Epinephrine Released During Traumatic Events May Strengthen Contextual Fear Memory Through Increased Hippocampus mRNA Expression of Nr4a Transcription Factors

Abstract

Epinephrine (EPI) strengthens contextual fear memories by acting on peripheral β2-adrenoceptors. Phenylethanolamine-N-methyltransferase-knockout (Pnmt-KO) mice are EPI-deficient mice and have reduced contextual fear learning. Our aim was to evaluate the molecular mechanisms by which peripheral EPI strengthens contextual fear memory and if a β2-adrenoceptor antagonist can erase contextual fear memories. Pnmt-KO and wild-type (WT) mice were submitted to fear conditioning (FC) procedure after treatment with EPI, norepinephrine (NE), EPI plus ICI 118,551 (selective β2-adrenoceptor antagonist), ICI 118,551 or vehicle (NaCl 0.9%). Catecholamines were separated and quantified by high performance liquid chromatography-electrochemical detection (HPLC-ED). Blood glucose was measured by coulometry. Real-time polymerase chain reaction (qPCR) was used to evaluate mRNA expression of nuclear receptor 4a1 (Nr4a1), Nr4a2 and Nr4a3 in hippocampus samples. In WT mice, plasma EPI concentration was significantly higher after fear acquisition (FA) compared with mice without the test. NE did not increase in plasma after FA and did not strengthen contextual fear memory, contrary to EPI. Freezing induced by EPI was blocked by ICI 118,551 in Pnmt-KO mice. In WT mice, ICI 118,551 blocked blood glucose release into the bloodstream after FA and decreased contextual fear memory. Nr4a1, Nr4a2 and Nr4a3 mRNA expression decreased in Pnmt-KO mice compared with WT mice after FC procedure. In Pnmt-KO mice, EPI induced an increase in mRNA expression of Nr4a2 compared to vehicle. In conclusion, EPI increases in plasma after an aversive experience, possibly improving long-term and old memories, by acting on peripheral β2-adrenoceptors. Glucose could be the mediator of peripheral EPI in the central nervous system, inducing the expression of Nr4a transcription factor genes involved in consolidation of contextual fear memories.

Epinephrine May Contribute to the Persistence of Traumatic Memories in a Post-traumatic Stress Disorder Animal Model

“…Previous studies showed Nr4a subfamily genes expression in the hippocampus to be upregulated after training of fear conditioning procedure contributing to contextual memory consolidation on the next day (von Hertzen and Giese, 2005;Hawk and Abel, 2011;Hawk et al, 2012). Also, we have already shown that glucose may be a mediator of EPI in the central nervous system and could be important to induce the expression of the Nr4a family genes involved in contextual fear memories (Oliveira et al, 2018). The NR4A transcription factors induce the expression of several target genes, such as the brain-derived neurotrophic factor (Bdnf ) gene suggested to play an important role in hippocampus-dependent contextual fear memory (Mizuno et al, 2012).…”

“…We have already suggested that after a fear event, EPI is released from the adrenal gland to the bloodstream. Afterward, EPI may act in β 2 -adrenoceptors inducing liver cells to release a transient glucose surge into the blood which may be a mediator in the central nervous system strengthening contextual fear memories (Alves et al, 2016;Oliveira et al, 2018).…”

“…qPCR was performed in hippocampus samples collected 3 h after day 0 of PTSD induction, as previously described (Moreira-Rodrigues et al, 2007a;Mendes et al, 2018;Oliveira et al, 2018). Total RNA isolation was carried out with the illustra TM RNAspin Mini RNA Isolation Kit (GE Healthcare Life Sciences, Buckinghamshire, UK).…”

“…These genes encode for three transcription factors, namely Nr4a1, Nr4a2, and Nr4a3, which mediate several cellular responses (Hazel et al, 1988;Law et al, 1992;Ohkura et al, 1996). Besides their involvement in physiologic processes such as energy metabolism, inflammatory responses, and hypothalamic-pituitary-adrenal axis regulation (Wilson et al, 1993;Honkaniemi et al, 1994;Murphy and Conneely, 1997;Maira et al, 1999), these genes have been implicated in contextual fear memory formation (Liu et al, 1994;Woronicz et al, 1994;Fernandez et al, 2000;Pei et al, 2006;Rojas et al, 2007;Hawk and Abel, 2011;Oliveira et al, 2018). Previous studies showed that contextual fear conditioning induces Nr4a genes transcription in the hippocampus, a brain structure involved in the acquisition of contextual fear conditioning in response to stress stimuli (von Hertzen and Giese, 2005;Hawk et al, 2012;Mizuno et al, 2012;Oliveira et al, 2018).…”

Chemistry of Emotions - A Review

“…This response is important for survival and adaptation in nature. Epinephrine may induce liver cells to release glucose into the bloodstream and glucose may lead to a subsequent increase of the energy source in the central nervous system and enhance contextual fear learning [23] . Studies have shown that the amygdala is critical to fear responses and emotional memory.…”