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The prefrontal cortex (PFC) is implicated in processing of the affective state of others through non-verbal communication. This social cognitive function is thought to rely on an intact cortical neuronal excitatory and inhibitory balance. Here combining in vivo electrophysiology with a behavioral task for affective state discrimination in mice, we show a differential activation of medial PFC (mPFC) neurons during social exploration that depends on the affective state of the conspecific. Optogenetic manipulations revealed a double dissociation between the role of interneurons in social cognition. Specifically, inhibition of mPFC somatostatin (SOM+), but not of parvalbumin (PV+) interneurons, abolishes affective state discrimination. Accordingly, synchronized activation of mPFC SOM+ interneurons selectively induces social discrimination. As visualized by in vivo single-cell microendoscopic Ca2+ imaging, an increased synchronous activity of mPFC SOM+ interneurons, guiding inhibition of pyramidal neurons, is associated with affective state discrimination. Our findings provide new insights into the neurobiological mechanisms of affective state discrimination. Scheggia et al. show that a specific subpopulation of cortical neurons expressing somatostatin in the prefrontal cortex has a primary role in orchestrating the ability of mice to discriminate positive and negative affective states in others.
Mice can discriminate conspecifics based on the affective state Related to Fig. 1. a-f, Data derived from n=8 mice. a, Top, Experimental design of the ADT. One demonstrator was given water access for 1 hour before the test, after 23 hours of water deprivation (‘relief’, yellow), while the other demonstrator had ad libitum water access (‘neutral’, grey). Increased exploration (sniffing, in seconds) to the relieved compared to neutral demonstrator (left, showed in 120-seconds beams, two-tailed multiple t-test, Bonferroni correction, 2 min: t=3.85, df=14, p=0.005; right, showed in 60-seconds beams, 60s: t=3.6, df=14, p=0.017, 120s: t=2.77, df=14, p=0.014). b, No difference in average number of visits to each zone (two-tailed multiple t-test, Bonferroni correction, t=0.22, df=14, p>0.999) c, Longer visits of observers in the zone related to the relief demonstrators (two-tailed multiple t-test, Bonferroni correction, 2 min: t=3.89, df=14, p=0.004). d, Average distance of observers’ head to the relieved and the neutral demonstrators did not differ during ADT (two-tailed paired t-test, t=1.22, df=7, p=0.261). e, In female mice increased sniffing to the relieved compared to neutral, sex-matched, demonstrator (two-tailed multiple t-test, Bonferroni correction, 2 min: t=3.32, df=18, p=0.011; n=10 mice). f, No difference in grooming (two-tailed multiple t-test, Bonferroni correction, t=0.45, df=14, p=0.657) and rearing behaviors (t=0.00, df=14, p=0.998), and locomotor activity (one-way ANOVA, F(2,21)=1.59, p=0.226), displayed by the observers during the ADT with the neutral and the relieved demonstrators. g-l, Data derived from n=7 mice. g, Top, In the stress protocol one demonstrator (‘stress’, purple) was subjected to restraint stress test for 15 minutes culminating in the beginning of ADT. The other demonstrator (‘neutral’, grey) waited undisturbed in his home-cage. Bottom, mice showed increased sniffing to the stressed compared to neutral demonstrator (left, showed in 120-seconds beams, two-tailed multiple t-test, Bonferroni correction, 2 min: t=2.11, df=12, p=0.05; right, showed in 60-seconds beams, 60s: t=3.67, df=10, p=0.02, 120s: t=2.12, df=10, p=0.05; n=6 mice). h, Average number of visits to each zone did not differ (two-tailed multiple t-test, Bonferroni correction, t=0.81, df=12, p>0.999). i, Observers made longer visits in the zone related to the stressed demonstrators (two-tailed multiple t-test, Bonferroni correction, 2 min: t=3.46, df=12, p=0.017). j, Shorter average head distance of observer mice to the stressed demonstrator compared to neutral during the ADT (two-tailed paired t-test, t=5.31, df=7, p=0.001). k, Female mice showed increased sniffing to the stressed compared to neutral, sex-matched, demonstrators (two-tailed multiple t-test, Bonferroni correction, 2 min: t=2.69, df=18, p=0.044; n=11 mice). l, No difference in grooming (two-tailed multiple t-test, Bonferroni correction, t=0.84, df=12, p=0.708) and rearing behaviors (t=1.20, df=12, p=0.578), and locomotor activity (one-way ANOVA, F(2,18)=0.72, p=0.498) displayed by the observers during the ADT with the neutral and the stressed demonstrators. m, No correlation between discrimination index, calculated for the first two minutes of ADT, and grooming behavior of the stressed demonstrators (n=16, Pearson’s r=0.017, linear regression showed no significant deviation from zero, two-tailed p=0.949). n, No difference of average plasma corticosterone levels after ADT with two neutral demonstrators (gray), one relieved and one neutral (yellow), one stressed and one neutral demonstrator (purple) (one-way ANOVA, F(2,13)=1.08, p=0.367). o, First and second testing in the same ADT (‘relief’) showed similar behavioral pattern with increased sniffing towards the relieved demonstrator compared to the neutral (ADT 1: two-tailed multiple t-test, Bonferroni correction, 2 min: t=2.25, df=20, p=0.035; ADT 2: t=3.99, df=20, p=0.002; n=11). p, For each observer tested in the ADT with both protocol (relief and stress) a discrimination index was calculated to compared performance on ADT 1 (red) and ADT 2 (blue; discrimination index = exploration of “relief”/”stress” - exploration of “neutral” / total time of exploration). Positive index means discrimination between “affectively-altered” and “neutral”. Of 41 mice tested in ADT 1 and ADT 2 only 6 did not show a positive discrimination index on second testing. Average discrimination index did not differ between ADT 1 and ADT 2 (two-tailed unpaired t-test, t=1.73, df=80, p=0.089; n=41 mice). Bar and line graphs show mean ± s.e.m. * p<0.05, ** p<0.005. n.s. not significant.
