuit underlying emotion recognition.

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Fig. 1: A subpopulation of SOM-positive cells within the mPFC shows long-range projections to the RSC.
Fig. 2: mPFC-to-RSC SOM terminals are involved in emotion recognition.
Fig. 3: mPFC-to-RSC SOM terminals amplify RSC differential activation responses between encounter of a neutral versus emotionally altered mouse.
Fig. 4: RSC pyramidal neurons generally encode social information.
Fig. 5: RSC pyramidal neurons projecting to the mPFC regulate emotion recognition.
Fig. 6: FC of the DMN components during emotion recognition in humans.
Fig. 7: Emotion recognition deficits in genetic and pharmacological schizophrenia-relevant mouse models are associated with functional alterations of the mPFC–RSC inhibitory–excitatory circuit.

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Data availability

All scripts used in the paper were based on the provided scripts from the Tucker-Davis Technology database and were adjusted for our needs. The individual data and statistical analyses are shared on the open repository at https://doi.org/10.48557/FEXUTZ. All raw images, photometry recordings or videos are shared on reasonable request to the corresponding author due to their large sizes. Human data are available on the IMAGEN database via https://imagen-project.org/the-imagen-dataset/.

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Acknowledgements

We are grateful to G. Contarini, M. Morini, D. Cantatore, G. Pruzzo, B. Chiarenza, A. Monteforte and C. Chiabrera for technical support. We thank O. Yizhar for suggestions and discussions on optogenetics experiments. This work was supported by funding from the Istituto Italiano di Tecnologia, the Ministero della Salute (project GR-2016-02362413) and Fondazione Telethon Italia (project GGP19103) to F.P. Human experiments were supported by the ERC Advanced Grant STRATIFY (695313), Human Brain Project (HBP SGA 945539), the Horizon Europe project environMENTAL (101057429), an NSFC RFIS grant to G.S. and the National Natural Science Foundation of China (82102138) to X.C.

Author information

Author notes

  1. Daniel Dautan

    Present address: Bioclinicum, Karolinska Institute, Stockholm, Sweden

  2. These authors contributed equally: Daniel Dautan, Anna Monai.

Authors and Affiliations

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

    Daniel Dautan, Anna Monai, Federica Maltese, Cinzia Molent, Daniele Mauro, Federica Antonelli, Arianna Benedetti, Francesca Managò & Francesco Papaleo

  2. Centre for Population Neuroscience and Stratified Medicine (PONS), Institute for Science and Technology of Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, P. R. China

    Xiao Chang & Gunter Schumann

  3. Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive systems, Istituto Italiano di Tecnologia, Rovereto, Italy

    Alberto Galbusera, Marco Pagani & Alessandro Gozzi

  4. Optical Approaches to Brain Function Laboratory, Istituto Italiano di Tecnologia, Genova, Italy

    Dania Vecchia & Tommaso Fellin

  5. Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy

    Filippo Drago & Gian Marco Leggio

  6. Centre for Population Neuroscience and Stratified Medicine (PONS), Charite Mental Health, Department of Psychiatry and Psychotherapy, CCM, Charite Universitätsmedizin Berlin, Berlin, Germany

    Gunter Schumann

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  1. Daniel Dautan
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Contributions

Conceptualization: D.D. and F.P. Methodology and investigation: D.D., A.M., F. Maltese, X.C., D.M., C.M., F.A., A.B., F.D., G.M.L., A. Galbusera, D.V., M.P., A. Gozzi, G.S., F. Managò and F.P. Resource: T.F., A. Gozzi, G.S. and F.P. Writing: D.D., X.C., D.V., M.P., A. Gozzi and F.P. Visualization and analysis: D.D., A.M., F. Maltese, X.C., D.M., C.M., A. Galbusera, D.V., M.P., A. Gozzi, G.S., F. Managò and F.P. Human experiments: X.C. and G.S. Supervision: F.P. All the authors revised the manuscript. F. M. and X.C. participated equally as co-second authors.

