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Dynamics of social representation in the mouse prefrontal cortex

Nature Neuroscience volume 22, pages 2013–2022 (2019)Cite this article

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An Author Correction to this article was published on 03 March 2020

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Abstract

The prefrontal cortex (PFC) plays an important role in regulating social functions in mammals, and its dysfunction has been linked to social deficits in neurodevelopmental disorders. Yet little is known of how the PFC encodes social information and how social representations may be altered in such disorders. Here, we show that neurons in the medial PFC of freely behaving male mice preferentially respond to socially relevant olfactory cues. Population activity patterns in this region differed between social and nonsocial stimuli and underwent experience-dependent refinement. In mice lacking the autism-associated gene Cntnap2, both the categorization of sensory stimuli and the refinement of social representations were impaired. Noise levels in spontaneous population activity were higher in Cntnap2 knockouts and correlated with the degree to which social representations were disrupted. Our findings elucidate the encoding of social sensory cues in the medial PFC and provide a link between altered prefrontal dynamics and autism-associated social dysfunction.

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Fig. 1: Experimental setup for presentation of social and nonsocial olfactory cues to freely behaving mice.
Fig. 2: Social tuning in mPFC unit response.
Fig. 3: Distinct representation of social cues in the mPFC neuronal population code.
Fig. 4: Cntnap2–/– mice display impaired social behavior, but intact olfaction.
Fig. 5: Altered dynamics of social representation in the Cntnap2–/– mouse model of autism.
Fig. 6: Decoding of stimulus identity and social category from mPFC population code.
Fig. 7: Elevated neural noise correlates with deficits in social processing in Cntnap2–/– mice.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

The custom written analysis codes are available from the corresponding author upon reasonable request.

Change history

  • 03 March 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

This work was supported by grants from the Simons Foundation, the European Research Council (ERC 819496 PrefrontalMap and ERC 311238 NEURO-POPCODE), the Israel Science Foundation, the Israel–US Binational Science Foundation, the Adelis Foundation, the Lord Sieff of Brimpton Memorial Fund, and the Candice Appleton Family Trust. O.Y. is supported by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation and by the Gertrude and Philip Nollman Career Development Chair. E.S. receives support as the Joseph and Bessie Feinberg Professorial Chair.

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  1. These authors contributed equally: Dana Rubi Levy, Tal Tamir.

Authors and Affiliations

  1. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

    Dana Rubi Levy, Tal Tamir, Maya Kaufman, Ana Parabucki, Aharon Weissbrod, Elad Schneidman & Ofer Yizhar

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Contributions

D.R.L. and O.Y. designed the study, and D.R.L. and A.W. built the experimental setup. D.R.L. performed all experiments and analyzed the unit activity and behavioral data. A.P. and D.R.L. performed the sniffing experiments and analyses. D.R.L., T.T., O.Y. and E.S. performed the population coding analyses. M.K. contributed to the behavioral data analyses. D.R.L., O.Y., T.T. and E.S. wrote the manuscript.

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Correspondence to Ofer Yizhar.

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Extended data

Extended Data Fig. 1 Olfactometer calibrations and microarray electrode location.

(a) Latency to odor infusion from each of seven available odor ports. A pressure sensor was used to determine initiation of airflow into the chamber following TTL input indicating the opening of the appropriate solenoid. Each solenoid was tested 5 consecutive times (represented by individual circles). Mean ± s.e.m is presented. (b) Change in odor concentration at the center of the chamber. Measurements were taken using a volatile organic compound (VOC) meter following 5 s infusion of vapor from a 70% ethanol solution followed by infusion of clean air (5 repetitions). Shaded area marks stimulus presentation times. Mean ± s.e.m is presented. (c) Representative image depicting the location of an electrolytic lesion used to verify electrode position in the mPFC. Arrow indicates lesion location in the infralimbic cortex. (d) Schematic representation of electrode placement in recorded mice from all experimental groups. Location was determined using the most ventral end of localization lesion or electrode track. Average AP coordinates are marked.