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Affective state discrimination is enhanced between familiar conspecifics Related to Fig. 1. a-f, Data derived from n=7 mice. a, Top, Experimental design of the ADT with cagemates demonstrators. Observer and demonstrators were singly-housed 23 hours before testing. One demonstrator was given water access for 1 hour before the test, after 23 hours of water deprivation (“relief”, yellow), while the other demonstrator had ad libitum water access (“neutral”, gray). b, Increased sniffing to the relieved compared to neutral demonstrator (two-tailed multiple t-test, Bonferroni correction, 2 min: t=3.60, df=12, p=0.010, 4 min: t=3.35, df=12, p=0.017). c, Increased time spent in the zone related to the relieved demonstrator compared to the neutral (two-tailed multiple t-test, Bonferroni correction, 2 min: t=3.21, df=12, p=0.022, 4 min: t=2.37, df=12, p=0.035). d, Latency to make the first visit to the relieved demonstrator compared to the neutral (1.95±1.0 relief, 7.14±3.0, two-tailed paired t-test, t=1.37, df=6, p=0.13). e, Average number of visits to each zone did not differ (two-tailed multiple t-test, Bonferroni correction: t=0.63, df=12, p>0,999). f, When tested with cagemates, discrimination of relieved versus neutral demonstrators was longer as discrimination index was increased compared to mice tested with unfamiliar demonstrators (two-tailed multiple t-test, Bonferroni correction, 4 min: t=2.07, df=13, p=0.05). g-l, Data derived from n=7 mice. g, In the stress protocol using cage-mates, one demonstrator (“stress”, purple) was subjected to restraint stress test for 15 minutes culminating in the beginning of ADT. The other demonstrator (“neutral”, grey) waited undisturbed in his home-cage.. h, Increased sniffing to the stressed compared to neutral demonstrator (two-tailed multiple t-test, Bonferroni correction, 2 min: t=4.27, df=12, p=0.003; 6 min: t=5.16, df=12, p=0.0007). i, Increased time spent in the zone related to the stressed demonstrator compared to the neutral (two-tailed multiple t-test, Bonferroni correction, 6 min: t=6.13, df=12, p=0.0001). j, Shorter latency to make the first visit to the stressed demonstrator compared to the neutral (paired t-test, t=2.31, df=6, p=0.05). k, Average number of visits to each zone did not differ (two-tailed multiple t-test, Bonferroni correction: t=0.53, df=12, p>0,999). l, When tested with cage-mates, discrimination of the stressed versus the neutral demonstrators was longer as discrimination index was increased compared to mice tested with unfamiliar demonstrators (two-tailed multiple t-test, Bonferroni correction, 6 min: t=3.45, df=11, p=0.01). m, To rule out that social isolation 23 hours before testing (to allow water restriction of one cage-mate – “relief”) could have affected ADT with familiar mice, we tested singly-housed observers with unfamiliar demonstrators. Mice showed increased sniffing towards the relieved demonstrators (two-tailed multiple t-test, Bonferroni correction, 6 min: t=5.48, df=12, p=0.0004, n=7) and increased time spent in the related zone (two-tailed multiple t-test, Bonferroni correction, 6 min: t=2.86, df=12, p=0.041), only during the first 2 minutes of ADT, and not further, as showed in (b). Bar graphs show mean ± s.e.m. * p<0.05, ** p<0.005. *** p<0.0005.