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Correspondence to Francesco Papaleo.

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Extended data

Extended Data Fig. 1 Refer to Fig. 1.

In mice expressing TdTomato in all somatostatin neurons (SOM-tdT) quantification of immunolabelled somatostatin cell of the mPFC (a) revealed a high-colocalization (n = 3 mice, 91.31 + /-2.02% overlapping). The same immunostaining for (b) Calretinin (CR), (c) Nitric oxide synthase (NOS), or (d) Parvalbumin (PV) revealed (e) an overall low colocalization with TdTomato positive cells (CR:13.24 + /-1.29, PV: 7.32 + /-0.94, NOS: 9.50 + /-1.73%). (f-g) Following injection of Ctb-560 in the RSC of SOM-TdT mice, we observed CtB expressing cells across the entire cortex, including the different subregions of the mPFC (the cingulate, prelimbic and infralimbic cortex, repeated in 3 animals). (h-i) The overlapping of all sections containing the mPFC and the mapping of CtB-Positive neurons revealed a distribution along the different layers and the dorsoventral axis. Data are represented as means + /-SEM. Cg, cingulate cortex; PrL, Prelimbic cortex, iFl, infralimbic cortex. Bar plots are represented as mean ± SEM. * is used for P < 0.05.

Extended Data Fig. 2 Refer to Figs. 2–3.

(a) In SOM-cre mice AAV-DIO-Chrimson and AAV-DIO-GCaMP were injected in the mPFC to record and activate SOM neurons in the mPFC and their terminals in the RSC. (b) Activation of the soma induces an increase of the signal in both the mPFC and the RSC while (c) stimulation of the terminals results in an increased GCAmP signal only in the terminals but not in the soma. (d) SOM-cre mice receiving inhibition (red, AAV-DIO-NphR) or control (black, AAV-DIO-TdTomato) of the mPFC-to-RSC terminals when in the stress demonstrator zone, and sacrificed 30 min following the task for cFOS immunohistochemistry. (e) Ex vivo quantification of cFOS positive neurons in the RSC (n = 6 mice, 8 to 13 sections per mice within the PFC, *P < 0.0001). (f) SOM-cre mice (n = 4 males) were injected with AAV-DIO-Chrimson in the mPFC, receiving retroorbital administration of PHPeb-CAG-GCamP and implanted with a widefield miniscope above the RSC, while control mice (WT n = 2) received only the retroorbital administration of PHPeb-CAG-GCamP and implanted with a widefield miniscope above the RSC. (g) GCaMP-activity in the RSC during activation (5 Hz, 2 seconds long) of mPFC-to-RSC SOM terminals (red, n = 386 stimulations, *P < 0.0001 2 sec light period versus 5 sec baseline). Control mice were treated in the same way but not having injected the chrimson opsin (gray line, n = 100 stimulation). Left panel represent the average GCamP-Signal during the baseline (5 s) and the stimulation (2 s) across all stimulation trials. The cake graph shows that in opsin injected animals, 91.5% of the stimulation pulses delivered induced a reduction in the signal (353/386 stim) while a minor part was associated with an increase (20/386, 5.2%) or no significant changes (13/386, 3.4%). (h) SOM-cre mice injected in the mPFC with AAV-DIO-ChR2 (n = 8 mice) or AAV-DIO-NphR (n = 14), and tested for discrimination between an object and a mouse without light, with optostimulation (blue background), or photoinhibition (orange background), (*P < 0.05 mouse versus object). Light stimulation was delivered only during the first 2 minutes of the test. (i) Discrimination between a familiar and an unfamiliar mouse (n = 11) without light, with optostimulation (blue background) or photoinhibition (orange background), (*P < 0.05 familiar versus unfamiliar). Light stimulation was delivered during the first 2 minutes of the test. (j) Distance travelled during the emotion recognition with photoactivation (blue background) or photoinhibition (orange background, n = 6). (k-l) SOM-cre mice injected with AAV-DIO-YFP (Control, n = 6) and implanted with a LED on the RSC to deliver blue (blue background) or red light (orange background) during the first 2 minutes of the emotion recognition task. (*P < 0.05 neutral versus emotionally altered). (m) In all tested mice, most social contacts (95.95 + /-0.71%) between the observer and a demonstrator mouse occurred with entries of ≥2.5 s from crossing the stimulus mouse zone (n = 24 mice). (n) Calcium signal in WT mice (n = 9) injected with AAV-CamKII-GCamP in the RSC or SOM cre mice (same as Fig.3d) injected with AAV-DIO-Chrimson in the mPFC, before, during and after the delivery of red light (560 nm). Bar plots are represented as mean ± SEM. Whisker-plot presenting upper and lower quartile, mean and median. Complete statistics in Supplementary Table 3.

