Abstract
Fear and extinction learning are adaptive processes caused by molecular changes in specific neural circuits. Neurons expressing the corticotropin-releasing hormone gene (Crh) in central amygdala (CeA) are implicated in threat regulation, yet little is known of cell type-specific gene pathways mediating adaptive learning. We translationally profiled the transcriptome of CeA Crh-expressing cells (Crh neurons) after fear conditioning or extinction in mice using translating ribosome affinity purification (TRAP) and RNAseq. Differential gene expression and co-expression network analyses identified diverse networks activated or inhibited by fear vs extinction. Upstream regulator analysis demonstrated that extinction associates with reduced CREB expression, and viral vector-induced increased CREB expression in Crh neurons increased fear expression and inhibited extinction. These findings suggest that CREB, within CeA Crh neurons, may function as a molecular switch that regulates expression of fear and its extinction. Cell-type specific translational analyses may suggest targets useful for understanding and treating stress-related psychiatric illness.
Highlights
Fear and extinction learning are adaptive processes caused by molecular changes in specific neural circuits
To examine actively translating mRNA transcripts following fear conditioning (FC) or EXT, we generated a corticotropin-releasing hormone (CRH)-translating ribosome affinity purification (TRAP) mouse by crossing a corticotropin-releasing hormone gene (Crh)-Cre line with a Credependent eGFP-L10a line, which contains a fusion of eGFP with the L10a ribosomal protein (Fig. 1d)[47,57]
Mice were habituated to the behavioral apparatus twice for 10 min, fear conditioned (FC: 5 CS/US, 30 s conditioned stimulus (CS) at 6 kHz co-terminating with a 0.65 mA unconditioned stimulus (US), 90 s inter-trial interval (ITI)), or exposed only to the tone alone (TA) (TA: 5 × 30 s CS at 6 kHz, 90 s ITI), or fear conditioned fear extinguished (EXT: 30 × 30 s CS at 6 kHz, 60 s ITI) on consecutive days
Summary
Fear and extinction learning are adaptive processes caused by molecular changes in specific neural circuits. Neurons expressing the corticotropin-releasing hormone gene (Crh) in central amygdala (CeA) are implicated in threat regulation, yet little is known of cell type-specific gene pathways mediating adaptive learning. Upstream regulator analysis demonstrated that extinction associates with reduced CREB expression, and viral vector-induced increased CREB expression in Crh neurons increased fear expression and inhibited extinction These findings suggest that CREB, within CeA Crh neurons, may function as a molecular switch that regulates expression of fear and its extinction. Within the CeA there are several molecularly distinct neuronal populations which mediate specific elements of fear conditioning (FC) and extinction (EXT) learning processes[23,24,25,26,27,28,29,30,31,32,33]. A mutually inhibitory circuit between Crh and Sst neurons gate the generation of active and passive fear responses[17]
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