Use of CRISPR/Cas9 Gene Targeting to Conditionally Delete Glucocorticoid Receptors in Rat Brain

Abstract

Glucocorticoid receptors (GR) have diverse functions relevant to maintenance of homeostasis and adaptation to environmental challenges. Understanding the importance of tissue-specific GR function in physiology and behavior has been hampered by near-ubiquitous localization in brain and body. Here we use CRISPR/Cas9 gene editing to create a conditional GR knockout in Sprague Dawley rats. To test the impact of cell-and region-specific GR deletion on physiology and behavior, we targeted GR knockout to output neurons of the prelimbic cortex. Prelimbic deletion of GR in females caused deficits in acquisition and extinction of fear memory during auditory fear conditioning, whereas males exhibit enhanced active-coping behavior during forced swim. Our data support the utility of this conditional knockout rat to afford high-precision deletion of GR across a variety of contexts, ranging from neuronal depletion to circuit-wide manipulations, leveraging the behavioral tractability and enhanced brain size of the rat as a model organism.