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Enhanced neuronal activity during exploration of conspecifics in an altered, but not neutral, affective state Related to Fig. 2. a, Up left, mice implanted with chronic recording electrodes showed increased exploration of the relieved demonstrator compared to the neutral one, during the first 2 minutes of testing (two-tailed unpaired t-test: t=2.33, df=10, p=0.0418; n=6 mice). Up right, electrode placement in the mPFC (Cg, cingulate; PL, prelimbic area; IL, infralimbic area). Bottom, increased average population (N=57) activity during the epoch before the exploration and the epoch in which the observer explored the relieved demonstrator (yellow), compared to the pre social exploration epoch (min2: p<0.0001; min4: p<0.0001; min6: p=0.000696) and compared to exploration of the neutral (gray, min2: p=0.020031, min4: p=0.016927; min6: p=0.47572; 3x2 RM ANOVA, exploration epoch and affective state, min2: F(2,112)=52.75, p<0.0001; min4: F(2,112) =54.75, p<0.0001; min6: F(2,112)=24.79, p<0.0001). The black arrows indicate the time of onset (upward arrow) and end (downward arrow) of significant separation of the activity between the two compared conditions. Increased average population activity during the end social exploration epoch of the relieved demonstrator compared to that during the following epoch (post social exploration epoch, min2: p=0.045877; min4: p=0.000218; min6: p=0.049170) and compared to the neutral (min2: p=0.000275; min4: p=0.001698; min6: p=0.001408 2x2 RM ANOVA, exploration epoch and affective state, min2: F(1,56)=7.07, p=0.010161; min4: F(1,56)=7.17, p=0.009716; min6: F(1,56)=4.7, p= 0.034324). b, Hierarchical clustering method was used to separate recorded cells, during the ADT with one relieved and one neutral demonstrator, into the following populations: wide spiking (putative pyramidal cell, green, N=33) or narrow spiking (putative interneurons; orange, N=24). c, Frequency distribution of preference indexes (PIs) for the relief or neutral affective state in the NS (orange) and WS (green) neuronal population during the exploration of conspecifics during all the test. The size of each circle is proportional to the number of single neurons (from N=1 to N=8). Independent-samples t-tests, min2: t=3.39015, p<0.002095; min4: t = 2.1174, p=0.04478; min6: 2.2808, p=0.031349. d, Up, mice showed more exploration of the stressed demonstrator than of the neutral demonstrator during the first 2 minutes of testing (n=7 mice, two-tailed unpaired t-test: t=4.12, df=12, p=0.0014). Bottom, increased average population (n=83) activity during the start social exploration epoch and the social exploration epoch towards the stressed demonstrator (purple), compared to the pre social exploration epoch (min2: p<0.0001; min4: p=0.000003; min6: p<0.0001) and compared to exploration of the neutral (gray, min2: p=0.006666; min4: p=0.001223; min6: p=0.000027; 3x2 RM ANOVA, exploration epoch and affective state, min2: F(2,164)=45.13, p<0.0001; min4: F(2,164)=60.42, p<0.0001; min6: F(2,164)=74.44, p<0.0001). Increased average population activity during end social exploration epoch of the stressed demonstrator compared to the following epoch (post social exploration epoch, min2: p<0.0001; min4: p=0.000002; min6: p=0.000001) and to the exploration of the neutral demonstrator (min2: p<0.0001; min4: p<0.0001; min6: p<0.0001; 2x2 RM ANOVA, exploration epoch and affective state, min2: F(1,82)=116.08, p<0.0001; min4: F(1,82)=48.95, p<0.0001; min6: F(1,82)=21.86, p<0.0001). e, Classification of recorded cells, during the ADT with one stressed and one neutral demonstrator, in NS (N=52) and WS as described in b. f, Frequency distribution of preference indexes (PIs) for the stress or neutral affective state in the NS (orange) and WS (green) neuronal population during the exploration of conspecifics during all the test. The size of each circle is proportional to the number of single neurons (from N=1 to N=13). Independent-samples two-tailed t-tests, min2: t = 2.62995, p=0.011206; min4: t = 4.55371, p=0.000029; min6: t = 3.43784, p=0.001137. g, Mice have been implanted with recording electrodes in the mPFC and tested in the ADT with two naïve “neutral” demonstrators. Mice equally explored the two demonstrator and did not show observable discrimination. h, Classification of the recorded cells (N=82) in NS (N=55) and WS cells (N=27) as described in b during the ADT with two neutral demonstrators. i, Top, population responses calculated as an average of the activity of NS neurons (N=55) during “Habituation”, “Pre-exploration”, “Exploration onset”, “Exploration offset”, and “Post-exploration” periods towards neutral demonstrator 1 (pink) and neutral demonstrator 2 (green) (mean ± s.e.m.). *p<0.05 versus exploration of the neutral mouse. Bottom, normalized population activity of NS neurons (n=55) during exploration of both neutral demonstrators was stronger compared to the entire pre-exploration period (min2: p=0.0417281; min4: p=0.016125; min6: p=0.047255) without any difference between the two mice (min2: p=0.135825; min4: p=0.789647; min6: p=0.666470; 3x2 RM ANOVA, exploration epoch and affective state, min2: F(2,108)=0.61, p=0.55; min4: F(2,108)=0.67, p=0.51; min6: F(2,108)=2.06, p=0.07). Other legends as in (c). j, Same analyses as in (i) but for WS (N=27). Top, population responses calculated as an average of the activity of WS neurons during “Habituation”, “Pre-exploration”, “Exploration onset”, “Exploration offset”, and “Post-exploration periods” towards two neutral demonstrators (mean ± s.e.m.). *p<0.05 versus exploration of the neutral mouse. Bottom, Normalized population activity of WS neurons (n=27) during exploration of both neutral demonstrators was stronger compared to the pre-exploration period (min2: p=0.028877; min4: p=0.0499772; min6: p=0.00326), without any difference between the two mice (min2: p=0.356287; min4: p=0.598312; min6: p=0.583072; 3x2 RM ANOVA, exploration epoch and affective state, min2: F(2,52)=0.9, p=0.4; min4: F(2,52)=0.8, p=0.45; min6: F(2,52)=2.8, p=0.07).
