The role of NR4A transcription factors in memory formation

In various physiological contexts, Nr4a genes are transcribed in response to external stimuli as part of an immediate early response that initiates a cascade of gene expression ultimately leading to distinct physiological outcomes in each of these contexts. The signaling pathway that initiates Nr4a gene expression in most of these contexts consists of elevated intracellular cAMP activating PKA, which in turn leads to phosphorylation of CREB and new gene synthesis. This cAMP–PKA–CREB pathway is a central molecular pathway in the formation of a long-term memory. Indeed, learning induces Nr4a family gene expression, and long-term memory formation requires at least two waves of transcription after learning, suggesting that NR4A nuclear receptors may contribute to the second of these waves of gene expression. In this article, we review insights gained in other physiological contexts regarding Nr4a function and regulation, and highlight how these lessons can be applied to the study of memory formation.