Muscarinic-Dependent miR-182 and QR2 Expression Regulation in the Anterior Insula Enables Novel Taste Learning

Abstract

In a similar manner to other learning paradigms, intact muscarinic acetylcholine receptor (mAChR) neurotransmission or protein synthesis regulation in the anterior insular cortex (aIC) is necessary for appetitive taste learning. Here we describe a parallel, local molecular pathway, where γ-aminobutyric acid type a receptor (GABA_AR) control of mAChR activation causes upregulation of microRNA-182 (miR-182) and quinone reductase 2 (QR2) mRNA destabilization in the rodent aIC. Damage to long-term memory by prevention of this process, with the use of mAChR antagonist scopolamine prior to novel taste learning, can be rescued by local QR2 inhibition, demonstrating that QR2 acts downstream of local muscarinic activation. Furthermore, we prove for the first time the presence of endogenous QR2 co-factors in the brain, establishing QR2 as a functional reductase there. In turn, we show that QR2 activity causes the generation of reactive oxygen species, leading to modulation in Kv2.1 redox state. QR2 expression reduction therefore is a previously unaccounted mode of mAChR mediated inflammation reduction, and thus adds QR2 to the cadre of redox modulators in the brain. The concomitant reduction in QR2 activity during memory consolidation suggests a complementary mechanism to the well-established molecular processes of this phase, by which the cortex gleans important information from general sensory stimuli. This places QR2 as a promising new target to tackle neurodegenerative inflammation and the associated impediment of novel memory formation in diseases such as Alzheimer’s disease.

Significance Statement Most studies on molecular mechanisms underlying memory consolidation have thus far focused on the transformation of electrical and synaptic activity to post-translation modifications, mRNA translation, and gene transcription regulation. Here, we explore a less studied mechanism, of the removal of an innate constraint to allow the formation of long-term memory. Our findings point to a pathway of GABA_A receptor control of mAChR activation, which causes upregulation of miR-182, which can in turn lead to destabilization of QR2 mRNA in the rodent anterior insular cortex. The results propose a novel molecular cascade, complementary to the mRNA translation/transcription regulation underlying memory consolidation, by which the cortex gleans important information from general sensory stimuli.