LAUSR

Social dysfunctions belong to the core features of several psychiatric disorders, including autism spectrum disorder, personality disorders, and schizophrenia. In schizophrenia, these social deficits often persist after standard treatment and contribute to chronic functional disability (1). Therapeutic treatments targeting the neural systems supporting social cognition may be a promising tool for improving these deficits, for example by modulating the activation of brain regions involved in social processing with noninvasive brain stimulation or by neuroplasticity-based cognitive training; however, evidence regarding the success of these treatments is mixed (2). To develop effective neural interventions targeting these social deficits, it is pivotal to obtain a deeper understanding of the brain circuits underlying social preferences. Previous research has identified several brain regions that play a crucial role in social behavior, including the prefrontal control system and the basal ganglia. The basal ganglia are involved in motivational and emotional processing and may motivate social behavior by encoding the reward value of social interactions (3). The prefrontal cortex (PFC), in contrast, is causally involved in suppressing social preferences, as has been shown in both human and animal studies (4,5). Clinical findings suggest that the social dysfunctions in schizophrenia and autism spectrum disorder are related to aberrant PFC functioning (6,7), and therefore the PFC might be a promising intervention target for treating the social deficits in these disorders. However, in order to predict the effects of neural interventions on social behavior in psychiatric and healthy populations, it is important to determine the descending circuits underlying the PFC’s role in social behavior. While it is tempting to speculate that descending PFC projections top-down regulate activation in motivational and emotional circuits, direct evidence for this hypothesis has been missing so far. A novel study by Benekareddy et al. (8) provides this missing link. Combining chemogenetics with functional imaging in a series of elegant experiments on rats and mice, Benekareddy et al. (8) develop a causal networks account of the interactions between the PFC and brain circuits involved in motivation and emotion processing. They used the excitatory DREADD (designer receptor exclusively activated by designer drugs) hM3Dq—a chemogenetic tool that allows selective enhancement of the activation of neurons transduced with the DREADD—to test the impact of increased PFC activation on social behavior in the three-chamber test. The three-chamber test is an established indicator of social