Cell-Type Specific Interrogation of CeA Drd2 Neurons to Identify Targets for Pharmacological Modulation of Fear Extinction

Abstract

Behavioral and molecular characterization of cell-type specific populations governing fear learning and behavior is a promising avenue for the rational identification of potential therapeutics for fear-related disorders. Examining cell-type specific changes in neuronal translation following fear learning allows for targeted pharmacological intervention during fear extinction learning, mirroring possible treatment strategies in humans. Here we identify the central amygdala (CeA) Drd2-expressing population as a novel fear-supporting neuronal population that is molecularly distinct from other, previously identified, fear-supporting CeA populations. Sequencing of actively translating transcripts of Drd2 neurons using translating ribosome affinity purification (TRAP) technology identifies mRNAs that are differentially regulated following fear learning. Differentially expressed transcripts with potentially targetable gene products include Npy5r, Rxrg, Adora2a, Sst5r, Fgf3, Erbb4, Fkbp14, Dlk1, and Ssh3. Direct pharmacological manipulation of NPY5R, RXR, and ADORA2A confirms the importance of this cell population and these cell-type specific receptors in fear behavior. Furthermore, these findings validate the use of functionally identified specific cell populations to predict novel pharmacological targets for the modulation of emotional learning.