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

Ana Oliveira; Raquel Martinho; Paula Serrão; Mónica Moreira-Rodrigues

doi:10.3389/fnmol.2018.00334

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

Front Mol Neurosci. 2018 Sep 25:11:334. doi: 10.3389/fnmol.2018.00334. eCollection 2018.

Authors

Ana Oliveira^{1

2}, Raquel Martinho^{1

2}, Paula Serrão^{2

3}, Mónica Moreira-Rodrigues^{1

2}

Affiliations

¹ Laboratory of General Physiology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS/UP), Porto, Portugal.
² Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal.
³ Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal.

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.

Keywords: Nr4a transcription factors; contextual fear memory; epinephrine; phenylethanolamine-N-methyltransferase-knockout mice; traumatic experience; β2-adrenoceptors.