Extended Data Fig. 3 Refer to Figs. 2 and 7.

Optogenetic inhibition (NphR) and stimulation (ChR2) of mPFC-to-RSC SOM terminals during (a) stress emotion recognition in male (n = 5 for ChR2 and 6 for NphR) and female (n = 4 for ChR2 and 8 for NphR) observers, or (b) during relief emotion recognition in male (n = 5 for ChR2 and 6 for NphR) and female (n = 4 for ChR2 and 8 for NphR) observers (*P < 0.05 versus no light). (c) Fiber photometry signal of mPFC-to-RSC SOM terminals during emotion recognition when entering the neutral mouse zone (grey lines) or the zone of emotionally altered demonstrators (red lines) in all animals, or divided by males and females (n = 23; #P < 0.0001 versus baseline; *P < 0.005 versus neutral). Whisker-plot are presenting upper and lower quartile, mean and median. (d) Optogenetic ChR2 stimulation of the mPFC-to-RSC SOM terminals of male (n = 5) and female (n = 5) observers in neutral versus neutral recognition with entries to a randomly selected neutral mouse zone paired with 5 Hz stimulation (Stim). (e) Control group with no stimulation of the mPFC-to-RSC SOM terminals of male (n = 5) and female (n = 5) observers in neutral versus neutral recognition. (f) Observer mice tested with two neutral demonstrators. Entrance in one of these demonstrators (randomly chosen) triggered optogenetic inhibition (NphR) of the mPFC-to-RSC SOM terminals (continuous light). (*P < 0.05 neutral + stim versus neutral). (g) Dual stimulation of the mPFC-to-RSC SOM terminals in neutral versus neutral condition with entries to a randomly selected demonstrator paired with a short activation (200 ms, 5 Hz) follow by inhibition (continuous). (*P < 0.05 neutral + dual stim versus neutral). (h) Stress emotion recognition in ARC mice (+/+, + /- and -/-) in males (+/+ n = 10, +/- n = 9, -/- n = 9) and females (+/+ n = 5, +/- n = 6, -/- n = 4). (*P < 0.05 ARC + /+ neutral versus ARC + /+ stress). (i) Relief emotion recognition in ARC mice (+/+, + /- and -/-) in males and female (*P = 0.01 ARC + /+ neutral versus ARC+ /+ relief). (j) Emotion recognition with no PCP (PCP day 0), following acute PCP (PCP day 1) and 14 days PCP + 7 days washout (PCP day 21) in males (n = 5) and females (n = 6). Bar plots are represented as mean ± SEM. Whisker-plot presenting upper and lower quartile, mean and median. * is used for P < 0.05. Complete statistics in Supplementary Table 3.

Extended Data Fig. 4 Refer to Figs. 2 and 4.