Extended Data Fig. 2 Social tuning in the mPFC unit responses.

(a) Stimulus-evoked response across all recorded units per stimulus, sorted by response magnitude as calculated by the absolute change in firing rate from baseline. Color gradient represents the normalized change in firing rate calculated over 250 ms bins. Arrowheads mark the time of stimulus onset and offset. (b) Response Z-score distribution calculated for all recorded units in response to social (M/F) and nonsocial (B/P/H) cues. Circles represent maximum response of individual units to each stimulus category. Color code represents response specificity. Z score threshold (|Z| > 2) is represented by a dashed line. Units with Z > 15 were assigned with Z = 15 for presentation purposes. (c) Number of units significantly increasing (dark) and decreasing (bright) their firing rates in response to each presented stimulus. Color represents stimulus identity. (d) Stimulus specificity overlap within social (top) and nonsocial (bottom) units. Number of units in each category is indicated on the figure. Circle sizes are scaled to the relative number of units responding to each stimulus. (e) Relative ratio between social and nonsocial units, calculated using a continuous range of Z score thresholds. Arrow represents Z = 2. Note that the number of social units consistently exceeds that of nonsocial units starting at Z > 0.6 (f) Response magnitude for all presented stimuli for units significantly increasing their firing rate in response to stimulus presentations. Box plot depicts the interquartile range (IQR) and median, whiskers mark ± 1.5*IQR. One-way ANOVA, Fstimulus(4,131) = 1.603, P = 0.177. (nM = 45 units, nF = 46 units, nB = 9 units, nP = 12 units, nH = 24 units). For all panels: M, male; F, female; B, banana; P, peanut butter; H, hexanal; CA, clean air.

Extended Data Fig. 3 Social categorization generalizes over a range of stimulus concentrations.

Overall unit tuning, presented as normalized firing rate in response to male cues at three different concentrations (ML, MM, MH), female (F) banana (B) and peanut butter (P) stimuli. RM ANOVA with Bonferroni corrected post hoc comparisons. Fstimulus(5,440) = 7.458, P = 9.8 × 10−7 (n = 89 responsive units). Superscripts mark significant post hoc comparisons. Mean ± s.e.m (shaded area) is presented. (b) Overall unit tuning, presented as normalized firing rate in response to male (M) and female (F) stimuli, banana oil at three different concentrations (BL, BM, BH) and peanut butter oil (P). RM ANOVA with Bonferroni corrected post hoc comparisons. Fstimulus(5,285) = 9.856, P = 1.1 × 10−8 (n = 58 responsive units). Superscripts mark significant post hoc comparisons. Mean ± s.e.m (shaded area) is presented. For detailed statistics information see Supplementary Table 2. (c) Similarity matrices depicting the distance between population responses to the stimulus panel used in a (n = 4 C57BL/6 J mice). (d) Same as c but for the stimulus panel used in b (n = 3 C57BL/6 J mice). Norm. res.- normalized response.

Extended Data Fig. 4 Maximum entropy models accurately describe the encoding distributions of the stimuli.

(a) Normalized difference between the log-likelihood values of the pairwise maximum entropy model (ME2) and conditionally independent model, for each mouse. Models were trained over seven trials of a specific stimulus and tested on one held-out trial per stimulus. Each dot corresponds to one held-out trial for one specific stimulus (6 stimuli × 8 trials = 48 dots per mouse). Positive values indicate larger likelihood for the independent model over the ME2; the most likely model for each trial was then used for decoding analysis (see Fig. 6). (b) The empirical probabilities of population activity patterns of cells recorded in one mouse in response to one odor are plotted against the probabilities predicted by different models (gray dots, independent model; orange dots, ME2 model). Each dot corresponds to a single activity pattern observed during the experiment. The funnel marked by the dashed \ gray line indicates 99% confidence interval of the empirical measurement. Black dashed line shows equality. (c) The Jensen–Shannon divergences between the empirical joint probability distribution of activity patterns and the different models – ME2 (orange) and conditionally independent (gray). Black line indicates equality of the distance of the models from the test data, and the distance between the training and test data. Models were trained using randomly chosen 1750 samples, similar to the number of training data samples used for the decoding analysis (7 trials of 5 s each). Analysis was done using all recorded units from each mouse (up to 20 units) and the mean over ten randomly chosen training sets is plotted. While no model is consistently better than the other in capturing the distribution across all mice, both models clearly outperform the empirical model. Arrow indicates the example mouse shown in panel b.