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Photoinhibition of PV+ interneurons does not affect affective state discrimination Related to Fig. 3. a, Top, representative images of viral expression in the mPFC after injection with AAV-EF1a-DIO-eNpHR3.0-eYFP. Bottom, reconstruction of viral expression and location of optical fibers. Red areas represent the expression (higher expression = darker color) of AAV-EF1a-DIO-eNpHR3.0-eYFP in PV-cre mice. Findings were replicated in two independent experiments with similar results. Data derived from n=7 mice. b, PV-cre mice were tested in the ADT with one relieved and one neutral demonstrator. Photo-inhibition was performed for 2 minutes, from the beginning of the test, using continuous green light. c, No effect of PV+ photoinhibition on latency to made the first visit to the relieved demonstrator (two-way RM ANOVA, affective state (relief, neutral): F(1,12)=7.18, p=0.020). d, Optical inhibition of PV+ did not modify the number of visits to each demonstrator (two-way RM ANOVA, affective state (relief, neutral) x light (off,on): F(1,24)=0.38, p=0.541). e, PV-cre mice were tested in the ADT with one stressed and one neutral demonstrator. Photoinhibition was performed for 2 minutes, from the beginning of the test, using continuous green light. Data derived from n=7 mice. f, No effect of PV+ photoinhibition on latency to made the first visit to the stressed demonstrator (two-way RM ANOVA, affective state (stress, neutral): F(1,12)=12.75, p=0.003). g, Optical inhibition of PV+ did not modify the number of visits to each demonstrator (two-way RM ANOVA, affective state (stress, neutral) x light (off,on): F(1,24)=0.30, p=0.587). h and i, Optical inhibition of PV+ did not induce gross motor deficits during ADT in both relief (two-tailed multiple t-test, Bonferroni correction, distance travelled: t=0.35, df=12, p=0.730; average speed: t=1.10, df=12, p=0.290) and stress conditions (distance travelled: t=1.19, df=12, p=0.254; average speed: t=0.47, df=12, p=0.640). Bar and line graphs show mean ± s.e.m. * p<0.05.
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Photoinhibition of SOM+ interneurons abolishes affective state discrimination Related to Fig. 4. a, Top, representative images of viral expression in the mPFC (in rostro-caudal order) after injection with AAV-EF1a-DIO-eNpHR3.0-eYFP. Bottom, reconstruction of viral expression and location of optical fibers. Red areas represent the expression (higher expression = darker color) of AAV-EF1a-DIO-eNpHR3.0-eYFP in SOM-cre mice. Findings were replicated in four independent experiments with similar results. b, Increased exploration toward the odor of the relieved demonstrators compared to the neutral in light off and light on conditions (two-way RM ANOVA, affective state (relief, neutral): F(1,14)=12.65, p<0.005, n=8 mice), and no effects of SOM+ photo-inhibition (F(1,14)=0, p=0.99). c, Avoidance of the odor of the stressed demonstrators in in light off and light on conditions (two-way RM ANOVA, affective state (stress, neutral): F(1,10)=76.21, p<0.0001, n=6 mice), which SOM+ photo-inhibition did not change (F(1,10)=0.33, p=0.576). d and e, SOM+ photoinhibition with continuous green light for two minutes did not induce any gross motor change in both relief (two-tailed multiple t-test, Bonferroni correction, distance travelled: t=0.57, df=12, p=0.576; average speed: t=0.50, df=12, p=0.625) and stress conditions (distance travelled: t=0.69, df=12, p=0.498; average speed: t=0.45, df=12, p=0.658). Data derived from n=7 mice in each condition (relief, stress). f, Exploration of the relieved demonstrator was paired to SOM+ photo-inhibition throughout the test (n=8 mice). g, No preference to spend more time with the relieved demonstrator during photo-inhibition of SOM+, on the first two minutes of ADT (two-tailed multiple t-test, Bonferroni correction: t=0.47, df=14, p>0.999). h, No change of number of visits to each demonstrator during photoinhibition of SOM+ (two-tailed multiple t-test, Bonferroni correction: t=0.88, df=14, p>0.999). i, SOM+ photoinhibition paired to exploration of the relieved demonstrators did not induce any gross motor changes. j, Exploration of the relieved demonstrator was paired to SOM+ photo-inhibition throughout the test (n=9 mice). k, No difference in time spent with the two demonstrators during photoinhibition of SOM+ (two-tailed multiple t-test, Bonferroni correction: t=0.19, df=16, p>0.999). l, No difference of number of visits to stressed and neutral demonstrator during inhibition of SOM+ (two-tailed multiple t-test, Bonferroni correction: t=0.11, df=16, p>0.999). m, SOM+ photoinhibition paired to exploration of the stressed demonstrators did not induce any gross motor changes. n, Exploration of one naïve “neutral” demonstrator (“neutral 1”) was paired to SOM+ photoinhibition throughout the ADT (counterbalanced, left or right, across observers, continuous green light). Data derived from n=8 mice. SOM+ photoinhibition did not induce social discrimination or avoidance conditions (two-way RM ANOVA, time x light (on,off): F(359,2513)=0.21, p>0.999). No discrimination of the two neutral demonstrators without light stimulation (“No light”, two-way RM ANOVA, time x light (on,off): F(359,2513)=0.19, p>0.999). Bar and line graphs show mean ± s.e.m. * p<0.05.
