Competitive integration of time and reward explains value-sensitive foraging decisions and frontal cortex ramping dynamics.

The ability to make advantageous decisions is critical for animals to ensure their survival. Patch foraging is a natural decision-making process in which animals decide when to leave a patch of depleting resources to search for a new one. To study the algorithmic and neural basis of patch foraging behavior in a controlled laboratory setting, we developed a virtual foraging task for head-fixed mice. Mouse behavior could be explained by ramp-to-threshold models integrating time and rewards antagonistically. Accurate behavioral modeling required inclusion of a slowly varying "patience" variable, which modulated sensitivity to time. To investigate the neural basis of this decision-making process, we performed dense electrophysiological recordings with Neuropixels probes broadly throughout frontal cortex and underlying subcortical areas. We found that decision variables from the reward integrator model were represented in neural activity, most robustly in frontal cortical areas. Regression modeling followed by unsupervised clustering identified a subset of neurons with ramping activity. These neurons' firing rates ramped up gradually in single trials over long time scales (up to tens of seconds), were inhibited by rewards, and were better described as being generated by a continuous ramp rather than a discrete stepping process. Together, these results identify reward integration via a continuous ramping process in frontal cortex as a likely candidate for the mechanism by which the mammalian brain solves patch foraging problems.

Neural control of affiliative touch in prosocial interaction.

The ability to help and care for others fosters social cohesiveness and is vital to the physical and emotional well-being of social species, including humans1-3. Affiliative social touch, such as allogrooming (grooming behaviour directed towards another individual), is a major type of prosocial behaviour that provides comfort to others1-6. Affiliative touch serves to establish and strengthen social bonds between animals and can help to console distressed conspecifics. However, the neural circuits that promote prosocial affiliative touch have remained unclear. Here we show that mice exhibit affiliative allogrooming behaviour towards distressed partners, providing a consoling effect. The increase in allogrooming occurs in response to different types of stressors and can be elicited by olfactory cues from distressed individuals. Using microendoscopic calcium imaging, we find that neural activity in the medial amygdala (MeA) responds differentially to naive and distressed conspecifics and encodes allogrooming behaviour. Through intersectional functional manipulations, we establish a direct causal role of the MeA in controlling affiliative allogrooming and identify a select, tachykinin-expressing subpopulation of MeA GABAergic (γ-aminobutyric-acid-expressing) neurons that promote this behaviour through their projections to the medial preoptic area. Together, our study demonstrates that mice display prosocial comforting behaviour and reveals a neural circuit mechanism that underlies the encoding and control of affiliative touch during prosocial interactions.

Cortical Representations of Conspecific Sex Shape Social Behavior.

A central question related to virtually all social decisions is how animals integrate sex-specific cues from conspecifics. Using microendoscopic calcium imaging in mice, we find that sex information is represented in the dorsal medial prefrontal cortex (dmPFC) across excitatory and inhibitory neurons. These cells form a distributed code that differentiates the sex of conspecifics and is strengthened with social experience. While males and females both represent sex in the dmPFC, male mice show stronger encoding of female cues, and the relative strength of these sex representations predicts sex preference behavior. Using activity-dependent optogenetic manipulations of natively active ensembles, we further show that these specific representations modulate preference behavior toward males and females. Together, these results define a functional role for native representations of sex in shaping social behavior and reveal a neural mechanism underlying male- versus female-directed sociality.

A Multi-Brain Framework for Social Interaction.

Social interaction can be seen as a dynamic feedback loop that couples action, reaction, and internal cognitive processes across individual agents. A fuller understanding of the social brain requires a description of how the neural dynamics across coupled brains are linked and how they coevolve over time. We elaborate a multi-brain framework that considers social interaction as an integrated network of neural systems that dynamically shape behavior, shared cognitive states, and social relationships. We describe key findings from multi-brain experiments in humans and animal models that shed new light on the function of social circuits in health and disease. Finally, we discuss recent progress in elucidating the cellular-level mechanisms underlying inter-brain neural dynamics and outline key areas for future research.