Extended Data Fig. 5 Behavioral analysis of Cntnap2-/- mice.

(a) Open field test. Left: Mean distance travelled during test for WT (black, n = 8) and Cntnap2-/- mice (teal, n = 8). Two-sided Mann-Whitney U test, U = 28, P = 0.721. Right: Mean duration in center of arena. Two-sided Mann-Whitney U test, U = 28, P = 0.721. (b) Baseline sniffing quantifications for WT (black, n = 7 recording sessions) and Cntnap2-/- mice (teal, n = 6 sessions). Left: baseline sniffing frequency. Mann-Whitney U test, U = 26, P = 0.52. Right: baseline sniff amplitude. Mann-Whitney U test, U = 4, P = 0.014. Circles represents individual recording sessions. (c) Mean duration to find a buried food pellet for WT (black, n = 8) and Cntnap2-/- mice (teal, n = 8). Two-sided Mann-Whitney U test, U = 20, P = 0.234. (d) Mean duration of odor exploration, calculated as time sniffing odor port for WT (left, n = 7) and Cntnap2-/- mice (right, n = 7 mice). Duration is presented for first and second day of experiment (left to right) for each odor and each mouse. Two-way RM ANOVA with Bonferroni corrections. For WT: Fstimulus(5,30) = 15.444, P = 1.6 × 10−7; Fday(1,6) = 2.756, P = 0.148; Fstimulus*day(5,30) = 1.777, P = 0.148; for Cntnap2-/-: Fstimulus(5,30) = 11.862, P = 2.2 × 10−8; Fday(1,6) = 0.593, P = 0.470; Fstimulus*day(5,30) = 1.777, P = 0.203; (e) Left: Average latency to odor-evoked orientation responses for WT (black, n = 5) and Cntnap2-/- (teal, n = 6) mice in odor infusion chamber. Circles represent individual mice. Mixed-design RM ANOVA. Fgenotype(1,9) = 0.959, P = 0.352; Fstimulus(5,45) = 2.449, P = 0.048 with Dunnett’s test against clean air; Fgenotype*stimulus(5,45) = 0.163, P = 0.974. Right: mean probability of odor-evoked orientation responses. Mixed-design RM ANOVA. Fgenotype(1,9) = 0.040, P = 0.844; Fstimulus(5,45) = 3.304, P = 0.013 with Dunnett’s test against clean air; Fgenotype*stimulus(5,45) = 0.115, P = 0.988 (f) Locomotion levels of WT (black, n = 5) and Cntnap2-/- mice (teal, n = 6) in the odor infusion chamber during baseline and stimulus presentation (averaged across all presented odors). Two-sided Mann-Whitney U Test, For baseline: U = 7, P = 0.171; For stimulus: U = 10, P = 0.411. Circles represent individual mice unless otherwise indicated. For all panels: Mean ± s.e.m is presented. Note that some individual data points and error bars are covered by the mark of the mean. *P < 0.05. For detailed statistics information see Supplementary Table 2. M, male; F, female; B, banana; P, peanut butter; H, hexanal; CA, clean air. Base., baseline; Stim., Stimulus.

Extended Data Fig. 6 Altered response patterns to social and nonsocial stimuli in the mPFC of Cntnap2-/- mice.

