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Molecular Mechanisms of Memory Formation and Modification

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 46388

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Special Issue Editors

Dr. Timothy Jarome

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Guest Editor

School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
Interests: learning; memory; epigenetics; ubiquitin-proteasome system; reconsolidation

Dr. Janine Kwapis

E-Mail Website
Guest Editor

Pennsylvania State University, PA, USA
Interests: learning; memory; epigenetics; aging; circadian rhythms; updating; reconsolidation

Special Issue Information

Dear Colleagues,

Memory is vital to human functioning and controls future behavioral responses. Many neurological, neurodegenerative, and psychiatric disorders are associated with memory impairments or the presence of maladaptive memories. Thus, understanding the molecular mechanisms that control both normal and abnormal memory formation and modification is critical for treating many of the memory impairments that are present in a variety of diseases.

The formation of long-term memories is a complex process that requires the coordinated actions of hundreds to thousands of diverse signaling molecules within cells, a process called consolidation. Disruption of the molecular mechanisms underlying this consolidation process leads to the inability to acquire new memories. Further, these memories are not permanent and can be modified following retrieval via a process termed reconsolidation. While significant progress has been made in identifying the molecular mechanisms of memory consolidation and reconsolidation, much remains unknown. This special issue intends to help extend our knowledge of the molecular mechanisms involved in memory formation and modification following retrieval.

Contributions must focus on the molecular mechanisms of memory formation and/or reconsolidation, broadly defined. These contributions can study the molecular mechanisms of memory during disease or non-disease states. Submissions can be in the form of primary research reports, reviews or perspectives. Potential topics can include but are not limited to:

Transcriptional and translational mechanisms of memory consolidation or reconsolidation
Molecular mechanisms underlying memory modification following retrieval
Perspectives/Reviews on the molecular mechanisms of memory consolidation and/or reconsolidation

Dr. Timothy Jarome
Dr. Janine Kwapis
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

Learning
Memory
Consolidation
Reconsolidation
Transcription
Translation

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Published Papers (12 papers)

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Editorial

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3 pages, 167 KiB

Open AccessEditorial

Special Issue “Molecular Mechanisms of Memory Formation and Modification”

by Timothy J. Jarome and Janine L. Kwapis

Int. J. Mol. Sci. 2021, 22(8), 4113; https://doi.org/10.3390/ijms22084113 - 16 Apr 2021

Viewed by 1705

Abstract

Memory is vital to human functioning and controls future behavioral responses [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

Research

Jump to: Editorial, Review

19 pages, 3194 KiB

Open AccessArticle

Fluctuating NMDA Receptor Subunit Levels in Perirhinal Cortex Relate to Their Dynamic Roles in Object Memory Destabilization and Reconsolidation

by Cassidy E. Wideman, James Nguyen, Sean D. Jeffries and Boyer D. Winters

Int. J. Mol. Sci. 2021, 22(1), 67; https://doi.org/10.3390/ijms22010067 - 23 Dec 2020

Cited by 13 | Viewed by 2895

Abstract

Reminder cues can destabilize consolidated memories, rendering them modifiable before they return to a stable state through the process of reconsolidation. Older and stronger memories resist this process and require the presentation of reminders along with salient novel information in order to destabilize. Previously, we demonstrated in rats that novelty-induced object memory destabilization requires acetylcholine (ACh) activity at M₁ muscarinic receptors. Other research predominantly has focused on glutamate, which modulates fear memory destabilization and reconsolidation through GluN2B- and GluN2A-containing NMDARs, respectively. In the current study, we demonstrate the same dissociable roles of GluN2B- and N2A-containing NMDARs in perirhinal cortex (PRh) for object memory destabilization and reconsolidation when boundary conditions are absent. However, neither GluN2 receptor subtype was required for novelty-induced destabilization of remote, resistant memories. Furthermore, GluN2B and GluN2A subunit proteins were upregulated selectively in PRh 24 h after learning, but returned to baseline by 48 h, suggesting that NMDARs, unlike muscarinic receptors, have only a temporary role in object memory destabilization. Indeed, activation of M₁ receptors in PRh at the time of reactivation effectively destabilized remote memories despite inhibition of GluN2B-containing NMDARs. These findings suggest that cholinergic activity at M₁ receptors overrides boundary conditions to destabilize resistant memories when other established mechanisms are insufficient. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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14 pages, 1781 KiB

Open AccessArticle

DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation

by Shaghayegh Navabpour, Jessie Rogers, Taylor McFadden and Timothy J. Jarome

Int. J. Mol. Sci. 2020, 21(23), 8995; https://doi.org/10.3390/ijms21238995 - 26 Nov 2020

