Methylated Memory

Author: Sarah Kearns

Editors: Naiyiri Kaissarian, Patricia Garay, and Shweta Ramdas

If you saw a hippo on campus, you would remember it. But, would you expect that seeing such a pachyderm roaming on a university would alter the expression of your DNA? A recent study found that rats placed in an environment that tested their memory had alterations to their DNA, or epigenetic changes.

For a long while, we have generally known that neurons within the hippocampus of our brains are responsible for memory. The current model for memory storage is due to the plasticity of neuronal connections, but researchers have recently found that it also involves active changes at the genetic level. These changes come from external factors and are linked to retaining long-term memories, which has implications in stress-related learning and memory disorders.

The initial conception of memory was that of an infinite library-style cabinet system with each experience being logged, categorized, and put in its rightful place to be recalled later. Through more studies, the model for how memory works has changed. The newer, more accurate model of memory is based on neuronal signals being strengthened, like tire tracks on a dirt road. As your brain receives external stimuli in the form of light or sound, for example the images of your notes as you study, neurons translate those signals into an electrical impulse that allows for them to communicate with other neurons. The more you look at your notes, the stronger the connections, allowing you to recall the information on your upcoming exam.

Going a few levels deeper into the machinery of memory, researchers are looking beyond the cellular level to the genes within of the hippocampal neuronal cells of rats. They wanted to look at the changes in gene expression for different levels of learning by putting rats into different learning environments. One group was simply placed inside of a box for a few minutes (context learning), and one was placed into a box that registered small electric foot-shocks (threat-learning), with one “naive” group without any box acting as the control. Apart from learning all too quickly that the world is a dangerous place, the threat-learning rats had changes in their behavior and epigenomes demonstrating chemical genetic alterations.

MeMemory-fig1.png
Schematic of the experimental setup. Image Source: Sarah Kearns

Epigenetic gene regulation involves making a physical mark via a chemical modification to DNA without altering its sequence that has a lasting impact on gene activity. Even though DNA is the code of life, not all of it is expressed all the time. As such, epigenetic modifications are a method of regulating which genes turn on and off. These changes are usually additions of small groups, like methyl or acyl, to nucleotides that alter DNA’s structure without destroying it. Within the cells, DNA is coiled around histones, clusters of proteins that wind DNA up into chromosomes. For the genes within the chromosomes to be replicated, histones and DNA have to be unwound to expose areas where replication proteins can bind. Epigenetic tags contribute to coiling and uncoiling, where the latter allows for DNA replication. (The Genetics Learning Center from University of Utah has made an interactive demonstration.)

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Epigenetic modifications can change how DNA (blue) is packed. In this case, methylation (orange) causes the histones (grey) to compact preventing transcription and gene expression from occurring. Image Source: Sarah Kearns

With the threat-learned rats in particular, DNA methylation of the cytosine (C) nucleotide was increased within regions of DNA that are concentrated with a sequence of cytosine, followed by a guanine (G), separated by the phosphate backbone (p). These structures, known as “CpG islands,” are normally found near start sites of gene expression. Within the double helix, C is paired with G so modifications can be propagated after replication so the alterations are kept.

These changes in methylation of were only seen within the threat-learning group, and not within either the naive or context-learning group. Moreover, the changes were targeted towards specific functions like neuron generation, which corresponded to an increase in methylation. Memory was tested by seeing whether or not the rats paused, when placed back inside the box a week later demonstrating a physical behavior change based on memory of their previous experience, where only the threat-learning group showed a pausing behavior (results are shown in the cartoon below).

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The threat-learning group showed both the changed behavior of pausing when returned to the box and increased methylation changes to CpG islands. Image Source: Sarah Kearns

These observations together suggest that having intense experiences has a greater impact on both memory and epigenetic change. With learning related diseases —  such as Alzheimer’s Disease and, more directly related to these rat studies, PTSD —  being associated with changes in CpG methylation, there is a lot of interest in figuring out how to alleviate issues stemming from these disorders.

How exactly a change in methylation interacts with cellular machinery, and its relationship with neuronal stimuli, are still very much unclear. Using foot shocks, too, might be conflating memory- and fear-based alterations to the epigenome. But nevertheless, the observation that gene transcription can be altered in an experience-dependent way within the hippocampus suggests that DNA modifications may play a crucial role in the stabilization of long-term memory.

About the author:

kearns_professional

Sarah Kearns is a second-year PhD student at the University of Michigan studying Chemical Biology. She’s interested in using structural biology to probe substrate recognition in proteins to design better drug therapies. Outside of the lab, she writes for MiSciWriters for which she serves as a content editor and as the communications director. When not researching or writing about science, she is an open access advocate, an avid baker, and always has at least three books on her current reading list. Sarah has her own blog, Annotated Science, and can be found on Twitter.

Read all posts by Sarah here.

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