UCSF

Our behaviors during social interactions are wide-ranging and highly contextual. The norms that dictate how we should act vary based on who we are interacting with, societal context, and past experiences. Social cognition refers to the ability of animals to utilize both experience and the knowledge of learned social norms to select appropriate behaviors for specific contexts. The medial prefrontal cortex (mPFC) has a long-established role in executive function and cognition, and has also been found to be critical for the production of normal social behavior. However, the precise role of the mPFC in social behavior and the neural dynamics that occur in this region during social interaction have not been explored in great detail. Elucidating the precise role of the mPFC during social interaction is critical to understanding how abnormal social phenotypes arise in the array of psychiatric illnesses that impinge upon the PFC. One way to approach this problem is to utilize rodent models in combination with the wide array of molecular and genetic tools available in this system. These tools allow for studying the role of particular brain regions, neuron subtypes, and genes in behavior. Particularly, one tool that has expanded our understanding of the neural foundations of complex behavior is in vivo calcium imaging of neuronal activity with miniaturized, head-mounted microscopes. In combination with tools that allow for expression of the genetically encoded calcium indicator GCaMP in genetically-defined neuron subpopulations, this approach makes it possible to record activity specifically from cell types that have relevance to psychiatric disorders while animals can move and behave freely. Here, we describe two distinct studies that utilize this approach to record activity in the mPFC of mice from neuron populations that have been implicated in psychiatric disorders. In the first study, we record activity in layer 5 projection neurons of the mPFC in both wild-type mice and mice that have the Tbr1 gene deleted specifically in cortical layer 5 neurons. Tbr1 is a high-confidence autism risk-gene, and mPFC layer 5 projection neurons have been identified as a hub of autism risk-gene expression. We find that these Tbr1 layer 5 conditional knockout animals (Tbr1-cKO) display abnormal social and anxiety-related avoidance behaviors. During social interactions, encoding of behavior by correlated activity of mPFC neurons is diminished in cKO animals, while correlated activity remains intact during anxiety-related behavior. We also identify signals in mPFC neural ensembles that are predictive of approach-avoidance decisions, but are lost in the Tbr1 cKO mouse model. In the second study, we record specifically from mPFC neurons that express the dopamine receptor D2R, which has been implicated in disorders including schizophrenia and depression. We also record from mPFC D2R+ neurons after knocking out the D2R, to assess the role of the receptor itself in socially recruited activity. These animals performed the 3-chamber social assay, and we find significant center chamber associated activity in D2R+ neurons that is lost when the D2R is deleted. Inhibition of mPFC D2R+ neurons specifically in the center chamber of this task leads to an overall increase in the number of social interactions.