Cited by 17 | Viewed by 5755

Abstract

Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Furthermore, though recent evidence suggests that neuronal activity triggers DNA double-strand breaks (DSBs) in some early-response genes, it is currently unknown if DSBs contribute to the reconsolidation of a memory following retrieval. Here, using chromatin immunoprecipitation (ChIP) analyses, we report a significant overlap between DSBs and H3K4me3 in area CA1 of the hippocampus during the reconsolidation process. We found an increase in phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker of DSB, in the Npas4, but not c-fos, promoter region 5 min after retrieval, which correlated with increased H3K4me3 levels, suggesting that the two epigenetic marks may work in concert during the reconsolidation process. Consistent with this, in vivo siRNA-mediated knockdown of topoisomerase II β, the enzyme responsible for DSB, prior to retrieval, reduced Npas4 promoter-specific H2A.XpS139 and H3K4me3 levels and impaired long-term memory, indicating an indispensable role of DSBs in the memory reconsolidation process. Collectively, our data propose a novel mechanism for memory reconsolidation through increases in epigenetic-mediated transcriptional control via DNA double-strand breaks. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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9 pages, 2566 KiB

Open AccessCommunication

Degradation of Transcriptional Repressor ATF4 during Long-Term Synaptic Plasticity

by Spencer G. Smith, Kathryn A. Haynes and Ashok N. Hegde

Int. J. Mol. Sci. 2020, 21(22), 8543; https://doi.org/10.3390/ijms21228543 - 12 Nov 2020

Cited by 12 | Viewed by 2780

Abstract

Maintenance of long-term synaptic plasticity requires gene expression mediated by cAMP-responsive element binding protein (CREB). Gene expression driven by CREB can commence only if the inhibition by a transcriptional repressor activating transcription factor 4 (ATF4; also known as CREB2) is relieved. Previous research showed that the removal of ATF4 occurs through ubiquitin-proteasome-mediated proteolysis. Using chemically induced hippocampal long-term potentiation (cLTP) as a model system, we investigate the mechanisms that control ATF4 degradation. We observed that ATF4 phosphorylated at serine-219 increases upon induction of cLTP and decreases about 30 min thereafter. Proteasome inhibitor β-lactone prevents the decrease in ATF4. We found that the phosphorylation of ATF4 is mediated by cAMP-dependent protein kinase. Our initial experiments towards the identification of the ligase that mediates ubiquitination of ATF4 revealed a possible role for β-transducin repeat containing protein (β-TrCP). Regulation of ATF4 degradation is likely to be a mechanism for determining the threshold for gene expression underlying maintenance of long-term synaptic plasticity and by extension, long-term memory. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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14 pages, 2572 KiB

Open AccessArticle

Electroconvulsive Shock Does Not Impair the Reconsolidation of Cued and Contextual Pavlovian Threat Memory

by Hajira Elahi, Veronica Hong and Jonathan E. Ploski

Int. J. Mol. Sci. 2020, 21(19), 7072; https://doi.org/10.3390/ijms21197072 - 25 Sep 2020

Cited by 10 | Viewed by 3043

Abstract

Existing memories, when retrieved under certain circumstances, can undergo modification through the protein synthesis-dependent process of reconsolidation. Disruption of this process can lead to the weakening of a memory trace, an approach which is being examined as a potential treatment for disorders characterized by pathological memories, such as Post-Traumatic Stress Disorder. The success of this approach relies upon the ability to robustly attenuate reconsolidation; however, the available literature brings into question the reliability of the various drugs used to achieve such a blockade. The identification of a drug or intervention that can reliably disrupt reconsolidation without requiring intracranial access for administration would be extremely useful. Electroconvulsive shock (ECS) delivered after memory retrieval has been demonstrated in some studies to disrupt memory reconsolidation; however, there exists a paucity of literature characterizing its effects on Pavlovian fear memory. Considering this, we chose to examine ECS as an inexpensive and facile means to impair reconsolidation in rats. Here we show that electroconvulsive seizure induction, when administered after memory retrieval, (immediately, after 30 min, or after 1 h), does not impair the reconsolidation of cued or contextual Pavlovian fear memories. On the contrary, ECS administration immediately after extinction training may modestly impair the consolidation of fear extinction memory. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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10 pages, 1502 KiB