Reciprocal Copy Number Variations at 22q11.2 Produce Distinct and Convergent Neurobehavioral Impairments Relevant for Schizophrenia and Autism Spectrum Disorder.

BACKGROUND: 22q11.2 deletions and duplications are copy number variations (CNVs) that predispose to developmental neuropsychiatric disorders. Both CNVs are associated with autism spectrum disorder (ASD), while the deletion confers disproportionate risk for schizophrenia. Neurobehavioral profiles associated with these reciprocal CNVs in conjunction with brain imaging measures have not been reported. METHODS: We profiled the impact of 22q11.2 CNVs on neurobehavioral measures relevant to ASD and psychosis in 106 22q11.2 deletion carriers, 38 22q11.2 duplication carriers, and 82 demographically matched healthy control subjects. To determine whether brain-behavior relationships were altered in CNV carriers, we further tested for interactions between group and regional brain structure on neurobehavioral domains. RESULTS: Cognitive deficits were observed in both CNV groups, with the lowest IQs in deletion carriers. ASD and dimensionally measured ASD traits were elevated in both CNV groups; however, duplication carriers exhibited increased stereotypies compared to deletion carriers. Moreover, discriminant analysis using ASD subdomains distinguished between CNV cases with 76% accuracy. Both psychotic disorder diagnosis and dimensionally measured positive and negative symptoms were elevated in deletion carriers. Finally, healthy control subjects showed an inverse relationship between processing speed and cortical thickness in heteromodal association areas, which was absent in both CNV groups. CONCLUSIONS: 22q11.2 CNVs differentially modulate intellectual functioning and psychosis-related symptomatology but converge on broad ASD-related symptomatology. However, subtle differences in ASD profiles distinguish CNV groups. Processing speed impairments, coupled with the lack of normative relationship between processing speed and cortical thickness in CNV carriers, implicate aberrant development of the cortical mantle in the pathology underlying impaired processing speed ability.

Correlated Neural Activity and Encoding of Behavior across Brains of Socially Interacting Animals.

Social interactions involve complex decision-making tasks that are shaped by dynamic, mutual feedback between participants. An open question is whether and how emergent properties may arise across brains of socially interacting individuals to influence social decisions. By simultaneously performing microendoscopic calcium imaging in pairs of socially interacting mice, we find that animals exhibit interbrain correlations of neural activity in the prefrontal cortex that are dependent on ongoing social interaction. Activity synchrony arises from two neuronal populations that separately encode one's own behaviors and those of the social partner. Strikingly, interbrain correlations predict future social interactions as well as dominance relationships in a competitive context. Together, our study provides conclusive evidence for interbrain synchrony in rodents, uncovers how synchronization arises from activity at the single-cell level, and presents a role for interbrain neural activity coupling as a property of multi-animal systems in coordinating and sustaining social interactions between individuals.

Myelinating glia differentiation is regulated by extracellular matrix elasticity.

The mechanical properties of living tissues have a significant impact on cell differentiation, but remain unexplored in the context of myelin formation and repair. In the PNS, the extracellular matrix (ECM) incorporates a basal lamina significantly denser than the loosely organized CNS matrix. Inhibition of non-muscle myosin II (NMII) enhances central but impairs peripheral myelination and NMII has been implicated in cellular responses to changes in the elasticity of the ECM. To directly evaluate whether mechanotransduction plays a role in glial cell differentiation, we cultured Schwann cells (SC) and oligodendrocytes (OL) on matrices of variable elastic modulus, mimicking either their native environment or conditions found in injured tissue. We found that a rigid, lesion-like matrix inhibited branching and differentiation of OL in NMII-dependent manner. By contrast, SC developed normally in both soft and stiffer matrices. Although SC differentiation was not significantly affected by changes in matrix stiffness alone, we found that expression of Krox-20 was potentiated on rigid matrices at high laminin concentration. These findings are relevant to the design of biomaterials to promote healing and regeneration in both CNS and PNS, via transplantation of glial progenitors or the implantation of tissue scaffolds.