Conditional deletion of glucocorticoid receptors in rat brain results in sex-specific deficits in fear and coping behaviors

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 <i>GR</i> knockdown in Sprague Dawley rats. To test the impact of cell- and region-specific <i>GR</i> knockdown on physiology and behavior, we targeted <i>GR</i> knockdown to output neurons of the prelimbic cortex. Prelimbic knockdown of <i>GR</i> in females caused deficits in acquisition and extinction of fear memory during auditory fear conditioning, whereas males exhibited enhanced active-coping behavior during forced swim. Our data support the utility of this conditional knockdown rat to afford high-precision knockdown of <i>GR</i> 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.