Open AccessCommunication

Social Fear Memory Requires Two Stages of Protein Synthesis in Mice

by Johannes Kornhuber and Iulia Zoicas

Int. J. Mol. Sci. 2020, 21(15), 5537; https://doi.org/10.3390/ijms21155537 - 2 Aug 2020

Cited by 7 | Viewed by 3149

Abstract

It is well known that long-term consolidation of newly acquired information, including information related to social fear, require de novo protein synthesis. However, the temporal dynamics of protein synthesis during the consolidation of social fear memories is unclear. To address this question, mice received a single systemic injection with the protein synthesis inhibitor, anisomycin, at different time-points before or after social fear conditioning (SFC), and memory was assessed 24 h later. We showed that anisomycin impaired the consolidation of social fear memories in a time-point-dependent manner. Mice that received anisomycin 20 min before, immediately after, 6 h, or 8 h after SFC showed reduced expression of social fear, indicating impaired social fear memory, whereas anisomycin caused no effects when administered 4 h after SFC. These results suggest that consolidation of social fear memories requires two stages of protein synthesis: (1) an initial stage starting during or immediately after SFC, and (2) a second stage starting around 6 h after SFC and lasting for at least 5 h. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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19 pages, 4089 KiB

Open AccessArticle

by Sydney Trask, Brooke N. Dulka and Fred J. Helmstetter

Int. J. Mol. Sci. 2020, 21(15), 5352; https://doi.org/10.3390/ijms21155352 - 28 Jul 2020

Cited by 8 | Viewed by 3596

Abstract

Aging is associated with cognitive decline, including impairments in the ability to accurately form and recall memories. Some behavioral and brain changes associated with aging are evident as early as middle age, making the understanding of associated neurobiological mechanisms essential to aid in efforts aimed at slowing cognitive decline throughout the lifespan. Here, we found that both 15-month-old and 22-month-old rats showed impaired memory recall following trace fear conditioning. This behavioral deficit was accompanied by increased zif268 protein accumulation relative to 3-month-old animals in the medial prefrontal cortex, the dorsal and ventral hippocampi, the anterior and posterior retrosplenial cortices, the lateral amygdala, and the ventrolateral periaqueductal gray. Elevated zif268 protein levels corresponded with decreases in phosphorylation of the Rpt6 proteasome regulatory subunit, which is indicative of decreased engagement of activity-driven protein degradation. Together, these results identify several brain regions differentially impacted by aging and suggest that the accumulation of proteins associated with memory retrieval, through reduced proteolytic activity, is associated with age-related impairments in memory retention. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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13 pages, 1429 KiB

Open AccessArticle

Fear Learning Enhances Prefrontal Cortical Suppression of Auditory Thalamic Inputs to the Amygdala in Adults, but Not Adolescents

by Nicole C. Ferrara, Eliska Mrackova, Maxine K. Loh, Mallika Padival and J. Amiel Rosenkranz

Int. J. Mol. Sci. 2020, 21(8), 3008; https://doi.org/10.3390/ijms21083008 - 24 Apr 2020

Cited by 11 | Viewed by 3876

Abstract

Adolescence is characterized by increased susceptibility to the development of fear- and anxiety-related disorders. Adolescents also show elevated fear responding and aversive learning that is resistant to behavioral interventions, which may be related to alterations in the circuitry supporting fear learning. These features are linked to ongoing adolescent development of medial prefrontal cortical (PFC) inputs to the basolateral amygdala (BLA) that regulate neural activity and contribute to the refinement of fear responses. Here, we tested the hypothesis that the extent of PFC inhibition of the BLA following fear learning is greater in adults than in adolescents, using anesthetized in vivo recordings to measure local field potentials (LFPs) evoked by stimulation of PFC or auditory thalamic (MgN) inputs to BLA. We found that BLA LFPs evoked by stimulation of MgN inputs were enhanced in adults following fear conditioning. Fear conditioning also led to reduced summation of BLA LFPs evoked in response to PFC train stimulation, and increased the capacity of PFC inhibition of MgN inputs in adults. These data suggest that fear conditioning recruits additional inhibitory capacity by PFC inputs to BLA in adults, but that this capacity is weaker in adolescents. These results provide insight into how the development of PFC inputs may relate to age differences in memory retention and persistence following aversive learning. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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Review

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13 pages, 937 KiB

Open AccessReview

An Emerging Role of m6A in Memory: A Case for Translational Priming

by Amanda M. Leonetti, Ming Yin Chu, Fiona O. Ramnaraign, Samuel Holm and Brandon J. Walters

Int. J. Mol. Sci. 2020, 21(20), 7447; https://doi.org/10.3390/ijms21207447 - 9 Oct 2020