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Articles
https://doi.org/10.1038/s41593-019-0551-8
1Genetics of Cognition laboratory, Neuroscience area, Istituto Italiano di Tecnologia, Genova, Italy. 2Central Nervous System Diseases Research, Boehringer
Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. 3Neuroscience Institute, Italian National Research Council (CNR), Padua, Italy. 4Department of
Biomedical Sciences, University of Padua, Padua, Italy. 5Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. 6These authors
contributed equally: Diego Scheggia, Francesca Managò. *e-mail: francesco.papaleo@iit.it
Understanding the emotions of others by perception of facial
and body expressions is an ability that crucially affects
everyday life1. Impairments in recognition of emotions are
common in many neurodegenerative, neuropsychiatric, and neuro-
developmental disorders2,3. For example, emotion recognition defi-
cits are core features of autism spectrum disorders (ASDs)4 and are
strongly evident in schizophrenia5. These social cognitive impair-
ments might have a more deleterious impact on daily functioning
than non-social cognitive deficits6. Moreover, the management of
these social cognitive deficits remains inadequate, highlighting the
need for a deeper understanding of the mechanisms underlying the
ability to recognize affective state in others.
The ‘social brain, identified by human neuroimaging studies,
refers to a network that controls social cognitive processes in which
limbic and frontal regions may play a key role7,8. In particular, the
top-down control of social cognitive functions may be orchestrated
by the prefrontal cortex (PFC) over the limbic system9,10. Indeed,
damage to the medial PFC (mPFC) is associated with impaired
recognition of emotions11,12. Thus, the PFC is an attractive brain
region for the study of neurobiological mechanisms underlying
such behavior12. However, our understanding of the PFC neural cir-
cuits underpinning the recognition of emotion remains incomplete,
mainly owing to the resolution level of manipulations allowed in
humans and the lack of translational models.
Accumulating evidence indicates that the balance of neu-
ronal excitation and inhibition governs cortical functions13,14.
Perturbations in this balance are commonly invoked as a possible
final shared pathway in the etiology of ASD and schizophrenia15.
For example, in humans, reduced density of interneurons16,17 and
altered GABAergic signaling18,19 are common findings in the brains
of patients with ASD. In line with these findings in humans, dis-
ruption of the excitatory and inhibitory balance in the mPFC of
mice led to social exploration deficits and sociability impairments20.
Moreover, other rodent studies implicated the PFC in different
social functions, such as social interaction20,21, vicarious freezing22,23,
social hierarchy24,25, and affiliative behavior26. However, the involve-
ment of PFC circuits and related excitatory and inhibitory balance
in the ability to detect and process the expression of affective state
in others remains uncertain.
Here, we proposed that inhibitory neuron subpopulations
within the mPFC could differentially contribute to the processing
of affective state discrimination. To explore mPFC circuits involved
in affective state discrimination in a cell type-specific manner, we
used a rodent task approximating features of the human ‘emotion
recognition task’4. In particular, the task is designed to study the
ability of mice to discriminate conspecifics based on their affective
state. Using invivo electrophysiology and microendoscope imag-
ing, we demonstrated that the mPFC differentially responds to
conspecifics in an altered affective state. By optogenetic perturba-
tion experiments and microendoscope imaging we then dissected
the involvement of different mPFC neuronal subpopulations in
affective state discrimination. Together, our data support a model
in which, in the mPFC, synchronized activation of somatostatin
(SOM+), but not of parvalbumin (PV+) interneurons or pyrami-
dal neurons, is a primary substrate for the expression of affective
state discrimination.
Results
Mice can discriminate conspecifics based on altered affective
states. In the affective state discrimination task (ADT), we tested
Somatostatin interneurons in the prefrontal cortex
control affective state discrimination in mice
Diego Scheggia 1,6, Francesca Managò 1,6, Federica Maltese1, Stefania Bruni1, Marco Nigro1,
Daniel Dautan1, Patrick Latuske1,2, Gabriella Contarini1, Marta Gomez-Gonzalo3,4, Linda Maria Requie3,4,
Valentina Ferretti1, Giulia Castellani1, Daniele Mauro1, Alessandra Bonavia1, Giorgio Carmignoto3,4,
Ofer Yizhar 5 and Francesco Papaleo 1*
The prefrontal cortex (PFC) is implicated in processing of the affective state of others through non-verbal communication.
