Limbic progesterone receptors regulate spatial memory

Abstract

Progesterone and its receptors (PRs) participate in mating and reproduction, but their role in spatial declarative memory, is not understood. Male and female mice express PRs in regions that support spatial memory: the hippocampus and entorhinal cortex. PRs were predominantly expressed in excitatory neurons in Pgr-Cre mice injected with AAV-delivered flexed tdTomato. Furthermore, segesterone, a specific PR agonist, activated neurons in the entorhinal cortex (EC) and the hippocampus. We assessed the PR function in these spatial memory circuit neurons by examining the performance of mice lacking this receptor (PRKO) in novel object recognition, object placement, and Y-maze alternation tasks. In the recognition test, wild-type littermates spent significantly more time exploring the new object than male PRKO mice. The EC-specific deletion of PRs was sufficient to induce a deficit in detecting familiar versus never experienced or new objects. We confirmed deficits in spatial memory of PRKO mice by testing them on the Y-maze forced alternation task. In contrast to spatial tasks, PR removal did not alter the response to fear conditioning. PRs also support spatial memory in female mice. These studies provide novel insights into the role of PR in facilitating spatial, declarative memory in males and females, which may help with finding reproductive partners. SIGNIFICANCE STATEMENTBrain progesterone receptors play an essential role in facilitating mating and reproductive behaviors, but their role in spatial memory and, therefore, mate-finding is not described. Principal, excitatory neurons of the entorhinal cortex and hippocampus express progesterone receptors. These receptors facilitate spatial memory in male and female mice, which may enhance mate-finding reproductive function and food foraging.