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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.
... Recent studies indicate that these major inhibitory neuron subtypes play very distinct roles in neural circuits and perform different functions in behaving animals. For example, in medial prefrontal cortex (mPFC), SOM, but not PV, neuron activity is critical for discrimination of affective states during social interaction, whereas PV neuron activity is necessary for social investigation behavior [22]. In the amygdala, during threat conditioning, PV and SOM neurons are activated during distinct behavioral phases to exert bidirectional control on acquisition of fear [23]. ...
... In addition, we found impaired social novelty behavior in Fmr1 −/y -PV mice. PV neuron activity in mPFC has been implicated in mediating social behavior in mice [22,45,46]; therefore, it is not surprising that exaggerated protein synthesis in these cells may be associated with deficits in social behavior, as in our studies. On the other hand, de novo protein synthesis in hippocampal PV neurons was decreased rather than elevated upon cell type-specific deletion of Fmr1, which is inconsistent with the cellular function of FMRP as a translational repressor. ...
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Background Fragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice. Methods We used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons. Results De novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities. Limitations The mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors. Conclusions Our findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS.
... For animal experiments, no statistical methods were used to predetermine sample sizes, although sample sizes were consistent with those from previous studies [1,3,36,43]. No explicit randomization method was used to allocate animals to experimental groups and mice were tested and data processed by investigators blind to animal identity. ...
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The mechanisms underlying the dichotomic cortical/basal ganglia dopaminergic abnormalities in schizophrenia are unclear. Astrocytes are important non-neuronal modulators of brain circuits, but their role in dopaminergic system remains poorly explored. Microarray analyses, immunohistochemistry, and two-photon laser scanning microscopy revealed that Dys1 hypofunction increases the reactivity of astrocytes, which express only the Dys1A isoform. Notably, behavioral and electrochemical assessments in mice selectively lacking the Dys1A isoform unraveled a more prominent impact of Dys1A in behavioral and dopaminergic/D2 alterations related to basal ganglia, but not cortical functioning. Ex vivo electron microscopy and protein expression analyses indicated that selective Dys1A disruption might alter intracellular trafficking in astrocytes, but not in neurons. In agreement, Dys1A disruption only in astrocytes resulted in decreased motivation and sensorimotor gating deficits, increased astrocytic dopamine D2 receptors and decreased dopaminergic tone within basal ganglia. These processes might have clinical relevance because the caudate, but not the cortex, of patients with schizophrenia shows a reduction of the Dys1A isoform. Therefore, we started to show a hitherto unknown role for the Dys1A isoform in astrocytic-related modulation of basal ganglia behavioral and dopaminergic phenotypes, with relevance to schizophrenia.
... Normal mPFC activity is crucial for the expression of sociability, and others have reported social behavior impaired by dysfunction of the mPFC circuit or its afferent and efferent signaling 23,[43][44][45] . Disruptions in mPFC E/I balance in either direction (E > I or E < I) have been linked to multiple abnormal social behaviors [22][23][24]46 . ...
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Sociability is crucial for survival, whereas social avoidance is a feature of disorders such as Rett syndrome, which is caused by loss-of-function mutations in MECP2. To understand how a preference for social interactions is encoded, we used in vivo calcium imaging to compare medial prefrontal cortex (mPFC) activity in female wild-type and Mecp2-heterozygous mice during three-chamber tests. We found that mPFC pyramidal neurons in Mecp2-deficient mice are hypo-responsive to both social and nonsocial stimuli. Hypothesizing that this limited dynamic range restricts the circuit’s ability to disambiguate coactivity patterns for different stimuli, we suppressed the mPFC in wild-type mice and found that this eliminated both pattern decorrelation and social preference. Conversely, stimulating the mPFC in MeCP2-deficient mice restored social preference, but only if it was sufficient to restore pattern decorrelation. A loss of social preference could thus indicate impaired pattern decorrelation rather than true social avoidance.
... Prior reports indicated that numerous interneuronal subtypes exhibit high baseline firing rates [21][22][23][24]43 . Though calcium imaging has been extensively used to analyze interneuronal activity, both within the hippocampus 25,35-41 and cortex [53][54][55][56][57][58][59][60][61][62] , it is important to consider that this method may not fully capture the temporal dynamics of VGAT interneurons with high firing rates. Nevertheless, calcium imaging has been successfully used to target a wide variety of interneuron groups in the hippocampus including bistratified cells 25 , vasoactive intestinal peptide-expressing interneurons 36,37,39,41 , cck-expressing interneurons 40 and fast-spiking parvalbumin-expressing interneurons 25,38,40 ; these data have been used in analyses that required a high degree of temporal precision, such as the estimation of spike timing in relation to theta rhythm 35 , as well as analyses which, similar to the present study, necessitated the comparison of cell types with differing baseline firing rates 38 . ...