(a-b) Number of body rotation, head-tail distance, and number of entries without light and following optogenetic inhibition of mPFC-to-RSC SOM terminals (NphR-terminals) during recognition for (a) stress or (b) relief (*P < 0.0001 no light versus light). (c-d) Number of body rotation, head-tail distance, and number of entries without light and following optogenetic stimulation of mPFC-to-RSC SOM terminals (ChR2-terminals) during recognition for (c) stress or (d) relief (*P < 0.001 no light versus light). (e-f) Number of body rotation, head-tail distance, and number of entries without light and following optogenetic stimulation of RSC-pyramidal neurons during recognition for (e) stress or (f) relief (*P < 0.05 no light versus light). The increase in the number of entries in both the emotionally altered is associated with a reduction of social-interaction (Fig. 2) and less sniffing (see Fig. 4b-c). (g-h) Time spent in the no demonstrator mice zone subdivided by central area or close to the walls without light or following optogenetic stimulation of RSC-pyramidal neurons in (g) stress or (h) relief emotion recognition (Figures show only 0-2 min for clarity). (i-j) Time spent in the no demonstrator mice zone subdivided by central area or close to the walls without light or following optogenetic stimulation of mPFC-to-RSC SOM terminals in (i) stress or (j) relief emotion recognition. (k-l) Time spent in the no demonstrator mice zone subdivided by central area or close to the walls without light or following optogenetic inhibition of mPFC-to-RSC SOM terminals in (k) stress or (l) relief emotion recognition. Together with increased entrance (Extended Data Fig. 9c-d), these data suggest that opto inhibition of mPFC-to-RSC SOM terminals increase mouse willingness to interact with other mice, consistent with its increased emotion recognition effect (Fig. 2), unrelated to anxiety-like behaviors (effects both in center and walls time). (m) Grooming time in no stimulated side versus the side with optogenetic stimulation of RSC pyramidal neurons in a neutral versus neutral condition. (n) Grooming time in no stimulated side versus the side with optogenetic stimulation of mPFC-to-RSC SOM terminals in a neutral versus neutral condition. (o) Grooming time in no stimulated side versus the side with optogenetic inhibition of mPFC-to-RSC SOM terminals in a neutral versus neutral condition. Bar plots are represented as mean ± SEM. * is used for P < 0.05. Complete statistics in Supplementary Table 4.

Extended Data Fig. 5 Refer to Figs. 2–3–4.

Photometry recording of mPFC-to-RSC SOM terminals during recognition (a) between an object and a novel mouse (n = 4; object: green; mouse: grey. n = 25 entries to object, n = 34 entries to neutral) or (b) between a familiar and unfamiliar mouse (n = 29 entries to unfamiliar, n = 18 entries to familiar). (c-d) Photometry recording in SOM-cre mice (n = 6) injected with AAV-DIO-YFP in the mPFC and recorded in RSC during recognition (c) for stress (; stress: purple; neutral: grey; n = 199 entries to stress, n = 97 entries to neutral) or (d) relief (n = 198 entries to relief, n = 194 entries to neutral). (e) SOM-Cre mice (n = 4) were injected with AAV-DIO-GCAmP in the mPFC, and implanted with optic fibers both in the mPFC and RSC to record calcium activity of SOM cells at the level of the soma (Soma) or their terminals in the RSC (Term), allowing a direct correlation of both signals. (f) Calcium events in the Soma were selected as the threshold for the peristimulus analyses, showing that GCamP-signal increased in the mPFC (grey line), while presenting two patterns in the RSC, either an increase in 45% of the events (blue line) or a decrease (red line). (g) Som-cre mice were injected in the mPFC with AAV-DIO-ChR2 and AAV-DIO-NphR (n = 5 mice) and bilateral optic fiber was put on top of the RSC to test if activation or inhibition of mPFC-to-RSC SOM terminals could induce side preference in the absence of stimulus mice (empty) which are normally neutral in their side bias. (h) Short (250 ms) inhibition of the terminals (entire 6 minutes, n = 5 mice) prior to entry to a randomly selected side. (i) Activation of the terminals (n = 5 mice) only when in a randomly selected side zone. (j) Inhibition of the terminals (n = 5 mice) when in a randomly selected side zone. (k) Activation of the terminals (entire 6 minutes, n = 5 mice) prior to entry to a randomly selected side. (l) Number of entries in each zone during no stimulation (black bars), activation (blue bars) or inhibition (red bars) (n = 5 mice). For experiment empty-empty all mice were tested in all stimulation conditions. Whisker-plot are presenting upper and lower quartile, mean and median. Bar plots are represented as mean ± SEM. * is used for P < 0.05. Complete statistics in Supplementary Table 4.

