NR4A Transcription Factor Family: Key Regulators of Memory Formation

Memory formation is one of the most important functions of the brain regarding individual identity and survival, as well as propagation of a species. Decades of research at numerous levels has begun to elucidate the complex molecular, cellular, circuit, and brain-wide mechanisms underlying learning and memory. One of the key mechanisms involves gene expression required for changes in cellular structure and function, which ultimately give rise to long-lasting changes in behavior. Here, we review a unique transcription factor family, called the nuclear orphan receptor 4a (NR4A). The Nr4a gene family is involved in the development of the dopaminergic signaling system, and dynamically regulated in the adult brain with regard to memory formation. Intriguing results from studying how epigenetic mechanisms modulate synaptic plasticity and long-term memory formation also highlight the pivotal role the Nr4a genes may have in pushing the boundaries of memory formation. We review the discovery of the Nr4a gene family, the complex nature of their activity in transcriptional regulation, and the evidence suggesting they may be one of the most important set of immediate early genes and transcription factors involved in memory, age-related memory impairments, and neurological disease related cognitive dysfunction.