Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer's disease phenotype in mice.

Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit.

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

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 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.

The differential role of cortical protein synthesis in taste memory formation and persistence.

The current dogma suggests that the formation of long-term memory (LTM) is dependent on protein synthesis but persistence of the memory trace is not. However, many of the studies examining the effect of protein synthesis inhibitors (PSIs) on LTM persistence were performed in the hippocampus, which is known to have a time-dependent role in memory storage, rather than the cortex, which is considered to be the main structure to store long-term memories. Here we studied the effect of PSIs on LTM formation and persistence in male Wistar Hola ( ≥ 5) rats by infusing the protein synthesis inhibitor, anisomycin (100 μg, 1 μl), into the gustatory cortex (GC) during LTM formation and persistence in conditioned taste aversion (CTA).

mAChR-dependent decrease in proteasome activity in the gustatory cortex is necessary for novel taste learning.

Regulation of protein degradation via the ubiquitin proteasome system is crucial for normal learning and synaptic plasticity processes. While some studies reveal that increased proteasome degradation is necessary for different types of learning, others suggest the proteasome to be a negative regulator of plasticity. We aim to understand the molecular and cellular processes taking place in the gustatory cortex (GC), which underlie appetitive and aversive forms of taste learning.

Fluid consumption and taste novelty determines transcription temporal dynamics in the gustatory cortex.

Background: Novel taste memories, critical for animal survival, are consolidated to form long term memories which are dependent on translation regulation in the gustatory cortex (GC) hours following acquisition. However, the role of transcription regulation in the process is unknown.

Results: Here, we report that transcription in the GC is necessary for taste learning in rats, and that drinking and its consequences, as well as the novel taste experience, affect transcription in the GC during taste memory consolidation.

NMDAR-dependent proteasome activity in the gustatory cortex is necessary for conditioned taste aversion.

Taste information is processed in different brain structures in the mammalian brain, including the gustatory cortex (GC), which resides within the insular cortex. N-methyl-d-aspartate receptor (NMDAR) activity in the GC is necessary for the acquisition of conditioned taste aversion (CTA) but not positive novel taste learning. Previous studies have shown that taste memory consolidation requires intact protein synthesis in the GC.

Expression of Quinone Reductase-2 in the Cortex Is a Muscarinic Acetylcholine Receptor-Dependent Memory Consolidation Constraint.

Unlabelled: Learning of novel information, including novel taste, requires activation of neuromodulatory transmission mediated, for example, by the muscarinic acetylcholine receptors (mAChRs) in relevant brain structures. In addition, drugs enhancing the function of mAChRs are used to treat memory impairment and decline. However, the mechanisms underlying these effects are poorly understood.

Taste familiarity is inversely correlated with Arc/Arg3.1 hemispheric lateralization.

Biochemical, electrophysiological, and imaging studies suggest that the anterior part of the insular cortex (IC) serves as primary taste cortex, whereas fMRI studies in human propose that the anterior IC is also involved in processing of general novelty or saliency information. Here, we compared activity regulated cytoskeleton associated protein (Arc)/Arg3.1 protein levels in the rat IC following administration of familiar versus novel tastes.

Tyrosine phosphorylation of the 2B subunit of the NMDA receptor is necessary for taste memory formation.

We aimed to test whether tyrosine phosphorylation of the NMDA receptor (NMDAR) in the insular cortex is necessary for novel taste learning. We found that in rats, novel taste learning leads to elevated phosphorylation of tyrosine 1472 of the NR2B subunit of the NMDAR and increases the interaction of phosphorylated NR2B with the major postsynaptic scaffold protein PSD-95. Injection of the tyrosine kinase inhibitor genistein directly into the insular cortex of rats before novel taste exposure prevented the increase in NR2B tyrosine phosphorylation and behaviorally attenuated taste-memory formation.

Biphasic activation of the mTOR pathway in the gustatory cortex is correlated with and necessary for taste learning.

Different forms of memories and synaptic plasticity require synthesis of new proteins at the time of acquisition or immediately after. We are interested in the role of translation regulation in the cortex, the brain structure assumed to store long-term memories. The mammalian target of rapamycin, mTOR (also known as FRAP and RAFT-1), is part of a key signal transduction mechanism known to regulate translation of specific subset of mRNAs and to affect learning and synaptic plasticity.

ERK-dependent PSD-95 induction in the gustatory cortex is necessary for taste learning, but not retrieval.

The processes underlying long-term memory formation in the neocortex are poorly understood. Using taste learning, we found learning-related induction of PSD-95 in the gustatory cortex, which was temporally restricted, coupled to the learning of a novel, but not familiar, taste and controlled by ERK. Using temporally and spatially restricted RNA interference knockdown of PSD-95 in vivo, we found that PSD-95 induction is necessary for learning novel tastes, but not for the recollection of familiar ones.

Juvenile stress-induced alteration of maturation of the GABAA receptor alpha subunit in the rat.

Profound evidence indicates that GABAA receptors are important in the control of physiological response to stress and anxiety. The alpha subunit type composition contributes significantly to the functional characterization of the GABAA receptors. The alpha2, alpha3, alpha5 subunits are predominately expressed in the brain during embryonic and early postnatal periods of normal rats, whilst alpha1 are most prominent during later developmental stages.

A role for eukaryotic translation initiation factor 2B (eIF2B) in taste memory consolidation and in thermal control establishment during the critical period for sensory development.

All species exhibit critical periods for sensory development, yet very little is known about the molecules involved in the changes in the network wiring that underlies this process. Here the role of transcription regulation of the translation machinery was determined by evaluating the expression of eIF2Bepsilon, an essential component of translation initiation, in both taste-preference development and thermal control establishment in chicks. Analysis of the expression pattern of this gene after passive-avoidance training revealed clear induction of eIF2Bepsilon in both the mesopallium intermediomediale (IMM) and in the striatum mediale (StM).

Behavioral interference and C/EBPbeta expression in the insular-cortex reveal a prolonged time period for taste memory consolidation.

Memory consolidation is defined as the time window during which the memory trace is susceptible to behavioral, electrical, or pharmacological interventions. Here, we presented rats with two novel tastes at consecutive time intervals. Clear interference was evident when a novel taste formed the second taste input whereby, surprisingly, the time window for interference was found to last more than 10 h.

Different signal transduction cascades are activated simultaneously in the rat insular cortex and hippocampus following novel taste learning.

Novel taste learning is a robust one-trial incidental learning process, dependent on functional activity of the insular (taste) cortex. In contrast to that of the cortex, the role of the hippocampus in taste learning is controversial. We set out to identify the time courses of the activation of mitogen-associated protein kinase (MAPK), transcription factor cAMP-response element-binding protein (CREB) and Akt/PKB (protein kinase B) in the insular cortex and hippocampus of rats subsequent to novel taste learning.