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Blocking NRSF Function Rescues Spatial Memory Impaired by Early-Life Adversity and Reveals Unexpected Underlying Transcriptional Programs

26 Pages Posted: 16 Nov 2018 Sneak Peek Status: Under Review

See all articles by Anton Schulmann

Anton Schulmann

University of California, Irvine, School of Medicine, Department of Pediatrics; University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Jessica L. Bolton

University of California, Irvine, School of Medicine, Department of Pediatrics; University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Megan M. Curran

University of California, Irvine, School of Medicine, Department of Pediatrics; University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Limor Regev

University of California, Irvine, School of Medicine, Department of Pediatrics; University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Noriko Kamei

University of California, Irvine, School of Medicine, Department of Pediatrics; University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Akanksha Singh-Taylor

University of California, Irvine, School of Medicine, Department of Pediatrics; University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Shan Jiang

University of California, Irvine - Developmental and Cell Biology

Jenny Molet

University of California, Irvine, School of Medicine, Department of Pediatrics; University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Ali Mortazavi

University of California, Irvine - Developmental and Cell Biology

Tallie Z. Baram

University of California, Irvine, School of Medicine, Department of Pediatrics; University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology; University of California, Irvine - Department of Neurology

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Abstract

Adverse early-life experiences are associated with lifelong cognitive deficits and risk of memory loss and dementia, yet the underlying mechanisms remain unclear. Here we imposed early-life adversity by rearing rat pups in simulated poverty, assessed hippocampus-dependent memory in adulthood, and probed enduring changes in gene expression and the underlying transcriptional processes. Adversity-experiencing rats had poor spatial memory, associated with ~130 differentially expressed genes in dorsal hippocampus. Using bioinformatics, we identified the glucocorticoid receptor and, unexpectedly, the neuron-specific developmental transcription factor neuron-restrictive silencer factor (NRSF/REST) as putative upstream factors. To examine the role of the latter in adversity-induced memory problems, we blocked the binding of NRSF to the chromatin immediately following the adversity period. Transient interference with the function of NRSF rescued spatial memory in the exposed rats, without influencing non-hippocampus-dependent emotional functions. These findings establish a novel, surprising mechanism by which early-life adversity initiates long-lasting hippocampus-dependent memory deficits via enduring epigenetic programming mediated by NRSF.

Suggested Citation

Schulmann, Anton and Bolton, Jessica L. and Curran, Megan M. and Regev, Limor and Kamei, Noriko and Singh-Taylor, Akanksha and Jiang, Shan and Molet, Jenny and Mortazavi, Ali and Baram, Tallie Z., Blocking NRSF Function Rescues Spatial Memory Impaired by Early-Life Adversity and Reveals Unexpected Underlying Transcriptional Programs (November 14, 2018). Available at SSRN: https://ssrn.com/abstract=3284454 or http://dx.doi.org/10.2139/ssrn.3284454
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Anton Schulmann

University of California, Irvine, School of Medicine, Department of Pediatrics

Irvine, CA 92697-4475
United States

University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Irvine, CA 92697-4475
United States

Jessica L. Bolton

University of California, Irvine, School of Medicine, Department of Pediatrics

Irvine, CA 92697-4475
United States

University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Irvine, CA 92697-4475
United States

Megan M. Curran

University of California, Irvine, School of Medicine, Department of Pediatrics

Irvine, CA 92697-4475
United States

University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Irvine, CA 92697-4475
United States

Limor Regev

University of California, Irvine, School of Medicine, Department of Pediatrics

Irvine, CA 92697-4475
United States

University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Irvine, CA 92697-4475
United States

Noriko Kamei

University of California, Irvine, School of Medicine, Department of Pediatrics

Irvine, CA 92697-4475
United States

University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Irvine, CA 92697-4475
United States

Akanksha Singh-Taylor

University of California, Irvine, School of Medicine, Department of Pediatrics

Irvine, CA 92697-4475
United States

University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Irvine, CA 92697-4475
United States

Shan Jiang

University of California, Irvine - Developmental and Cell Biology

Irvine, CA 92697-4475
United States

Jenny Molet

University of California, Irvine, School of Medicine, Department of Pediatrics

Irvine, CA 92697-4475
United States

University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology

Irvine, CA 92697-4475
United States

Ali Mortazavi

University of California, Irvine - Developmental and Cell Biology

Irvine, CA 92697-4475
United States

Tallie Z. Baram (Contact Author)

University of California, Irvine, School of Medicine, Department of Pediatrics ( email )

Irvine, CA 92697-4475
United States

University of California, Irvine, School of Medicine, Department of Anatomy/Neurobiology ( email )

Irvine, CA 92697-4475
United States

University of California, Irvine - Department of Neurology ( email )

CA 92697
United States

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