Extended Data Fig. 6 Refer to Fig. 3.

(a) Schematic of the experiment in cortical slices containing mPFC. The blue oval indicates ChR2-positive SOM neurons. The gray triangle indicates ChR2-negative excitatory cells. (b) Representative current-clamp patch-clamp recording of a ChR2-negative excitatory cell showing the membrane potential responses to current injections (-50, +250, +300, +350 pA). (c) Left: five representative current traces (black) and their average (red) recorded at –50 mV in voltage-clamp configuration from a ChR2-negative excitatory neuron during photoactivation of ChR2-positive SOM cells in PFC. Currents are recorded in the presence of antagonists of glutamatergic ionotropic receptors (see methods for details). Laser power: 3.5 mW. Light pulse duration: 10 ms (top) and 2 ms (bottom). Right: same as in left using 15 mW of laser power. Note that current amplitude evoked with 10 ms long of blue light at 3.5 mW (top left) and 15 mW (top right) was similar. (d) Top left: schematic of the experiment in cortical slices containing RSC. The gray triangle indicates a ChR2-negative excitatory cell. The blue lines indicate ChR2-positive axonal projections from SOM interneurons in mPFC. Bottom left: representative current-clamp patch-clamp recording of a ChR2-negative excitatory cell showing the membrane potential responses to current injections (-50, +100, +150, +200, +250 pA). Right: representative current traces recorded at – 50 mV in voltage-clamp configuration from a RSC excitatory cell during 10 ms or 2 ms of blue light stimulation at 22 mW. No currents were recorded from this as well from other 9 excitatory cells in RSC during photoactivation of ChR2-positive axons originating from SOM neurons located in mPFC. (e) Representative current traces recorded at +10 mV in voltage-clamp configuration from a RSC excitatory cell during 10 ms or 2 ms of blue light stimulation at 15 mW. Bar plots are represented as mean ± SEM. * is used for P < 0.05. Complete statistics in Supplementary Table 4.

Extended Data Fig. 7 Refer to Fig. 4.

