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The Relation between Cognitive Injury, Network Stability, and Epigenetic Change Following Exposure to Space Radiation (NNX13AD60G)
Principal Investigator
Research Area:
Radiation health
Species Studied
Scientific Name: Mus musculus Species: Mouse

This project focused on changes in hippocampal network stability and epigenetic mechanisms involved in the development of cognitive dysfunction after space irradiation. Radiation exposure of the central nervous system (CNS) can significantly affect the hippocampus, a structure critical for cognitive function. During spatial exploration, when an animal enters a specific location a distinct cell responds (known as the cell's place field). As a result of these place fields, hippocampal pyramidal neurons in the CA areas display robust high frequency activity. The place fields create an environment-specific "map," thought to be critical in establishing the context of a memory. Following visits to an environment for a second time, the same cells form stable neural networks and respond as a result of cellular activity induced by a learning experience. While place fields are highly reproducible and stable across multiple visits to the same environment, this stability is not seen in when different environments are visited. The detrimental effects of charged particles on hippocampus-dependent cognition are likely associated with changes in hippocampal networks. Analysis of the precise temporal kinetics of the plasticity-related immediate early gene (IEG) activity-regulated cytoskeletal associated protein (Arc) using a method called cellular compartment analysis of temporal activity using fluorescence in situ hybridization (catFISH ) provides an ideal and reliable approach for studying network stability.

Gamma and space irradiation, including 56Fe ions and protons, induce changes in DNA methylation. Of significance for this project, recent studies show that a second form of DNA methylation, termed 5-hyrdroxymethylation (5hmC) is abundant and stable in the brain. The ten eleven translocation (TET) enzymes convert 5mC to 5hmC, which likely play a role in gene regulation because 5hmC is often found at promoters of active genes. In contrast, 5mC is found at the promoters of inactive genes. Changes in 5mC, which are induced by environmental exposures including radiation and behavioral modification, play a role in processes including cancer and neurological disease. A similar role for 5hMC can be assumed due to its abundance in the brain, though 5hmC changes after radiation exposure and in neurological disease has not yet been elucidated. The investigators hypothesized that the detrimental effects of charged particles on hippocampus-dependent cognition are associated with Arc-related changes in the hippocampal networks involved in synaptic plasticity and memory. They further hypothesized that these changes are related to perturbation of 5mC and/or 5hMC in the hippocampus that affect Arc expression and expression of other learning and memory genes in the same signaling pathways and networks.

To test these hypotheses, investigators used the following specific aims:

  1. Determine short- and long-term effects of irradiation with 56Fe ions or protons on novel object recognition and spatial learning and memory.
  2. Determine the short- and long-term effects of irradiation with 56Fe or 28Si ions or protons on hippocampal networks mediating spatial information processing, and whether the detrimental effects of charged particle radiation on hippocampus-dependent cognition are associated with changes in hippocampal network stability.
  3. Determine whether cognitive changes resulting from charged particle exposure are associated with altered DNA methylation (5mC and 5hMC) profiles for Arc and other genes involved in learning and memory in the same signaling pathways; and whether DNA methylation changes correlate with stable changes in gene expression.

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Olsen RH, Marzulla T, and Raber J. Impairment in extinction of contextual and cued fear following post-training whole-body irradiation. Frontiers in Behavioral Neurosciences. 2014. July 2; 8:231. []

Raber J. Novel images and novel locations of familiar images as sensitive translational cognitive tests in humans. Behavioral Brain Research. 2015. May 15; 285:53-9. []

Villasana LE, Akinyeke T, Weber S, and Raber J. Paradoxical effects of 137Cs irradiation on pharmacological stimulation of reactive oxygen species in hippocampal slices from apoE2 and apoE4 mice. Oncotarget. 2017. September 1;8(44):76587-605. [DOI]


Data Information
Data Availability
Archive is complete. Data sets are not publicly available but can be requested.
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Cognitive dysfunction
DNA methylation
Hippocampal network stability

Mission/Study Information
Mission Launch/Start Date Landing/End Date Duration
Ground 05/01/2009 In Progress

Human Research Program (HRP) Human Research Roadmap (HRR) Information
Crew health and performance is critical to successful human exploration beyond low Earth orbit. The Human Research Program (HRP) investigates and mitigates the highest risks to human health and performance, providing essential countermeasures and technologies for human space exploration. Risks include physiological and performance effects from hazards such as radiation, altered gravity, and hostile environments, as well as unique challenges in medical support, human factors, and behavioral health support. The HRP utilizes an Integrated Research Plan (IRP) to identify the approach and research activities planned to address these risks, which are assigned to specific Elements within the program. The Human Research Roadmap is the web-based tool for communicating the IRP content.

The Human Research Roadmap is located at:

+ Click here for information of how this experiment is contributing to the HRP's path for risk reduction.

Additional Information
Managing NASA Center
Johnson Space Center (JSC)
Responsible NASA Representative
Johnson Space Center LSDA Office
Project Manager: Terry Hill
Institutional Support
National Aeronautics and Space Administration (NASA)
Proposal Date
Proposal Source
2012 Space Radiobiology