Brain-wide electrical dynamics encode individual appetitive social behavior

Abstract

The architecture whereby activity across many brain regions integrates to encode individual appetitive social behavior remains unknown. Here we measure electrical activity from eight brain regions as mice engage in a social preference assay. We then use machine learning to discover a network that encodes the extent to which individual mice engage another mouse. This network is organized by theta oscillations leading from prelimbic cortex and amygdala that converge on the ventral tegmental area. Network activity is synchronized with cellular firing, and frequency-specific activation of a circuit within this network increases social behavior. Finally, the network generalizes, on a mouse-by-mouse basis, to encode individual differences in social behavior in healthy animals but fails to encode individual behavior in a 'high confidence' genetic model of autism. Thus, our findings reveal the architecture whereby the brain integrates distributed activity across timescales to encode an appetitive brain state underlying individual differences in social behavior.

Keywords: autism spectrum disorder; brain networks; electome; machine learning; social behavior.

Figure 1:. Approach to decode social appetitive behavior.

A) Schematic of the two-chamber social assay and B) automated scoring approach used to quantify social and object interaction. C) Mice exhibit stable interaction times across repeated sessions at the population level (n=36 mice). D) Schematic of machine learning model used to discover social-emotional brain state. E) Coding features that conceptually underlie a social-emotional brain state.

Figure 2:. An electome network encodes a social-appetitive brain state.

A) Machine learning was used to discover six networks composed of multi-regional LFP activity (n=28 mice; AMY, Cg, IL, PrL, NAc, Hip, MD, and VTA). The supervised electome network (blue; EN-Social) showed the strongest classification of social vs. object interactions. B) EN-Social event-related activity. Blue highlights identify time windows subjected to supervision by class (social vs. object). Data shown as mean±95% C.I. C) Decoding accuracy of EN-Social activity within animal vs. social preference (P=0.002 using spearman correlation).

Figure 3:. Social-appetitive electome network maps to cellular activity.

A) Cellular firing preference for object vs. social interactions during two-chamber assay (cellular activity analyzed from session #5). Significant differences were observed between the two conditions for 112/326 cells (P<0.05 using rank-sum test). B) Representative example of cell that showed activity correlated with EN-Social. Horizontal red and green lines signify object and social interactions, respectively. C) Cellular firing vs. EN-Social activity across the multi-regional population of cells (P<0.05 using permutation test; recorded from session #5 of two-chamber assay).

Figure 4:. Circuit elements within EN-Social fail to encode individual behavior.

A) Power and synchrony measures that compose EN-Social. Brain areas and oscillatory frequency bands ranging from 1 to 56Hz are shown around the rim of the circle plot. Spectral power measures that contribute to the electome are depicted by the highlights around the rim, and cross spectral (i.e., synchrony) measures are depicted by the lines connecting the brain regions through the center of the circle (electome activity is shown at a relative spectral density threshold of 0.33, signifying the 85^th percentile of retained features). B) Granger offset measures were used to quantify directionality within the electome network. Prominent directionality was observed across the theta (4–11Hz) frequency band (shown at a spectral density threshold of 0.33). Histograms quantify the number of lead and lagging circuit interactions for each brain region. C) Schematic of signal directionality within EN-Social. D) Decoding accuracy of EN-Social circuit elements for social vs. object interactions. E) Decoding accuracy of EN-Social circuit element activity within animal vs. social preference using spearman correlation. Threshold corresponds with P<0.05.

Figure 5:. Electome network generalizes to encode social brain state and valence.

A) Strategy for validating EN-Social. B) Activity in the EN-Social network increased during distinct social appetitive brain states (n = 10 new mice; P<0.05 using Friedman’s test, and post-hoc testing using sign-rank test with false discover rate correction). The position of the subject mouse is shown relative to an object or another experimental mouse on the bottom. C) EN-Social activity during water vs. sucrose consumption (left) and decoding accuracy vs. nose poke onset (right; n=7 new mice;). D) EN-Social activity during home cage and elevated plus maze recordings (n=19 mice, 7 of which were new to the study).

Figure 6:. EN-Social fails to encode individual responses to non-social stimuli or social aversion.

A) EN-Social decoding for sucrose/water verses the sucrose preference of individual mice (left). EN-Social decoding for open arm/closed arm verses the open arm avoidance (i.e., closed and center arm preference) of individual mice (right). B) Timeline for chronic social defeat stress experiment. C) Protocol utilized to induce and assess neural activity (top) and behavior (bottom) during socially aversive conditions. D) Decoding accuracy of CD1 vs. empty area compared to social avoidance of CD1 mice in susceptible animals.

Figure 7:. Causal activation of the prefrontal cortex to nucleus accumbens circuit element enhances EN-Social activity.

A) Strategy used to activate PL terminals in NAc. B) Experimental paradigm for FOSIT. C) Power spectral plots showing increased 10Hz oscillatory activity during blue light stimulation. Plots show representative spectral patterns from a mouse during blue (left) and yellow (middle) light stimulation trials included in analysis. Representative plots from mouse that showed increased 10Hz activity across all brain regions during blue light stimulation (right). D) Strategy used for EN-Social validation. E) EN-Social activity during blue light stimulation. Network activity was pooled across periods of social interaction by the subject mice and compared between the blue and yellow light stimulation periods. F) Social (left; P<0.05) and object interaction time (right; P>0.05) during blue and yellow light stimulation (all technical replicates are shown).

Figure 8:. Electome network fails to encode individual social preference in a genetic model of autism spectrum disorder.

A-B) Ank2 mice and their littermate controls were subjected to two-chamber social assay. C) Both groups showed preference for social interactions (P>0.05). D-E) Representative LFP activity in d) wild type and e) Ank2 mice showing no seizure activity. F) EN-Social activity during social and object interactions (P<0.05 for conditions; P>0.05 for genotype effects). G-H) EN-Social activity vs. appetitive social behavior in G) wild-type mice (P<0.05) and H) Ank2 mutants (P>0.05). I) Network activity during sucrose consumption in wild-type mice and Ank2 mutants (P>0.05). J) Summary of EN-Social function in Ank2 mutants.