Cell types controlling social behavior in extended amygdala and nucleus accumbens

Project summary Social anxiety disorder is the most common anxiety disorder in the United States, and ~40% of affected individuals do not respond to existing treatments. A limited knowledge of the neural circuits modulating anxiety impedes innovation for new therapeutic strategies. Recent sequencing data highlight the diversity of neuronal

cell types in the brain, but a key challenge is determining how different cell types function in behaviorally relevant contexts. The answer to this question is important because many genetically defined cell types are evolutionarily conserved across humans, primates, and rodents. One way to link cell types to behavior is with

activity-dependent tagging. The first methods (TRAP, tetTag) used the expression of immediate early genes to label neurons that are active in specific behavioral contexts. These systems were revolutionary, but the temporal resolution of these methods is limited (hours) while behavior can occur over minutes. The Fast Light

and Calcium-Regulated Expression (FLiCRE) system combines light- and calcium-dependent tagging methods to label cells that are activated during a discrete timepoint (~10 min), when a behavior of interest is expressed. We will use the FLiCRE system to tag cells in brain regions that modulate social approach (nucleus

accumbens, NAc) and avoidance behaviors (bed nucleus of the stria terminalis, BNST). We will genetically define these cells using single cell RNAseq and then functionally define them using optogenetic manipulations. We will use FLiCRE to tag cells in the BNST of mice exhibiting social avoidance and use single nucleus RNA

sequencing (snRNAseq) to genetically define these cells to test the hypothesis that a subset of Oxtr cell types are active in stressful social contexts. Pharmacological activation of oxytocin receptors in the BNST is necessary and sufficient for drive social avoidance. We will then use optogenetics to functionally define these

cells. We predict that inhibition of BNST cells tagged during social avoidance will increase social approach. Next, we will use FLiCRE to tag cells in the NAc of mice exhibiting social approach. We will use snRNAseq to test the hypothesis that Oxtr interneurons are active during social approach, because oxytocin receptors in the

NAc promote social approach. We will then use optogenetics to inhibit these cells and predict that inhibition will decrease social approach. Our research team is ideally suited to execute these studies. Dr. Trainor's lab delineated oxytocin receptor-dependent pathways of social approach and avoidance. Dr. Kim developed the

FLiCRE construct and used it to identify a novel cell type in NAc that drives aversion. Dr. Tollkuhn is a molecular biologist and expert on using single nucleus RNAsequencing in brain. Dr. Wiltgen has successfully performed optogenetic manipulations of neurons labeled via activity-dependent tagging. Our analyses will

identify cell types that modulate social approach and avoidance behaviors, which could lead to novel insights into how to selectively target these cells.