Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

Abstract

Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the b-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the b-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another b-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM.

Corticosteroids and the brain

“…Almost without exception, this involves G-protein-coupled receptors, which upon binding of the ligand mediate actions that develop within minutes and generally are short lasting, due to dissociation of the ligand from the receptor or other processes like internalization (Magalhaes et al 2012). Still, secondary long-lasting actions frequently occur for example through the involvement of CREB (Chai et al 2014).…”

Inhibition of Lactate Transport Erases Drug Memory and Prevents Drug Relapse

“…The synaptosomes were extracted for examination of MCTs based on previous reports (33,34). Whole-cell lysis was prepared to examine the expression of phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB), phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated cofilin (pcofilin), CREB, ERK, and cofilin.…”

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

“…Guide cannulae for viral infusions and pharmacological infusions (23 gauge; Plastics One, Roanoke, VA, USA) were bilaterally implanted 1 mm above the CA1 (anterior/posterior, − 3.8 mm; medial/lateral, ± 2.0 mm; dorsal/ventral, − 2.5 mm) and CA3 (anterior/posterior, − 3.8 mm; medial/ lateral, ± 3.8 mm; dorsal/ventral, − 3.2 mm) areas of the hippocampus (Chai et al, 2014;Paxinos and Watson, 2005). The cannulae were anchored to the skull with stainless-steel screws and dental cement.…”

“…The contextual fear conditioning procedure was based on our previous studies, with minor modifications (Chai et al, 2014). The rats were handled for 3 days before conditioning.…”

“…Crude cytoplasmic and synaptosomal membrane fractions were collected based on our previous studies (Chai et al, 2014;Jian et al, 2014;Liu et al, 2014;Lu et al, 2005). After decapitation, the brains were rapidly extracted and frozen in − 60°C N-hexane.…”