(a-b) Wild type mice (n = 6 males) were injected with AAV-CamKII-GCamP6 in the RSC to allow the recording of GCamP signal from RSC pyramidal cells during recognition (a) for stress (stress: purple; neutral: grey; #P < 0.001 versus baseline; *P = 0.03 neutral versus stress; n = 77 entries to stress, n = 57 entries to neutral) and (b) relief (relief: yellow; neutral: grey; #P = 0.02 relief versus baseline; n = 122 entries to relief, n = 120 entries to neutral). Isosbetic signal was collected on the red wavelength to remove artifact and movement control. (c-d) Wild-type mice (n = 6 males) injected bilaterally in the RSC with AAV-CamKII-ChR2 with light on or off for the first 2 minutes of the (c) stress and (d) relief emotion recognition test (*P < 0.05 versus no stimulation). (e) Same stimulation protocol, but this time in the second two minutes interval of the task (*P < 0.05 stress light off versus all other groups). (f-i) WT mice (n = 12 females) were bilaterally injected in the RSC with either AAV-CamKII-NphR (orange, n = 6 females) or AAV-CamKII-ChR2 (blue, n = 6 females), and after at least 4 weeks a 560 nm continuous light or 450 nm 5 Hz light was delivered during the first two minutes of the object/mouse and familiar/unfamiliar recognition task for inhibition or activation, respectively, of RSC pyramidal neurons. Time (in seconds) spent sniffing a mouse/familiar (gray bars), or an unfamiliar (violet bars) or object (green bars) displayed by the same observer mice without light stimulation (first column), with photoinhibition (second column, orange background) or photostimulation (third column, blue background) performed for 2 minutes from the beginning of the test (f, *P < 0.05 object versus mouse) (h, *P < 0.01 familiar versus unfamiliar). (g,i) A direct comparison of the no light (gray circles), photoinhibition (orange triangle), and photostimulation (blue squares) conditions by the discrimination index (*P < 0.05 versus ChR2). (j-m) These same mice were then tested with optogenetic stimulation in an empty versus empty discrimination (n = 6 mice) (P > 0.05 stimulated side versus no stimulated side). Empty-side paired stimulation had similarly no effects in (k) the total distance traveled (P = 0.59), (l) the number of zones entries (P = 0.59), and (m) the time spent in the zone (P = 0.99). (n-q) When these same mice were tested in these same conditions but in the presence of two neutral mice (one being paired to 5 Hz stimulation), we found no significant effect (n) on the time spent in the zone (P = 0.11), (o) the distance traveled (P = 0.09), and (q) the time in each zone (P = 0.08), but a significant effect of the stimulation in (p) the number of entries (P = 0.01 stimulated versus no stimulated side). The same animals were tested in both empty versus empty and Neutral versus Neutral. Bar plots are represented as mean ± SEM. Complete statistics in Supplementary Table 5.

Extended Data Fig. 8 Refer to Fig. 4.

(a) Following injection in the RSC of AAV-CamKII-YFP in wild-type mice (n = 3), we found YFP-positive signal in different brain regions including the medial prefrontal cortex (mPFC), the dorsomedial striatum (DMS), the cingulate (CG), the contralateral retrosplenial cortex (RSC), and the lateroposterior thalamic nuclei (LP).

Extended Data Fig. 9 Refer to Fig. 6.

(a) Seed-based connectivity mapping of the right (upper row) and left (bottom row) somatosensory cortex (SS) in ARC + /+ and ARC-/- littermates. Red-yellow represents brain regions showing significant rsfMRI functional connectivity with the right and left SS cortex in control  ARC+ /+ (left) and ARC -/- mice (middle). Seed regions are depicted in green. No changes of functional connectivity of the right and left SS were identified in ARC-/- mutants compared to  ARC+ /+ mice (right). (b) Unimpaired rsfMRI connectivity between right and left SS cortex was also quantified in reference volumes of interest (t = 0.70, P = 0.49) (n = 11 ARC+/+, n = 11 ARC-/-, unpaired two-tailed T-test). (c) SOM- ARC+ /- mice (n = 8) injected with AAV-DIO-NphR in the mPFC and implanted with a LED above the RSC present no emotion recognition in absence of light stimulation (paired two-tailed T-test; 0-2 min: P = 0.40 neutral versus stress; 2-4 min: P = 0.11 neutral versus stress; 4-6 min: P = 0.38 neutral versus stress). Bar plots are represented as mean ± SEM. * is used for P < 0.05. (d) Graphical resume of the photometry results obtained in the PCP-treated animals (n = 11 mice) during no drug condition (No PCP), acute (PCP day1) and chronic (PCP day 21) treatments. All same animals were tested in no PCP, PCP day 1 and PCP day 21. Arrow represents the variation of GCamP signal during entries to the stress (purple) or the neutral (grey) demonstrators. The thickness of the arrow is used for the relative strength of the signal variation.

Extended Data Table 1 Refer to Fig 6
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Supplementary Information

Supplementary Tables 1–5. Detailed statistical analyses for Figs. 1–5 and Extended Data Figs. 2–7.

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Dautan, D., Monai, A., Maltese, F. et al. Cortico-cortical transfer of socially derived information gates emotion recognition. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01647-x

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