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

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          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 GABA A receptor control of mAChR activation causes upregulation of miRNA-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 before 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 cofactors 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.

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          Most cited references 49

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          The role of acetylcholine in learning and memory.

          Pharmacological data clearly indicate that both muscarinic and nicotinic acetylcholine receptors have a role in the encoding of new memories. Localized lesions and antagonist infusions demonstrate the anatomical locus of these cholinergic effects, and computational modeling links the function of cholinergic modulation to specific cellular effects within these regions. Acetylcholine has been shown to increase the strength of afferent input relative to feedback, to contribute to theta rhythm oscillations, activate intrinsic mechanisms for persistent spiking, and increase the modification of synapses. These effects might enhance different types of encoding in different cortical structures. In particular, the effects in entorhinal and perirhinal cortex and hippocampus might be important for encoding new episodic memories.
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            Comparative Proteomic Analysis of Eleven Common Cell Lines Reveals Ubiquitous but Varying Expression of Most Proteins*

            Deep proteomic analysis of mammalian cell lines would yield an inventory of the building blocks of the most commonly used systems in biological research. Mass spectrometry-based proteomics can identify and quantify proteins in a global and unbiased manner and can highlight the cellular processes that are altered between such systems. We analyzed 11 human cell lines using an LTQ-Orbitrap family mass spectrometer with a “high field” Orbitrap mass analyzer with improved resolution and sequencing speed. We identified a total of 11,731 proteins, and on average 10,361 ± 120 proteins in each cell line. This very high proteome coverage enabled analysis of a broad range of processes and functions. Despite the distinct origins of the cell lines, our quantitative results showed surprisingly high similarity in terms of expressed proteins. Nevertheless, this global similarity of the proteomes did not imply equal expression levels of individual proteins across the 11 cell lines, as we found significant differences in expression levels for an estimated two-third of them. The variability in cellular expression levels was similar for low and high abundance proteins, and even many of the most highly expressed proteins with household roles showed significant differences between cells. Metabolic pathways, which have high redundancy, exhibited variable expression, whereas basic cellular functions such as the basal transcription machinery varied much less. We harness knowledge of these cell line proteomes for the construction of a broad coverage “super-SILAC” quantification standard. Together with the accompanying paper (Schaab, C. MCP 2012, PMID: 22301388) (17) these data can be used to obtain reference expression profiles for proteins of interest both within and across cell line proteomes.
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              Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability

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                Author and article information

                Journal
                eNeuro
                eNeuro
                eneuro
                eneuro
                eNeuro
                eNeuro
                Society for Neuroscience
                2373-2822
                20 March 2020
                29 May 2020
                May-Jun 2020
                : 7
                : 3
                Affiliations
                [1 ]Sagol Department of Neuroscience, University of Haifa , Haifa 3498838, Israel
                [2 ]Center for Gene Manipulation in the Brain, University of Haifa , Haifa 3498838, Israel
                Author notes

                The authors declare no competing financial interests.

                Author contributions: N.L.G., J.D., and K.R. designed research; N.L.G., A.E., and J.D. performed research; E.E. contributed unpublished reagents/analytic tools; N.L.G. analyzed data; N.L.G. and K.R. wrote the paper.

                This research was funded with the support of the Legacy Heritage Biomedical Science Partnership Program of the Israel Science Foundation (Grant 604/15 to K.R.). N.L.G. is a recipient of the University of Haifa President Fellowship for Excellent Students (Fellowship 501100005717).

                Correspondence should be addressed to Kobi Rosenblum at kobir@ 123456psy.haifa.ac.il .
                Article
                eN-NWR-0067-20
                10.1523/ENEURO.0067-20.2020
                7266141
                32217627
                Copyright © 2020 Gould et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 63, Pages: 15, Words: 00
                Product
                Funding
                Funded by: http://doi.org/10.13039/501100003977Israel Science Foundation (ISF)
                Award ID: 604/15
                Funded by: http://doi.org/10.13039/501100005717University of Haifa
                Categories
                1
                Research Article: New Research
                Cognition and Behavior
                Custom metadata
                May/June 2020

                ros, machr, mir-182, nqo2, oxidative stress, qr2

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