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Dissertation
Unraveling novel regulators of hippocampal long-term memory consolidation
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008343
Abstract
Long-term memory consolidation is a dynamic biological process that relies on activity-dependent transcription, epigenetic regulation, and proteostasis to drive cellular and circuit-level adaptations to experience-induced neuronal activity. Although these processes constitute three mechanistic facets of long-term memory, a comprehensive molecular understanding of how they operate, and the specific molecular mediators involved, remain in its infancy. This thesis investigates novel molecular regulators of hippocampal long-term memory consolidation through the lens of epigenomic, transcriptomic, and proteostasis mechanisms. Histone lysine crotonylation (Kcr), an evolutionarily conserved non-acetyl histone acylation, is identified as a key epigenetic regulator of long-term memory. Spatial learning induces distinct, region-specific patterns of Kcr across hippocampal subregions. Experimental manipulation of Kcr levels bidirectionally impacts memory outcomes: reduction in Kcr impairs, while increases in Kcr enhance long-term memory. Single-nuclei multiomic analyses demonstrate that Kcr regulates chromatin conformation and transcription of genes associated with glutamatergic neurotransmission, and functional imaging reveals that Kcr enhances activity-dependent glutamate neurotransmission. Collectively, these findings establish Kcr as a molecular interface that links chromatin plasticity, synaptic function, and behavioral outcomes.
This work further defines a critical role for the NR4A family of transcription factors in regulating transcriptional programs critical for memory consolidation. NR4A factors are rapidly induced in hippocampal neurons following spatial learning, and learning-responsive Nr4A induction exhibits distinct, spatially preserved signatures across the rodent hippocampus. Utilizing a transgenic dominant negative (DN) mouse model of Nr4A, we demonstrate that Nr4A regulates the expression of genes encoding endoplasmic reticulum (ER) chaperones. Disruption of NR4A function results in deficits in long-term memory, whereas reinstating chaperone expression in these mice reverses these impairments. Additionally, activation of NR4A signaling or downstream proteostasis pathways ameliorates cognitive deficits in mouse models of neurodegeneration, underscoring their therapeutic potential.
The functional relevance of proteostasis networks in memory consolidation is also explored. Beyond their canonical roles in protein folding and serving as sentinels of the cellular stress response, very little is known regarding the role of molecular chaperones in regulating synaptic function and memory consolidation. This study sheds novel mechanistic insights that transcriptional regulation of protein folding machinery and the function of molecular chaperones is not just integral to the stabilization of memory traces but bears therapeutic promise in ameliorating cognitive decline associated with Alzheimer’s Disease and related Dementias (ADRD).
Collectively, this work advances a unifying framework in which non-acetyl histone acylations, spatially and cell-type-specific learning-induced transcriptional programs, and chaperone-dependent proteostasis mechanisms converge to regulate long-term memory consolidation. By integrating these previously distinct domains, this research provides new mechanistic insights into the molecular basis of memory and identifies potential targets for therapeutic intervention in neurodegenerative disorders.
Details
- Title: Subtitle
- Unraveling novel regulators of hippocampal long-term memory consolidation
- Creators
- Utsav Mukherjee
- Contributors
- Ted Abel (Advisor)Rory A Fisher (Committee Member)Stefan Strack (Committee Member)Carl Andrew Frank (Committee Member)Jon M Resch (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008343
- Publisher
- University of Iowa
- Number of pages
- xiii, 168 pages
- Copyright
- Copyright 2026 Utsav Mukherjee
- Language
- English
- Date submitted
- 04/27/2026
- Description illustrations
- illustrations, graphs
- Description bibliographic
- Includes bibliographical references (pages 136-155).
- Public Abstract (ETD)
The ability to form lasting memories is fundamental to how we learn, adapt, and navigate the world. Although decades of research have identified key processes involved in memory storage, much of the underlying biology remains elusive. This work examines these questions by focusing on the hippocampus, a brain region that is essential for memory storage. It identifies a previously underexplored class of epigenetic modification (chemical changes that regulate gene expression without altering DNA sequence) called histone crotonylation as a critical switch of memory storage. Specifically, this work shows that histone crotonylation helps regulate long-term memory and improves how effectively hippocampal neurons communicate with each other. In addition, this study uncovers a critical function for a group of activity-responsive genes known as NR4A in regulating memory storage. The Nr4A genes are responsible for regulating the expression of molecular chaperones - proteins that ensure proper folding of other proteins. In addition to its well-established role in protecting cells from stress, this protein quality control network emerges as a molecular mediator in the consolidation of nascent learning experiences. Together, these findings point to a more integrated framework for understanding memory, in which mechanisms of gene regulation, activity-dependent gene expression, and protein homeostasis work in concert. This expanded framework provides new insight into how memories persist over time and may inform future approaches to treating cognitive decline associated with neurodegenerative disorders.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9985176973202771
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