(a) Stimulus-evoked responses across all recorded units per stimulus, sorted by response magnitude as calculated by the change in firing rate from baseline for WT (top) and Cntnap2-/- (bottom) mice. Color gradient represents the change in firing rate from baseline, calculated over 250 ms bins. Arrows mark the time of stimulus onset and offset. (b) Response Z-score distribution calculated for all recorded units in WT (left) and Cntnap2-/- mice (right) in response to social (M/F) and nonsocial (B/P/H) cues. Circles represent maximum response of individual units to each stimulus category. Color code represents response specificity. Z score threshold (|Z|  > 2) is represented by a dashed line. Units with Z > 15 were assigned with Z = 15 for presentation purposes. (c) Number of units significantly increasing (dark) and decreasing (bright) their firing rates in response to each presented stimulus in wt (black) and Cntnap2-/- (teal) mice. (d) Relative ratio between social and nonsocial units, calculated using a continuous range of Z score thresholds for wt (black) and Cntnap2-/- (teal) mice. Arrows represent Z = 2. Linear regression analysis (0 ≤ Z ≤ 3, n = 32 measurements for each genotype), FWT(1,30) = 1088.42, P = 3.9 × 10−25, R2WT = 0.973. FCntnap2-/-(1,30) = 652.294, P = 6.5 × 10−22, R2Cntnap2-/- = 0.956; BWT = 1.106, BCntnap2-/- = 0.425, with non-overlapping 95% confidence intervals as a measure of statistical significant difference between regression lines. For all panels: *P < 0.05, M, male; F, female; B, banana; P, peanut butter; H, hexanal; CA, clean air.

Extended Data Fig. 7 Experience-dependent changes in stimulus-evoked unit responses.

(a) Stimulus-evoked PSTHs portraying mean response Z-score of cue-responsive units in the first (left) and second (right) recording sessions, for wt (top) and Cntnap2-/- (bottom) mice. Color code represents stimulus identity. Shaded areas mark stimulus presentation time. Mean ± s.e.m is presented. (b) Stimulus specificity among cue responsive units in the first (left) and second (right) recording sessions, in WT (top) and Cntnap2-/- (bottom) mice. Colors represent stimulus identity. For WT, nday1 = 82 units, nday2 = 77 units; for Cntnap2-/- mice, nday1 = 74 units, nday2 = 57 units. For all panels: M, male; F, female; B, banana; P, peanut butter; H, hexanal; CA, clean air.

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2.

Reporting Summary

Supplementary Video 1

Time-resolved trajectory of odor-evoked population activity in the mPFC of a wild-type C57BL/6J mouse. Representative 2D projections of the neuronal population trajectories before, during and after stimulus presentation (15 s time-window, 5 s for each phase, where each point was estimated in 150-ms bins, n = 15 units). Colors represent odor identity. Here, the first two principal components accounted for 75% of the variance. Time indication is relative to stimulus onset.

Supplementary Video 2

Time-resolved trajectory of odor-evoked population activity in the mPFC of a Cntnap2+/+ mouse. Representative 2D projections of the neuronal population trajectories before, during and after stimulus presentation (15 s time-window, 5 s for each phase, where each point was estimated in 150-ms bins, n = 22 unis). Colors represent odor identity. Here, the first two principal components accounted for 78% of the variance. Time indication is relative to stimulus onset.

Supplementary Video 3

Time-resolved trajectory of odor-evoked population activity in the mPFC of a Cntnap2–/– mouse. Representative 2D projections of the neuronal population trajectories before, during and after stimulus presentation (15 s time-window, 5 s for each phase, where each point was estimated in 150-ms bins, n = 17 unis). Colors represent odor identity. Here, the first two principal components accounted for 82% of the variance. Time indication is relative to stimulus onset.

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Levy, D.R., Tamir, T., Kaufman, M. et al. Dynamics of social representation in the mouse prefrontal cortex. Nat Neurosci 22, 2013–2022 (2019). https://doi.org/10.1038/s41593-019-0531-z

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