neurosciencextracreditfall2021

[neurosciencextracreditfall2021]

[neurosciencextracreditfall2021]

[neurosciencextracreditfall2021]

[neurosciencextracreditfall2021]

[neurosciencextracreditfall2021]

Extra Credit Blog Post on Research Article: Neuroepigenetics and Space Radiation

As we enter a new era of space exploration, it is important to realize the potential dangers this poses to humans. If we want astronauts to return home without cognitive dysfunction—and I think we all do—it is important to understand the effects of deep space radiation on the brain. Consequently, Acharya et al. explored this very topic in their 2017 research article entitled “Epigenetic determinants of space radiation-induced cognitive dysfunction.” In their paper, they explore the effects radiation has on producing cognitive impairments and how these impairments are accompanied by “functional and structural changes including oxidative stress, neuroinflammation, and degradation of neuronal architecture” (Acharya et al., 2017). Specifically, this study explored the role of neuroepigenetics—the study of how changes to cellular genomes affect the expression of certain genes in the nervous system—as the foundation of these effects.

Some of the most important factors to cognition involve epigenetic mechanisms such as DNA methylation and histone modifications. DNA methylation refers to the addition of methyl groups to DNA which can stop the transcription of genes through both steric hindrance (the physical blocking) of transcription factors (TFs), as well as the recruitment of “readers”: enzymes that read this methylation and conform the DNA into a more “unreadable” configuration. Histone modifications refer to the addition or removal of groups (such as methyl and acetyl groups) on the histone proteins that DNA is wound around in its chromatin state. The “tighter” the DNA is wound around the histone, the harder it is to be read and vice versa. These epigenetic mechanisms have been shown to have effects in memory formation and addictive behavior, thus making them targets of interest in this study as influencers of cognition.

The methylation of DNA is regulated by appropriately named DNA methyltransferases (DNMTs) that transfer a methyl group to the 5-position of cytosine residues in DNA; these methylated cytosine (5mC)—specifically at sites of gene promoters—are usually associated with transcriptional repression. Moreover, DNA methylation can self-perpetuate because of the activity of maintenance DMNTs, such as DNMT1; and in fully mature neurons, DNMT3a and 3b are specifically important because it has been shown that they have a role in modifying previously un-methylated cytosines. Additionally, these 5mC’s can be modified by TET enzymes (such as TET3, which is linked to learning and memory function) in the CNS, oxidizing them into 5hmC’s; these 5hmC’s can then be deaminated and return the DNA to an unmethylated state, thus allowing them to act as markers of gene expression (transcription) as opposed to gene silencing. Consequently, this type of dynamic regulation of epigenetic factors can act as sources of “cellular plasticity… in response to external stimuli” (Acharya et al., 2017), such as exposure to galactic radiation.

In their results, Acharya et al. found that the irradiated mice had elevated levels of 5mC and 5hmC in hippocampal and cortical neurons that correlated with impaired abilities to perform various behavioral tasks that tested different dimensions of memory and cognition (such as the novel object recognition, object in place, and temporal order tasks). The increase of 5mC was rapid, being detectable only 2 hours after exposure to radiation while 5hmC did not increase 2 or 24 hours after exposure, indicating that it takes longer for this modification to occur. Moreover, the changes of 5mC and 5hmC levels coincided with increased levels of DNA methylating enzymes (DNMT3a, TET1 and TET3). Both TET1 and TET3 were found to be elevated one month post-radiation exposure (at the same time when increased levels of 5hmC are seen); however, it is unclear which of the two enzymes specifically play a role in the conversion of 5mC to 5hmC. Levels of DNMT3a were also found to be increased one month after radiation exposure. Additionally, it was found that treatment of these mice with 5-ITU (an inhibitor of methylation) granted protection against and mitigation of the effects of radiation exposure, improving cognition to the level of non-irradiated mice.

Although the results of this study suggest that further research is required to fully understand the effects of radiation on the brain, it is interesting how the findings of this study establish the possibility that neuroepigenetic mechanisms (and regulation) can significantly contribute to the functional and structural changes that affect the brain—and subsequently cognition—post-radiation exposure. One interesting follow up study would be to investigate the differences between specific DNA methylation (methylation at specific sites) and global (methylation at various places on the genome) levels of 5mC and 5hmC and how/if that alters gene expression to affect cellular phenotype.