This social cognitive function is thought to rely on an intact cortical neuronal excitatory and inhibitory balance. Here combin-
ing invivo electrophysiology with a behavioral task for affective state discrimination in mice, we show a differential activation
of medial PFC (mPFC) neurons during social exploration that depends on the affective state of the conspecific. Optogenetic
manipulations revealed a double dissociation between the role of interneurons in social cognition. Specifically, inhibition of
mPFC somatostatin (SOM+), but not of parvalbumin (PV+) interneurons, abolishes affective state discrimination. Accordingly,
synchronized activation of mPFC SOM+ interneurons selectively induces social discrimination. As visualized by invivo single-
cell microendoscopic Ca2+ imaging, an increased synchronous activity of mPFC SOM+ interneurons, guiding inhibition of pyra-
midal neurons, is associated with affective state discrimination. Our findings provide new insights into the neurobiological
mechanisms of affective state discrimination.
NATURE NEUROSCIENCE | VOL 23 | JANUARY 2020 | 47–60 | www.nature.com/natureneuroscience 47
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... Néanmoins, d'autres études s'avèrent nécesaires pour utiliser la température corporelle comme moyen de détecter ce que ressent l'animal. Les résultats montrent que la souris passe plus de temps dans le compartiment associé à l'état positif ou à l'état négatif que dans le compartiment émotionnellement neutre (Ferretti et al., 2019;Scheggia et al., 2020). Ces expériences ont montré que les souris sont capables de discriminer les états émotionnels de leurs congénères. ...
... Les auteurs ont également montré que les projections oxcytocinergiques du noyau paraventriculaire de l'hypothalamus vers le noyau central de l'amygdale (CeA) sont responsables de la discrimination des émotions (Ferretti et al., 2019). Une autre étude, réalisée par la même équipe, a montré que les interneurones exprimant la somatostatine (SOM) dans le cortex préfrontal (CPF) sont impliqués dans la discrimination des états affectifs (Scheggia et al., 2020). Ces deux études suggèrent donc un circuit préfrontoamygdalien serait impliqué dans la discrimination des états affectifs d'autrui. ...
... (Ferguson and Gao, 2018). Une étude (Scheggia et al., 2020) a montré que les interneurones PV dans le cortex préfrontal des souris sont impliqués dans l'investigation sociale et que les interneurones SOM sont impliqués dans la discrimination de l'état affectif. ...
Thesis
Dans le monde animal, les rongeurs, comme tous les autres mammifères, interagissent en permanence avec leurs congénères. Interagir socialement consiste à choisir entre plusieurs options d'actions qui tiennent compte de son état interne propre et de la prédiction quant à aux réactions possibles de son (ou ses) congénères. Les interactions sociales constituent donc un modèle de prise de décision. Le cortex préfrontal est une structure cérébrale clef des prises de décision, qu'elles soient sociales ou non. Des études précédentes au laboratoire ont établi, chez la souris, que la modulation par l'acétylcholine des récepteurs nicotiniques du cortex préfrontal sous-tend les processus de décision lors d'interactions sociales. Néanmoins, ces études ne permettent pas de connaître précisément le rôle de l'acétylcholine au sein du cortex préfrontal, car ils ont été obtenus chez des souris présentant également des altérations d'autres neurotransmetteurs. En outre, notre équipe comme d'autres, a montré que la communication vocale ultrasonore, régie par l'équilibre entre les systèmes cholinergique et dopaminergique, est un des éléments importants des interactions sociales chez la souris adulte, sans qu'on connaisse actuellement son rôle exact.Dans ce contexte, l'objectif de ma thèse est de comprendre l'effet de la modulation de la libération de l'acétylcholine dans le cortex préfrontal dans les comportements sociaux et d'investiguer quels paramètres de ces comportements sont plus particulièrement contrôlés par ce neurotransmetteur. Pour ce faire nous allons utiliser des souris ChAT-IRES-Cre exprimant la cre recombinase au sein des neurones cholinergiques, dont nous montrons ici qu'elles présentent un phénotype social et de communication vocale normal. Couplée à l'activation ou l'inhibition optogénétique de la libération d'acétylcholine spécifiquement dans les terminaisons préfrontales, l'utilisation de tests comportementaux variés a permis d'obtenir plusieurs résultats novateurs : 1) La modulation de l'innervation cholinergique préfrontale ne modifie pas la motivation à interagir avec un congénère. 2) La libération d'acétylcholine provoque une diminution la dominance et des approches sociales, ainsi qu'une augmentation de la fréquence des vocalisations ultrasonores alors que l'inhibition de la libération d'acétylcholine provoque une diminution de la dominance et une augmentation des approches sociales ainsi qu'une diminution de la fréquence des vocalisations ultrasonores. 3) La synchronisation des vocalisations ultrasonores avec les comportements sociaux ne permet pas d'associer leur émission à un comportement spécifique, renforçant l'idée que ces vocalisations transmettent une information générale relative à l'état émotionnel de l'animal émetteur. 4) La modulation cholinergique provoque également des interruptions plus fréquentes du contact social par le congénère non stimulé, laissant penser que ce dernier perçoit l'action et la vocalisation de son congénère comme inappropriée.Ces résultats, associés aux données de la littérature actuelle, permettent d'émettre l'hypothèse que la modulation cholinergique du cortex préfrontal est au cœur de l'intégration de plusieurs paramètres sociaux perçus chez les congénères, intégration qui aboutit à la construction de décisions sociales adaptées. L'acétylcholine préfrontale joue un rôle déterminant dans la libération locale d'autres neurotransmetteurs -dopamine, sérotonine, noradrénaline, GABA, glutamate…- par l'intermédiaire de récepteurs nicotiniques distribués sur tous les compartiments cellulaires, et permet le maintien de la balance excitation/inhibition du cortex préfrontal, ce qui a rendu son étude délicate jusqu'ici. Les résultats obtenus au cours de ma thèse montrent, pour la première fois, le rôle déterminant et spécifique de l'acétylcholine préfrontale, indépendamment des autres neurotransmetteurs, dans la cognition sociale, une fonction largement altérée dans les pathologies mentales.