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The CA1 region of the hippocampus contains both glutamatergic pyramidal cells and GABAergic interneurons. Numerous reports have characterized glutamatergic CAMK2A cell activity, showing how these cells respond to environmental changes such as local cue rotation and context re-sizing. Additionally, the long-term stability of spatial encoding and turnover of these cells across days is also well-characterized. In contrast, these classic hippocampal experiments have never been conducted with CA1 GABAergic cells. Here, we use chronic calcium imaging of male and female mice to compare the neural activity of VGAT and CAMK2A cells during exploration of unaltered environments and also during exposure to contexts before and after rotating and changing the length of the context across multiple recording days. Intriguingly, compared to CAMK2A cells, VGAT cells showed decreased remapping induced by environmental changes, such as context rotations and contextual length resizing. However, GABAergic neurons were also less likely than glutamatergic neurons to remain active and exhibit consistent place coding across recording days. Interestingly, despite showing significant spatial remapping across days, GABAergic cells had stable speed encoding between days. Thus, compared to glutamatergic cells, spatial encoding of GABAergic cells is more stable during within-session environmental perturbations, but is less stable across days. These insights may be crucial in accurately modeling the features and constraints of hippocampal dynamics in spatial coding.
Article
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The endocannabinoid system has been implicated in both social and cognitive processing. The endocannabinoid metabolism inhibitor, URB597, dose-dependently improves non-social memory in adult Wistar and Sprague Dawley rats, whereas its effect on social interaction (SI) is affected by both rat strain and drug dose. Lister Hooded rats consistently respond differently to drug treatment in general compared with albino strains. This study sought to investigate the effects of different doses of URB597 on social and non-social memory in Lister Hooded rats, as well as analyzing the behavioral composition of the SI. Males were tested for novel object recognition (NOR), social preference (between an object and an unfamiliar rat), social novelty recognition (for a familiar vs. unfamiliar rat) and SI with an unfamiliar rat. URB597 (0.1 or 0.3 mg/kg) or vehicle was given 30 min before testing. During SI testing, total interaction time was assessed along with time spent on aggressive and explorative behaviors. Lister Hooded rats displayed expected non-social and social memory and social preference, which was not affected by URB597. During SI, URB597 did not affect total interaction time. However, the high dose increased aggression, compared to vehicle, and decreased anogenital sniffing, compared to the low dose of URB597. In summary, URB597 did not affect NOR, social preference or social recognition memory but did have subtle behavioral effects during SI in Lister hooded rats. Based on our findings we argue for the importance of considering strain as well as the detailed composition of behavior when investigating drug effects on social behavior.
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Humans show distinct social behaviours when we evaluate an individual as being a member of the same group and recognize social similarity to the individual. One example is more accurate identification of emotion in that individual. Our previous studies proposed that rats recognize social similarity to certain strains of unfamiliar rats. It is therefore possible that the strain of unfamiliar conspecifics affects stress identification in rats. Wistar subject rats were allowed to explore a pair of unfamiliar Wistar, Sprague-Dawley (SD), Long-Evans (LE), or Fischer344 (F344) stimulus rats. To induce differences in stress, one of the stimulus rats had received foot shocks immediately before the test. It was found that the subjects showed biased interaction towards the shocked Wistar and SD stimulus rats, but not toward the shocked LE or F344 stimulus rats. Subsequent experiments confirmed that the biased interaction towards the shocked Wistar and SD stimulus rats was driven by stress in these stimulus rats. In addition, the lack of biased interaction towards the shocked LE and F344 stimulus rats did not appear to be due to procedural reasons. The experiment using LE subject rats further confirmed that the shocked LE stimulus rats emitted distress signals. These results suggested that Wistar rats could identify stress in unfamiliar Wistar and SD rats, but not in unfamiliar LE or F344 rats. Therefore, rats appear to recognize social similarity to certain unfamiliar strains of rats.
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Stress can trigger enduring changes in neural circuits and synapses. The behavioral and hormonal consequences of stress can also be transmitted to others, but whether this transmitted stress has similar effects on synapses is not known. We found that authentic stress and transmitted stress in mice primed paraventricular nucleus of the hypothalamus (PVN) corticotropin-releasing hormone (CRH) neurons, enabling the induction of metaplasticity at glutamate synapses. In female mice that were subjected to authentic stress, this metaplasticity was diminished following interactions with a naive partner. Transmission from the stressed subject to the naive partner required the activation of PVN CRH neurons in both subject and partner to drive and detect the release of a putative alarm pheromone from the stressed mouse. Finally, metaplasticity could be transmitted sequentially from the stressed subject to multiple partners. Our findings demonstrate that transmitted stress has the same lasting effects on glutamate synapses as authentic stress and reveal an unexpected role for PVN CRH neurons in transmitting distress signals among individuals.
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Oxytocin receptor (Oxtr) signaling in neural circuits mediating discrimination of social stimuli and affiliation or avoidance behavior is thought to guide social recognition. Remarkably, the physiological functions of Oxtrs in the hippocampus are not known. Here we demonstrate using genetic and pharmacological approaches that Oxtrs in the anterior dentate gyrus (aDG) and anterior CA2/CA3 (aCA2/CA3) of mice are necessary for discrimination of social, but not non-social, stimuli. Further, Oxtrs in aCA2/CA3 neurons recruit a population-based coding mechanism to mediate social stimuli discrimination. Optogenetic terminal-specific attenuation revealed a critical role for aCA2/CA3 outputs to posterior CA1 for discrimination of social stimuli. In contrast, aCA2/CA3 projections to aCA1 mediate discrimination of non-social stimuli. These studies identify a role for an aDG-CA2/CA3 axis of Oxtr expressing cells in discrimination of social stimuli and delineate a pathway relaying social memory computations in the anterior hippocampus to the posterior hippocampus to guide social recognition.
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