Cited by 30 | Viewed by 4998

Abstract

Investigation into the role of methylation of the adenosine base (m6A) of RNA has only recently begun, but it quickly became apparent that m6A is able to control and fine-tune many aspects of mRNA, from splicing to translation. The ability of m6A to regulate translation distally, away from traditional sites near the nucleus, quickly caught the eye of neuroscientists because of implications for selective protein translation at synapses. Work in the brain has demonstrated how m6A is functionally required for many neuronal functions, but two in particular are covered at length here: The role of m6A in 1) neuron development; and 2) memory formation. The purpose of this review is not to cover all data about m6A in the brain. Instead, this review will focus on connecting mechanisms of m6A function in neuron development, with m6A’s known function in memory formation. We will introduce the concept of “translational priming” and discuss how current data fit into this model, then speculate how m6A-mediated translational priming during memory consolidation can regulate learning and memory locally at the synapse. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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28 pages, 1277 KiB

Open AccessReview

Epigenetic Mechanisms of Learning and Memory: Implications for Aging

by Samantha D. Creighton, Gilda Stefanelli, Anas Reda and Iva B. Zovkic

Int. J. Mol. Sci. 2020, 21(18), 6918; https://doi.org/10.3390/ijms21186918 - 21 Sep 2020

Cited by 22 | Viewed by 5108

Abstract

The neuronal epigenome is highly sensitive to external events and its function is vital for producing stable behavioral outcomes, such as the formation of long-lasting memories. The importance of epigenetic regulation in memory is now well established and growing evidence points to altered epigenome function in the aging brain as a contributing factor to age-related memory decline. In this review, we first summarize the typical role of epigenetic factors in memory processing in a healthy young brain, then discuss the aspects of this system that are altered with aging. There is general agreement that many epigenetic marks are modified with aging, but there are still substantial inconsistencies in the precise nature of these changes and their link with memory decline. Here, we discuss the potential source of age-related changes in the epigenome and their implications for therapeutic intervention in age-related cognitive decline. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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20 pages, 677 KiB

Open AccessReview

The Emerging Role of ATP-Dependent Chromatin Remodeling in Memory and Substance Use Disorders

by Alberto J. López, Julia K. Hecking and André O. White

Int. J. Mol. Sci. 2020, 21(18), 6816; https://doi.org/10.3390/ijms21186816 - 17 Sep 2020

Cited by 11 | Viewed by 3869

Abstract

Long-term memory formation requires coordinated regulation of gene expression and persistent changes in cell function. For decades, research has implicated histone modifications in regulating chromatin compaction necessary for experience-dependent changes to gene expression and cell function during memory formation. Recent evidence suggests that another epigenetic mechanism, ATP-dependent chromatin remodeling, works in concert with the histone-modifying enzymes to produce large-scale changes to chromatin structure. This review examines how histone-modifying enzymes and chromatin remodelers restructure chromatin to facilitate memory formation. We highlight the emerging evidence implicating ATP-dependent chromatin remodeling as an essential mechanism that mediates activity-dependent gene expression, plasticity, and cell function in developing and adult brains. Finally, we discuss how studies that target chromatin remodelers have expanded our understanding of the role that these complexes play in substance use disorders. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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18 pages, 595 KiB

Open AccessReview

Molecular Mechanisms of Reconsolidation-Dependent Memory Updating

by Lauren Bellfy and Janine L. Kwapis

Int. J. Mol. Sci. 2020, 21(18), 6580; https://doi.org/10.3390/ijms21186580 - 9 Sep 2020

Cited by 29 | Viewed by 4520

Abstract

Memory is not a stable record of experience, but instead is an ongoing process that allows existing memories to be modified with new information through a reconsolidation-dependent updating process. For a previously stable memory to be updated, the memory must first become labile through a process called destabilization. Destabilization is a protein degradation-dependent process that occurs when new information is presented. Following destabilization, a memory becomes stable again through a protein synthesis-dependent process called restabilization. Much work remains to fully characterize the mechanisms that underlie both destabilization and subsequent restabilization, however. In this article, we briefly review the discovery of reconsolidation as a potential mechanism for memory updating. We then discuss the behavioral paradigms that have been used to identify the molecular mechanisms of reconsolidation-dependent memory updating. Finally, we outline what is known about the molecular mechanisms that support the memory updating process. Understanding the molecular mechanisms underlying reconsolidation-dependent memory updating is an important step toward leveraging this process in a therapeutic setting to modify maladaptive memories and to improve memory when it fails. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)

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