... A key node in the cognitive social brain of rodents is the medial prefrontal cortex (mPFC) 6 . The mPFC controls social approach 7 , representations of social partners 8 , and empathic-like processes 9 . In nonsocial contexts, the prelimbic subregion (PL) of the mPFC is necessary for rodents to learn associations between actions and their likely outcomes 10 , which is necessary for behavioral flexibility 11 and inhibitory control 12 when reward likelihood or contingencies change. ...
... Our findings suggest that social experiences influence later choice, though they do not preclude the possibility that some sensory quality of the social experience, such as scent or warmth, accounts for SIFC. To test this possibility, we next trained mice to respond to food pellets, then paired one of the pellets with a cotton swab that had been rubbed on a novel, same-age, same-sex conspecific using a procedure that can cause avoidance or approach in other social conditioning tasks 9 . The other pellet was paired with a clean cotton swab (Fig. 4a). ...
... To test the ability of olfactory cues to drive SIFC, one of the pellets was paired with a cotton swab that had been swabbed all over the body, mouth, and anogenital region of a novel female conspecific to trigger affective state discrimination in mice 9 . The other pellet was paired with a clean cotton swab. ...
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Social experiences influence decision making, including decision making lacking explicit social content, yet mechanistic factors are unclear. We developed a new procedure, social incentivization of future choice (SIFC). Female mice are trained to nose poke for equally-preferred foods, then one food is paired with a novel conspecific, and the other with a novel object. Mice later respond more for the conspecific-associated food. Thus, prior social experience incentivizes later instrumental choice. SIFC is pervasive, occurring following multiple types of social experiences, and is not attributable to warmth or olfactory cues alone. SIFC requires the prelimbic prefrontal cortex (PL), but not the neighboring orbitofrontal cortex. Further, inputs from the basolateral amygdala to the PL and outputs to the nucleus accumbens are necessary for SIFC, but not memory for a conspecific. Basolateral amygdala→PL connections may signal the salience of social information, leading to the prioritization of coincident rewards via PL→nucleus accumbens outputs. Social experiences influence future decision making. The authors here establish a method for quantifying this phenomenon in mice and identify an amygdalo-frontal-striatal circuit controlling how social context shapes decisions.
... An essential component of emotional contagion is the ability to detect, recognize, and react to the emotional state or arousal of other conspecifics. To assess affective state discrimination ability in rodents, a behavioral paradigm was recently developed by Scheggia et al. [120], in which emotional state recognition (also termed 'affective state discrimination') was estimated by comparing the time an "observer" subject spent investigating a "demonstrator" in a neutral state versus one under an arousing affective state (positive or negative). C57BL/6J mice of both sexes preferred the emotionally aroused conspecific experiencing either a positive or a negative affective state over a neutral conspecific. ...
... C57BL/6J mice of both sexes preferred the emotionally aroused conspecific experiencing either a positive or a negative affective state over a neutral conspecific. This ability depends on oxytocin signaling in the paraventricular nucleus (PVN)-Central Amygdala (CeA) pathway, and on inhibition mediated by somatostatin-expressing (SOM) interneurons in the pre-frontal cortex (PFC) [20,120]. These behavioral observations imply that demonstrators transmit cues about their affective state, which are then detected by observers using different sensory modalities. ...
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Main In recent years, substantial advances in social neuroscience have been realized, including the generation of numerous rodent models of autism spectrum disorder. Still, it can be argued that those methods currently being used to analyze animal social behavior create a bottleneck that significantly slows down progress in this field. Indeed, the bulk of research still relies on a small number of simple behavioral paradigms, the results of which are assessed without considering behavioral dynamics. Moreover, only few variables are examined in each paradigm, thus overlooking a significant portion of the complexity that characterizes social interaction between two conspecifics, subsequently hindering our understanding of the neural mechanisms governing different aspects of social behavior. We further demonstrate these constraints by discussing the most commonly used paradigm for assessing rodent social behavior, the three-chamber test. We also point to the fact that although emotions greatly influence human social behavior, we lack reliable means for assessing the emotional state of animals during social tasks. As such, we also discuss current evidence supporting the existence of pro-social emotions and emotional cognition in animal models. We further suggest that adequate social behavior analysis requires a novel multimodal approach that employs automated and simultaneous measurements of multiple behavioral and physiological variables at high temporal resolution in socially interacting animals. We accordingly describe several computerized systems and computational tools for acquiring and analyzing such measurements. Finally, we address several behavioral and physiological variables that can be used to assess socio-emotional states in animal models and thus elucidate intricacies of social behavior so as to attain deeper insight into the brain mechanisms that mediate such behaviors. Conclusions In summary, we suggest that combining automated multimodal measurements with machine-learning algorithms will help define socio-emotional states and determine their dynamics during various types of social tasks, thus enabling a more thorough understanding of the complexity of social behavior.
