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

Gould, Nathaniel; Elkobi, Alina; Edry, Efrat; Daume, Jonathan; Rosenblum, Kobi

doi:10.1523/eneuro.0067-20.2020

Cited by 11 publications

(41 citation statements)

References 61 publications

(68 reference statements)

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“…We have previously shown that miR-182 causes suppression of QR2 mRNA in the aIC (Gould et al, 2020). Since miR-182 is Figure 2.…”

Section: Novelty Of the Context Reduces Qr2 Expression Via Mir-182 Upregulationmentioning

confidence: 98%

“…Brains were stored at À80°C and then transferred to a cryostat (CM 1950, Leica Microsystems), whereupon they were equilibrated to À15°C. CA1 samples were removed from 0.5-mm-thick coronal slices (from bregma: AP À1.355 mm, to bregma: AP À2.48 mm) (Franklin and Paxinos, 2008) with the use of a tissue punching device, while control aIC samples were taken as previously described (Gould et al, 2020). For DAT Cre mice LC inactivation experiments, brains were removed and split with a coronal cut, separating the dorsal hippocampus and LC containing anterior and posterior parts of the brain.…”

Section: Brain Dissection and Tissue Preparationmentioning

confidence: 99%

“…1i) to mice with QR2 shRNA, implying the QR2 gene product (i.e., the QR2 enzyme) directly as being the cause for the observed memory enhancement. Since the QR2 enzyme has been shown to act as a ROS modulating reductase in the brain (Gould et al, 2020), we assessed how QR2 inhibition would affect CA1. Mice were therefore injected with S29434 (8 mg/kg, i.p.)…”

Section: Qr2 Inhibition or Reduced Expression In Ca1 Improves Trace Fear Conditioning Memorymentioning

confidence: 99%

“…Recently, we identified quinone reductase 2 (QR2) as an important component in novel taste memory formation in the anterior insular cortex (aIC), acting in parallel to the well-known and previously described mechanisms downstream to neuromodulation (Rappaport et al, 2015;Gould et al, 2020). QR2 is a poorly understood enzyme, which unlike its closely related antioxidant enzyme NQO1, does not recognize NADH as cofactor and acts on deleterious substrates which can lead to the generation of ROS (Cassagnes et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…QR2 is a poorly understood enzyme, which unlike its closely related antioxidant enzyme NQO1, does not recognize NADH as cofactor and acts on deleterious substrates which can lead to the generation of ROS (Cassagnes et al, 2015). Importantly, the removal of QR2 from the aIC 3 h following novel taste learning lowers physiological ROS locally, thus modulating redox-sensitive components, such as Kv2.1 channels in a form of closely controlled oxidative eustress (Niki, 2016;Gould et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Dopamine-Dependent QR2 Pathway Activation in CA1 Interneurons Enhances Novel Memory Formation

et al. 2020

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The formation of memory for a novel experience is a critical cognitive capacity. The ability to form novel memories is sensitive to age-related pathologies and disease, to which prolonged metabolic stress is a major contributing factor. Presently, we describe a dopamine-dependent redox modulation pathway within the hippocampus of male mice that promotes memory consolidation. Namely, following novel information acquisition, quinone reductase 2 (QR2) is suppressed by miRNA-182 (miR-182) in the CA1 region of the hippocampus via dopamine D1 receptor (D1R) activation, a process largely facilitated by locus coeruleus activity. This pathway activation reduces ROS generated by QR2 enzymatic activity, a process that alters the intrinsic properties of CA1 interneurons 3 h following learning, in a form of oxidative eustress. Interestingly, novel experience decreases QR2 expression predominately in inhibitory interneurons. Additionally, we find that in aged animals this newly described QR2 pathway is chronically under activated, resulting in miR-182 underexpression and QR2 overexpression. This leads to accumulative oxidative stress, which can be seen in CA1 via increased levels of oxidized, inactivated potassium channel Kv2.1, which undergoes disulfide bridge oligomerization. This newly described interneuron-specific molecular pathway lies alongside the known mRNA translation-dependent processes necessary for long-term memory formation, entrained by dopamine in CA1. It is a process crucial for the distinguishing features of novel memory, and points to a promising new target for memory enhancement in aging and age-dependent diseases.

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“…We have previously shown that miR-182 causes suppression of QR2 mRNA in the aIC (Gould et al, 2020). Since miR-182 is Figure 2.…”

Section: Novelty Of the Context Reduces Qr2 Expression Via Mir-182 Upregulationmentioning

confidence: 98%

Section: Brain Dissection and Tissue Preparationmentioning

confidence: 99%

Section: Qr2 Inhibition or Reduced Expression In Ca1 Improves Trace Fear Conditioning Memorymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dopamine-Dependent QR2 Pathway Activation in CA1 Interneurons Enhances Novel Memory Formation

et al. 2020

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Homeostatic Shrinkage of Dendritic Spines Requires Melatonin Type 3 Receptor Activation During Sleep

Li,

et al. 2024

Advanced Science

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High‐frequency oscillatory activity in cognition‐related neural circuits during wakefulness consistently induces the growth of dendritic spines and axonal terminals. Although these structural changes are essential for cognitive functions, it is hypothesized that if these newly expanded structures fail to establish functional connections, they may become superfluous. Sleep is believed to facilitate the reduction of such redundant structures to maintain neural homeostasis. However, the mechanisms underlying this pruning process during sleep remain poorly understood. In this study, that melatonin type 3 receptors (MT3Rs) are selectively expressed in the stellate neurons of the medial entorhinal cortex (MEC) is demonstrated, an area where high melatonin levels are detected during sleep. Activation of MT3Rs during sleep initiates the shrinkage of dendritic spines in stellate neurons by downregulating neural network activity and dephosphorylating synaptic proteins in the MEC. This process is disrupted when MT3R expression is knocked down or when MT3Rs are blocked during sleep. Notably, interference with MT3Rs in the MEC during sleep impairs the acquisition of spatial memory but does not affect object memory acquisition following sleep. These findings reveal novel molecular mechanisms involving melatonin and MT3Rs in the regulation of dendritic spine shrinkage during sleep, which is crucial for the acquisition and consolidation of spatial memory.

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Discovery of a potent melatonin-based inhibitor of quinone reductase-2 with neuroprotective and neurogenic properties

Herrera-Arozamena,

Estrada-Valencia,

García-Díez

et al. 2024

European Journal of Medicinal Chemistry

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

Abstract: Number of pages: 35 (including figures & legends, not including extended data) ⁘ Number of figures (5), tables (0), multimedia (0), and 3D models (0) (separately)

Cited by 11 publications

References 61 publications

Dopamine-Dependent QR2 Pathway Activation in CA1 Interneurons Enhances Novel Memory Formation

Dopamine-Dependent QR2 Pathway Activation in CA1 Interneurons Enhances Novel Memory Formation

Homeostatic Shrinkage of Dendritic Spines Requires Melatonin Type 3 Receptor Activation During Sleep

Discovery of a potent melatonin-based inhibitor of quinone reductase-2 with neuroprotective and neurogenic properties

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