... Mammals live in social groups with dominant and subordinate members, which determine a hierarchy that can affect multiple behaviors 23 and represent an important variable in social relationships and prosocial behaviors 24 . Moreover, socially close individuals share more easily subjective affective states of another trough emotional contagion 24,25 . All forms of empathy, including emotional contagion, are fundamental to adjusting one's own behavior with pro-social intention in group living animals 26 . ...
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Decisions in social contexts might lead to choices favoring self- or others-interest, depending on the relationships between individuals. Prosocial and helping behaviors are evolutionary conserved across mammals. However, the neurobiological bases of choices that benefit others at a personal cost are not understood. Here, we revealed the role of the basolateral amygdala (BLA) in altruistic and selfish choices. We developed a two-choice social decision-making task in which mice could decide to share or not a positive reinforcement with their conspecifics. Preference for altruistic choices was more evident in males and if the conspecific was familiar. In particular, altruistic choices were associated with social dominance and affective state matching between individuals. Chemogenetic BLA neuronal silencing induced lower ranking hierarchy and less preference for altruistic choices. This provides a neurobiological comparative model of altruistic and selfish choices versus dominance hierarchy and emotional contagion, with relevance to pathologies associated with dysfunctions in social decision-making.
... Therefore, other explanations should be considered, such as the emotional engagement between the actor and recipient. Mice can discriminate 40 and share 41 the affective state of their conspecifics. Indeed, mice that expressed a preference for altruistic choices displayed more empathy-like behaviors. ...
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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. Scheggia and colleagues present a social decision-making assay in which mice display altruistic or selfish choices. The authors show that projections between the prefrontal cortex and the basolateral amygdala are involved in the control of the two different choices.
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Introduction: Altered signaling or function of acetylcholine (ACh) has been reported in various neurological diseases, including Alzheimer’s disease, Tourette syndrome, epilepsy among others. Many neurons that release ACh also co-transmit the neurotransmitter gamma-aminobutyrate (GABA) at synapses in the hippocampus, striatum, substantia nigra, and medial prefrontal cortex (mPFC). Although ACh transmission is crucial for higher brain functions such as learning and memory, the role of co-transmitted GABA from ACh neurons in brain function remains unknown. Thus, the overarching goal of this study was to investigate how a systemic loss of GABA co-transmission from ACh neurons affected the behavioral performance of mice. Methods: To do this, we used a conditional knock-out mouse of the vesicular GABA transporter (vGAT) crossed with the ChAT-Cre driver line to selectively ablate GABA co-transmission at ACh synapses. In a comprehensive series of standardized behavioral assays, we compared Cre-negative control mice with Cre-positive vGAT knock-out mice of both sexes. Results: Loss of GABA co-transmission from ACh neurons did not disrupt the animal’s sociability, motor skills or sensation. However, in the absence of GABA co-transmission, we found significant alterations in social, spatial and fear memory as well as a reduced reliance on striatum-dependent response strategies in a T-maze. In addition, male conditional knockout (CKO) mice showed increased locomotion. Discussion: Taken together, the loss of GABA co-transmission leads to deficits in higher brain functions and behaviors. Therefore, we propose that ACh/GABA co-transmission modulates neural circuitry involved in the affected behaviors.
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Neuropeptides can exert volume modulation in neuronal networks, which account for a well-calibrated and fine-tuned regulation that depends on the sensory and behavioral contexts. For example, oxytocin (OT) and oxytocin receptor (OTR) trigger a signaling pattern encompassing intracellular cascades, synaptic plasticity, gene expression, and network regulation, that together function to increase the signal-to-noise ratio for sensory-dependent stress/threat and social responses. Activation of OTRs in emotional circuits within the limbic forebrain is necessary to acquire stress/threat responses. When emotional memories are retrieved, OTR-expressing cells act as gatekeepers of the threat response choice/discrimination. OT signaling has also been implicated in modulating social-exposure elicited responses in the neural circuits within the limbic forebrain. In this review, we describe the cellular and molecular mechanisms that underlie the neuromodulation by OT, and how OT signaling in specific neural circuits and cell populations mediate stress/threat and social behaviors. OT and downstream signaling cascades are heavily implicated in neuropsychiatric disorders characterized by emotional and social dysregulation. Thus, a mechanistic understanding of downstream cellular effects of OT in relevant cell types and neural circuits can help design effective intervention techniques for a variety of neuropsychiatric disorders.
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